Effects of AZD1775 on the PK substrates for CYP3A, CYP2C19, CYP1A2 and on QT interval in patients with advanced cancer

Study identifier:D6014C00006

ClinicalTrials.gov identifier:NCT03333824

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase I Open-label Study to Evaluate the Effect of Multiple Doses of AZD1775 on the Pharmacokinetics of Substrates for CYP3A, CYP2C19, CYP1A2 and to Provide Data on the Effect of AZD1775 on QT Interval in Patients with Advanced Solid Tumours

Medical condition

Solid tumours

Phase

Phase 1

Healthy volunteers

Study drug

CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP3A (midazolam), Kytril (granisetron), Wee-1 kinase inhibitor AZD1775

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 99 Years

Date

Study Start Date: 01 Dec 2017

Primary Completion Date: 22 Jan 2019

Study Completion Date: 22 Jan 2019

Study design

Allocation: Non-randomized
Endpoint Classification: Pharmacokinetics
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Aug 2023 by AstraZeneca

Collaborators

Quintiles, Inc.

Inclusion and exclusion criteria

Inclusion Criteria

o Has read and understands the informed consent form (ICF) and has given written informed consent prior to any study procedures.
o Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable.
o Any prior palliative radiation must have been completed at least 7 days prior to the start of study treatment (first administration of cocktail [Part A Day -8]), and patients must have recovered from any acute adverse effects prior to the start of study treatment.
o Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 1.
o Baseline laboratory values within 7 days of study treatment initiation (first administration of cocktail [Part A Day -8]):
• Absolute neutrophil count (ANC) ≥1500/μL.
• Haemoglobin ≥9 g/dL.
• Platelets ≥100,000/μL.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) or ≤5 x ULN if known hepatic metastases.
• Serum bilirubin within normal limits (WNL) or ≤1.5 x ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert’s Syndrome.
• Serum creatinine ≤1.5 x ULN, or measured creatinine clearance (CrCl) calculated by Cockcroft-Gault method ≥45 mL/min (confirmation of creatinine clearance is only required when creatinine is >1.5 x ULN).
CrCl (glomerular filtration rate) = (140-age) x (weight/kg) x F
(72 x serum creatinine mg/dL)
awhere F = 0.85 for females and F = 1 for males
o Female patients who are not of childbearing potential and fertile females of childbearing potential who agree to use adequate contraceptive measures that are in place during screening (or consent), for the duration of the study, and for 1 month after treatment stops, and who are not breastfeeding, and who have a negative serum or urine pregnancy test prior to the start of study treatment (first administration of cocktail [Part A Day -8]). Any patient taking an oral contraceptive must be discussed with the Medical Monitor to ensure that there will be no interaction with the brand of oral contraceptive and cocktail of drugs prior to trial entry to confirm eligibility.
o Male patients should be willing to use barrier contraception (ie, condoms) for the duration of the study and for 3 months after study treatment discontinuation.
o Female and/or male patients ≥18 years of age.
o Willingness and ability to comply with the study and follow-up procedures.
For inclusion in the optional genetic component of the study for all the patients:
o Provision of informed consent for genetic research. If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study, as long as all the eligibility criteria are met.

Exclusion Criteria

o Involvement in the planning and/or conduct of the study (applies to both AstraZeneca personnel and/or personnel at the study centre).
o Previous enrolment or randomisation and received study treatment in the present study. Patients can, however, be re-screened if the reason for the screen failure no longer exists.
o Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases – defined as metastasis having no evidence of progression or haemorrhage for at least 2 weeks after treatment (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.
o Use of any anti-cancer treatment drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775. For drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the prior treatment and administration of AZD1775 treatment is required.
o No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent is to be permitted while patient is receiving study treatment. Patients on LHRH analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the Investigator.
o Previous radiation therapy completed ≤7 days prior to the start of study treatment (i.e., first administration of cocktail [Part A Day -8]).
o Major surgical procedures ≤28 days of beginning study treatment (i.e., first administration of cocktail [Part A Day -8]), or minor surgical procedures ≤7 days. No waiting period required following port-a-cath placement or other central venous access placement.
o Grade >1 toxicities from previous cancer therapy, according to the Common Terminology Criteria for Adverse Events [CTCAE]), excluding alopecia or anorexia.
o Patient has an inability to swallow oral medications. Note: Patient may not have a percutaneous endoscopic gastrostomy tube or be receiving total parenteral nutrition.
o Patients suffering from conditions which are likely to adversely affect gastrointestinal motility and/or transit (for example, diarrhoea, vomiting or nausea, gastroparesis, irritable bowel syndrome and malabsorption), or patients with gastrointestinal resection (e.g., partial or total gastrectomy) likely to interfere with absorption of study treatment).
o Patients who are not non-smokers or light smokers (no more than 5 cigarettes per day) and who cannot abstain from smoking from 2 weeks prior to first dose of cocktail until after the last PK sample collection in Part B.
o Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the start of treatment (i.e., first administration of cocktail [Part A Day -8]).
o Excessive intake of caffeine (more than 6 cups of coffee or equivalent per day) and/or consumption of any caffeine containing drinks or food, e.g., coffee, tea, chocolate, caffeine-containing energy drinks (e.g., Red Bull), or cola within 36 hours of administration of the cocktail on Day -8.
o Patient has had prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, which cannot be discontinued 2 weeks prior to the first administration of AZD1775 (Part A Day 1), or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks prior to beginning study treatment (i.e., first administration of cocktail [Part A Day -8]) and withheld throughout the study until 2 weeks after the last administration of AZD1775. Co-administration of aprepitant or fosaprepitant during this study is prohibited. Any patient taking an oral contraceptive must be discussed with the Medical Monitor to ensure that there will be no interaction with the brand of oral contraceptive and cocktail of drugs prior to trial entry to confirm eligibility.
o Patient has had prescription or non-prescription drugs or other products known to be moderate to strong inhibitors/inducers of CYP1A2 or CYP2C19 which cannot be discontinued 2 weeks prior to beginning study treatment (ie, first administration of cocktail [Part A Day -8]) and withheld through Day 4 of Part A
o Patient has had adjustments to prescription or non-prescription drugs or other products known to be mild inhibitors and/or inducers of CYP3A4 within 1 week prior to the first dose of the cocktail (Part A Day -8).
o Herbal preparations taken within 7 days beginning study treatment (i.e., first administration of cocktail [Part A Day -8]). However, in the case of St John’s wort, patients cannot have taken this herbal preparation 21 days prior to first dose of cocktail (Part A Day -8). In the case of Angelica root (Bhai Zhi), patients cannot have taken this herbal preparation 2 weeks prior to beginning study treatment (ie, first administration of cocktail [Part A Day -8]).
o Patients taking any concomitant medications that might affect QT/QTc intervals.
o Patients who have taken any proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, pantoprazole, etc.) within 7 days of beginning study treatment (i.e., first administration of cocktail [Part A Day -8]).
o Patients who cannot withhold antacids for 6 hours or H2-antagonists (cimetidine, ranitidine, famotidine, nizatidine) for up to 96 hours at a time (24 hours prior to and following cocktail administration and 24 hours prior to and following AZD1775 administration) .
o Patients who have received midazolam and/or omeprazole (or esomeprazole) within 14 days of beginning study treatment (i.e., first administration of cocktail [Part A Day -8]).
o Any known hypersensitivity or contraindication to the cocktail drugs (caffeine, omeprazole and midazolam) or AZD1775, or to the components thereof.
o Any of the following cardio-vascular conditions currently or within the last 6 months:
• Unstable angina pectoris.
• Congestive heart failure ≥ Class 2 as defined by the New York Heart Association
• Acute myocardial infarction.
• Significant conduction abnormalities, e.g., atrioventricular block II and III, sick sinus syndrome even if controlled with medication, as well as complete left bundle branch block (complete LBBB).
• Ventricular or supraventricular arrhythmias.
• Insufficiently controlled hypertension, i.e., >160/100 mm Hg.
• Cardiac devices (pacemaker, implantable cardioverter defibrillator, cardiac resynchronisation therapy device, etc.) that can affect the ST-T wave morphology and has a subsequent negative impact on the accuracy of the QTc measurement
o Patients with centrally reviewed QT interval (specifically QTc calculated using the Fridericia formula) >450 ms [QTcF]) obtained from 3 dECGs 2 to 5 minutes apart at study entry, or congenital long QT syndrome.
o AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
o Pregnant or lactating female patients.
o Serious, symptomatic active infection at the time of study entry, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment.
o Presence of other active invasive cancers.
o Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
o Active infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
Any of the following is regarded as a criterion for exclusion from the optional pharmacogenetic part of the study:
o Previous bone marrow transplant.
o Non-leukocyte depleted whole blood product within 120 days of the genetic sample collection.

Location

Research Site

Greenville, SC, United States, 29605

Location

Research Site

Tucson, AZ, United States, 85724

Location

Research Site

Houston, TX, United States, 77030

Location

Research Site

Lebanon, NH, United States, 03756

Location

Research Site

Providence, RI, United States, 02903

Location

Research Site

Indianapolis, IN, United States, 46202

Location

Research Site

Los Angeles, CA, United States, 90048

Location

Research Site

Silver Spring, MD, United States, 20910

Arms	Assigned Interventions
Experimental: Wee-1 kinase inhibitor AZD1775 To evaluate the effect of multiple doses of AZD1775 on the PK of substrates for CYP3A (midazolam), CYP2C19 (omeprazole), CYP1A2 (caffeine) and to evaluate the effect of multiple doses of AZD1775 on QT interval	Drug: CYP1A2 (caffeine) In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3. Drug: CYP2C19 (omeprazole) In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3. Drug: CYP3A (midazolam) In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3. Drug: Kytril (granisetron) Patients should be administered Kytril (granisetron) 1 mg orally, under fasted conditions (-2 to 2 hours away from meals), 30 minutes prior to administration of the AZD1775 capsules with a small amount of water. Drug: Wee-1 kinase inhibitor AZD1775 Multiple doses of 225 mg AZD1775, (3 x 75 mg, printed capsules) administered orally. The drug class of AZD1775 is Wee-1 kinase inhibitor.

Arms

Assigned Interventions

Experimental: Wee-1 kinase inhibitor AZD1775
To evaluate the effect of multiple doses of AZD1775 on the PK of substrates for CYP3A (midazolam), CYP2C19 (omeprazole), CYP1A2 (caffeine) and to evaluate the effect of multiple doses of AZD1775 on QT interval

Drug: CYP1A2 (caffeine)
In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.

Drug: CYP2C19 (omeprazole)
In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.

Drug: CYP3A (midazolam)
In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.

Drug: Kytril (granisetron)
Patients should be administered Kytril (granisetron) 1 mg orally, under fasted conditions (-2 to 2 hours away from meals), 30 minutes prior to administration of the AZD1775 capsules with a small amount of water.

Drug: Wee-1 kinase inhibitor AZD1775
Multiple doses of 225 mg AZD1775, (3 x 75 mg, printed capsules) administered orally. The drug class of AZD1775 is Wee-1 kinase inhibitor.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This was a Phase 1, open-label, non-randomised, 2-part study conducted at 7 study centres in the United States. Part A assessed effect of adavosertib (AZD1775) on pharmacokinetics (PK) of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole) and CYP3A (midazolam). Part B assessed effect on QT interval following multiple doses of adavosertib.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
In Part A, patients with advanced solid tumours received a cocktail of 3 drugs alone (Period 1) and in combination with adavosertib at steady state (Period 2). Patients completing Part A and who were eligible to continue, received further treatment with adavosertib in Part B. Each treatment period was separated by a washout period of 7 to 14 days.

Reporting Groups

	Description
All Patients	Part A: Adavosertib 225 milligrams (mg) (3 x 75 mg capsules) was administered orally twice daily (BID) on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 millilitre [mL] of 2 mg/mL syrup formulation) was administered orally as a single dose alone on Day -8 (Period 1) and in combination with the last dose of adavosertib at steady state in the morning of Day 3 (Period 2). Part B: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Description

All Patients

Part A: Adavosertib 225 milligrams (mg) (3 x 75 mg capsules) was administered orally twice daily (BID) on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 millilitre [mL] of 2 mg/mL syrup formulation) was administered orally as a single dose alone on Day -8 (Period 1) and in combination with the last dose of adavosertib at steady state in the morning of Day 3 (Period 2).
Part B: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Participant Flow: Overall Study

	All Patients
STARTED	33
Received cocktail on Day -8 in Part A	33
Received adavosertib in Part A	30
Received adavosertib in Part B	21
COMPLETED	19
NOT COMPLETED	14
Study terminated by Sponsor	4
Withdrawal by Subject	2
Protocol withdrawal criterion met	3
Death	1
Adverse Event	4

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Safety analysis set included all patients who received at least 1 dose of study treatment (adavosertib or cocktail).

Reporting Groups

	Description
All Patients	Part A: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered orally as a single dose alone on Day -8 (Period 1) and in combination with the last dose of adavosertib at steady state in the morning of Day 3 (Period 2). Part B: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Description

All Patients

Part A: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered orally as a single dose alone on Day -8 (Period 1) and in combination with the last dose of adavosertib at steady state in the morning of Day 3 (Period 2). Part B: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Baseline Measures

	All Patients
Number of Participants [units: Participants]	33
Age Continuous [units: years] Mean ± Standard Deviation	60.3 ± 8.8
Sex: Female, Male [units: ]
Female	18
Male	15
Race/Ethnicity, Customized [units: ]
Asian	1
Black or African American	4
White	28
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	2
Not Hispanic or Latino	30
Unknown or Not Reported	1

Outcome Measures

1. Primary Outcome Measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours (h) post-dose. ]

Measure Type	Primary
Measure Name	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of AUC for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. AUC was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable observed concentration divided by the elimination rate constant (λz; estimated by log-linear least-squares (LS) regression of the terminal part of the concentration-time curve). Note: For cocktail analytes caffeine and midazolam, unit of measure for AUC was nanogramshour/millilitre (ngh/mL) and for omeprazole was nanomolarhour (nMh).
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours (h) post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: ngh/mL or nMh] Geometric Mean (Geometric Coefficient of Variation)
Caffeine	38510 (44.69%)	57280 (46.66%)
Omeprazole	5909 (97.54%)	10040 (83.12%)
Midazolam	39.90 (67.22%)	53.91 (40.94%)

Statistical Analysis 1 for Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	149.06
90% Confidence Interval	( 131.25 to 169.28 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Caffeine. Natural log transformed AUC values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 2 for Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	180.21
90% Confidence Interval	( 145.71 to 222.88 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Omeprazole. Natural log transformed AUC values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 3 for Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	155.25
90% Confidence Interval	( 138.56 to 173.94 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Midazolam. Natural log transformed AUC values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

2. Primary Outcome Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time “t” of the Last Quantifiable Concentration (AUC0-t) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Primary
Measure Name	Area Under the Plasma Concentration-time Curve From Time Zero to the Time “t” of the Last Quantifiable Concentration (AUC0-t) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of AUC0-t for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. AUC0-t was calculated by linear up/log down trapezoidal summation. Note: For cocktail analytes caffeine and midazolam, unit of measure for AUC0-t was ngh/mL and for omeprazole was nMh.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Area Under the Plasma Concentration-time Curve From Time Zero to the Time “t” of the Last Quantifiable Concentration (AUC0-t) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: ngh/mL or nMh] Geometric Mean (Geometric Coefficient of Variation)
Caffeine	40090 (48.00%)	63520 (40.33%)
Omeprazole	3860 (149.7%)	6901 (109.3%)
Midazolam	36.49 (66.43%)	51.93 (42.82%)

Statistical Analysis 1 for Area Under the Plasma Concentration-time Curve From Time Zero to the Time “t” of the Last Quantifiable Concentration (AUC0-t) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	160.83
90% Confidence Interval	( 143.32 to 180.47 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Caffeine. Natural log transformed AUC0-t values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 2 for Area Under the Plasma Concentration-time Curve From Time Zero to the Time “t” of the Last Quantifiable Concentration (AUC0-t) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	198.06
90% Confidence Interval	( 160.31 to 244.69 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Omeprazole. Natural log transformed AUC0-t values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 3 for Area Under the Plasma Concentration-time Curve From Time Zero to the Time “t” of the Last Quantifiable Concentration (AUC0-t) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	155.24
90% Confidence Interval	( 140.48 to 171.54 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Midazolam. Natural log transformed AUC0-t values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

3. Primary Outcome Measure: Maximum Plasma Drug Concentration (Cmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Primary
Measure Name	Maximum Plasma Drug Concentration (Cmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of Cmax for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. Cmax was obtained directly from the observed concentration versus time data. Note: For cocktail analytes caffeine and midazolam, unit of measure for Cmax was ng/mL and for omeprazole was nM.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Maximum Plasma Drug Concentration (Cmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: ng/mL or nM] Geometric Mean (Geometric Coefficient of Variation)
Caffeine	6168 (36.26%)	6430 (27.22%)
Omeprazole	1374 (99.93%)	1915 (81.46%)
Midazolam	15.13 (52.40%)	19.43 (40.87%)

Statistical Analysis 1 for Maximum Plasma Drug Concentration (Cmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	103.84
90% Confidence Interval	( 92.24 to 116.89 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Caffeine. Natural log transformed Cmax values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 2 for Maximum Plasma Drug Concentration (Cmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	145.49
90% Confidence Interval	( 114.00 to 185.70 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Omeprazole. Natural log transformed Cmax values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 3 for Maximum Plasma Drug Concentration (Cmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

Groups^[1]	All groups
Other^[5]	138.50
90% Confidence Interval	( 118.89 to 161.34 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Midazolam. Natural log transformed Cmax values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

4. Primary Outcome Measure: Mean Time-matched Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia’s Formula (ΔQTcF): Part B [ Time Frame: dECG was performed on Day 1 and Day 3 in Part B of the study at the following time points: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h post-dose. ]

Measure Type	Primary
Measure Name	Mean Time-matched Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia’s Formula (ΔQTcF): Part B
Measure Description	Digital electrocardiogram (dECG) assessments were performed to determine mean time-matched change from baseline values for QTcF (i.e., ΔQTcF) from baseline (pre-dose) to Day 3 over 0.5 to 24 h following administration of adavosertib alone in Part B.
Time Frame	dECG was performed on Day 1 and Day 3 in Part B of the study at the following time points: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety analysis set included all patients who received at least 1 dose of study treatment (adavosertib or cocktail).

Reporting Groups

	Description
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	21
Mean Time-matched Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia’s Formula (ΔQTcF): Part B [units: millisecond] Mean (90% Confidence Interval)
Day 1, Pre-dose	-0.3 (-4.2 to 3.6)
Day 1, 0.5 h	-6.3 (-10.1 to -2.6)
Day 1, 1 h	-2.4 (-5.6 to 0.8)
Day 1, 2 h	-2.1 (-7.5 to 3.4)
Day 1, 3 h	1.1 (-3.5 to 5.8)
Day 1, 4 h	-0.7 (-5.4 to 3.9)
Day 1, 6 h	-4.0 (-7.4 to -0.5)
Day 1, 8 h	-3.9 (-7.8 to 0.1)
Day 1, 12 h	-2.2 (-5.7 to 1.3)
Day 1, 24 h	-4.2 (-8.6 to 0.2)
Day 3, Pre-dose	-0.6 (-8.6 to 7.5)
Day 3, 0.5 h	-0.4 (-6.2 to 5.4)
Day 3, 1 h	-0.2 (-5.9 to 5.5)
Day 3, 2 h	2.9 (-2.7 to 8.4)
Day 3, 3 h	7.3 (0.3 to 14.3)
Day 3, 4 h	-2.7 (-9.6 to 4.2)
Day 3, 6 h	-1.2 (-6.6 to 4.2)
Day 3, 8 h	-1.8 (-7.4 to 3.7)
Day 3, 12 h	1.8 (-3.0 to 6.6)
Day 3, 24 h	1.0 (-5.6 to 7.6)

No statistical analysis provided for Mean Time-matched Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia’s Formula (ΔQTcF): Part B

5. Secondary Outcome Measure: Time to Reach Maximum Plasma Concentration (tmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Time to Reach Maximum Plasma Concentration (tmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of tmax for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. tmax was obtained directly from the observed concentration versus time data.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Time to Reach Maximum Plasma Concentration (tmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: h] Median (Full Range)
Caffeine	0.50 (0.25 to 3.00)	0.73 (0.25 to 3.03)
Omeprazole	2.97 (0.70 to 6.03)	3.88 (0.50 to 8.02)
Midazolam	0.50 (0.18 to 1.02)	0.48 (0.23 to 0.98)

No statistical analysis provided for Time to Reach Maximum Plasma Concentration (tmax) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

6. Secondary Outcome Measure: Terminal Half-life (t1/2) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Terminal Half-life (t1/2) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of t1/2 for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. For determination of t1/2, visual assessment was used to identify the terminal linear phase of the concentration-time profile.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Terminal Half-life (t1/2) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: h] Mean (Standard Deviation)
Caffeine	6.412 (3.812)	13.45 (6.834)
Omeprazole	2.016 (1.020)	2.468 (1.269)
Midazolam	5.539 (2.561)	6.642 (3.044)

No statistical analysis provided for Terminal Half-life (t1/2) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

7. Secondary Outcome Measure: Apparent Clearance (CL/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Apparent Clearance (CL/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of CL/F for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. CL/F was estimated as dose divided by AUC.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Apparent Clearance (CL/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: Litres/hour (L/h)] Mean (Standard Deviation)
Caffeine	5.652 (2.457)	3.829 (1.921)
Omeprazole	13.27 (10.47)	7.631 (7.346)
Midazolam	58.96 (34.28)	39.74 (14.52)

No statistical analysis provided for Apparent Clearance (CL/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

8. Secondary Outcome Measure: Apparent Volume of Distribution (Vz/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Apparent Volume of Distribution (Vz/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A
Measure Description	Assessment of Vz/F for cocktail parent compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. Vz/F was estimated by dividing CL/F by λz.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Apparent Volume of Distribution (Vz/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A [units: L] Mean (Standard Deviation)
Caffeine	39.30 (15.01)	37.90 (12.12)
Omeprazole	28.33 (16.58)	19.76 (10.06)
Midazolam	409.9 (211.5)	364.1 (182.7)

No statistical analysis provided for Apparent Volume of Distribution (Vz/F) for Cocktail Parent Compounds (Caffeine, Omeprazole and Midazolam): Part A

9. Secondary Outcome Measure: AUC for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	AUC for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1-Hydroxy-Midazolam): Part A
Measure Description	Assessment of AUC for cocktail metabolite compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. AUC was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable observed concentration divided by λz. Note: For cocktail metabolite analytes paraxanthine and 1’-hydroxy-midazolam, unit of measure for AUC was ngh/mL and for 5-hydroxy-omeprazole was nMh.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
AUC for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1-Hydroxy-Midazolam): Part A [units: ngh/mL or nMh] Geometric Mean (Geometric Coefficient of Variation)
Paraxanthine	18310 (19.50%)	NA (NA%)^[1]
5-Hydroxy-Omeprazole	2154 (54.77%)	2639 (42.97%)
1-Hydroxy-Midazolam	15.47 (71.29%)	21.23 (45.31%)

Statistical Analysis 1 for AUC for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	99.81
90% Confidence Interval	( 65.04 to 153.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Paraxanthine. Natural log transformed AUC values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 2 for AUC for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	142.95
90% Confidence Interval	( 123.82 to 165.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = 5-Hydroxy-Omeprazole. Natural log transformed AUC values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 3 for AUC for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	153.46
90% Confidence Interval	( 130.97 to 179.80 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = 1-Hydroxy-Midazolam. Natural log transformed AUC values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

10. Secondary Outcome Measure: AUC0-t for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	AUC0-t for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of AUC0-t for cocktail metabolite compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. AUC0-t was calculated by linear up/log down trapezoidal summation. Note: For cocktail metabolite analytes paraxanthine and 1’-hydroxy-midazolam, unit of measure for AUC0-t was ngh/mL and for 5 hydroxy omeprazole was nMh.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
AUC0-t for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: ngh/mL or nMh] Geometric Mean (Geometric Coefficient of Variation)
Paraxanthine	18740 (24.48%)	18110 (24.47%)
5-Hydroxy-Omeprazole	1779 (58.77%)	2397 (42.88%)
1’-Hydroxy-Midazolam	14.53 (64.53%)	20.65 (49.47%)

Statistical Analysis 1 for AUC0-t for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	101.17
90% Confidence Interval	( 91.74 to 111.56 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Paraxanthine. Natural log transformed AUC0-t values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 2 for AUC0-t for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	148.82
90% Confidence Interval	( 129.64 to 170.84 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = 5-Hydroxy-Omeprazole. Natural log transformed AUC0-t values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 3 for AUC0-t for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	158.24
90% Confidence Interval	( 139.09 to 180.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = 1-Hydroxy-Midazolam. Natural log transformed AUC0-t values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

11. Secondary Outcome Measure: Cmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Cmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of Cmax for cocktail metabolite compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. Cmax was obtained directly from the observed concentration versus time data. Note: For cocktail metabolite analytes paraxanthine and 1’-hydroxy-midazolam, unit of measure for Cmax was ng/mL and for 5 hydroxy omeprazole was nM.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Cmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: ng/mL or nM] Geometric Mean (Geometric Coefficient of Variation)
Paraxanthine	1274 (23.52%)	974.5 (29.91%)
5-Hydroxy-Omeprazole	461.1 (71.38%)	398.2 (57.27%)
1-Hydroxy-Midazolam	6.277 (76.46%)	8.011 (55.74%)

Statistical Analysis 1 for Cmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	81.23
90% Confidence Interval	( 74.57 to 88.49 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = Paraxanthine. Natural log transformed Cmax values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 2 for Cmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	92.87
90% Confidence Interval	( 78.59 to 109.75 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = 5-Hydroxy-Omeprazole. Natural log transformed Cmax values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

Statistical Analysis 3 for Cmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

Groups^[1]	All groups
Other^[5]	133.37
90% Confidence Interval	( 106.48 to 167.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyte = 1-Hydroxy-Midazolam. Natural log transformed Cmax values were compared between treatments using a linear mixed-effects model with a fixed effect for treatment and a random effect for patient.
[5]	Other relevant estimation information:
	Period 2 versus Period 1 (Part A)

12. Secondary Outcome Measure: tmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	tmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of tmax for cocktail metabolite compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. tmax was obtained directly from the observed concentration versus time data.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
tmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: h] Median (Full Range)
Paraxanthine	7.98 (4.00 to 11.78)	9.93 (5.98 to 24.93)
5-Hydroxy-Omeprazole	3.00 (0.70 to 6.03)	3.95 (1.83 to 7.75)
1’-Hydroxy-Midazolam	0.51 (0.28 to 2.08)	0.50 (0.23 to 1.00)

No statistical analysis provided for tmax for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

13. Secondary Outcome Measure: t1/2 for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	t1/2 for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of t1/2 for cocktail metabolite compounds in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. For determination of t1/2, visual assessment was used to identify the terminal linear phase of the concentration-time profile.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
t1/2 for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: h] Mean (Standard Deviation)
Paraxanthine	6.951 (2.681)	12.16 (5.423)
5-Hydroxy-Omeprazole	2.696 (1.711)	4.455 (4.689)
1’-Hydroxy-Midazolam	7.159 (6.079)	7.643 (7.147)

No statistical analysis provided for t1/2 for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

14. Secondary Outcome Measure: Metabolite to Parent AUC Ratio (MRAUC) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Metabolite to Parent AUC Ratio (MRAUC) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of MRAUC for each metabolite in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. Ratios were calculated for paraxanthine to caffeine, 5-hydroxy-omeprazole to omeprazole and 1’-hydroxy-midazolam to midazolam.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Metabolite to Parent AUC Ratio (MRAUC) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: ratio] Mean (Standard Deviation)
Paraxanthine	0.6493 (0.09576)	NA (NA)^[1]
5-Hydroxy-Omeprazole	0.4997 (0.3279)	0.4628 (0.4232)
1-Hydroxy-Midazolam	0.4145 (0.1732)	0.4462 (0.2197)

No statistical analysis provided for Metabolite to Parent AUC Ratio (MRAUC) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

15. Secondary Outcome Measure: Metabolite to Parent AUC0-t Ratio (MRAUC0-t) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Metabolite to Parent AUC0-t Ratio (MRAUC0-t) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of MRAUC0-t for each metabolite in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. Ratios were calculated for paraxanthine to caffeine, 5-hydroxy-omeprazole to omeprazole and 1’-hydroxy-midazolam to midazolam.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Metabolite to Parent AUC0-t Ratio (MRAUC0-t) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: ratio] Mean (Standard Deviation)
Paraxanthine	0.5382 (0.1260)	0.3245 (0.1298)
5-Hydroxy-Omeprazole	0.7285 (0.7406)	0.5038 (0.4405)
1-Hydroxy-Midazolam	0.4327 (0.2043)	0.4369 (0.2016)

No statistical analysis provided for Metabolite to Parent AUC0-t Ratio (MRAUC0-t) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

16. Secondary Outcome Measure: Metabolite to Parent Cmax Ratio (MRCmax) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [ Time Frame: Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Metabolite to Parent Cmax Ratio (MRCmax) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A
Measure Description	Assessment of MRCmax for each metabolite in Part A following administration of a single dose of the cocktail alone and the cocktail in combination with adavosertib at steady state. Ratios were calculated for paraxanthine to caffeine, 5-hydroxy-omeprazole to omeprazole and 1’-hydroxy-midazolam to midazolam.
Time Frame	Blood samples were collected on Day -8 in Period 1 and on Day 3 in Period 2, in Part A of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set for Part A included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail (or metabolites) or adavosertib collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Cocktail Alone: Part A, Day-8 (Period 1)	Patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A.
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.

Measured Values

	Cocktail Alone: Part A, Day-8 (Period 1)	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)
Number of Participants Analyzed [units:participants]	30	22
Metabolite to Parent Cmax Ratio (MRCmax) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A [units: ratio] Mean (Standard Deviation)
Paraxanthine	0.2315 (0.05297)	0.1593 (0.04550)
5-Hydroxy-Omeprazole	0.5266 (0.5627)	0.3011 (0.2651)
1-Hydroxy-Midazolam	0.4656 (0.2077)	0.4344 (0.1551)

No statistical analysis provided for Metabolite to Parent Cmax Ratio (MRCmax) for Cocktail Metabolites (Paraxanthine, 5-Hydroxy-Omeprazole and 1’-Hydroxy-Midazolam): Part A

17. Secondary Outcome Measure: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12) for adavosertib: Part A and Part B [ Time Frame: Blood samples were collected on Day 3 in Part A of the study, and on Day 1 and Day 3 in Part B. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B). ]

Measure Type	Secondary
Measure Name	Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12) for adavosertib: Part A and Part B
Measure Description	Assessment of AUC0-12 for adavosertib in Part A following administration of the cocktail in combination with adavosertib at steady state, and in Part B following administration of adavosertib alone. AUC0-12 was calculated using t12 for the end time of the area, where t12 was the actual elapsed sample time at the nominal 12-h time point.
Time Frame	Blood samples were collected on Day 3 in Part A of the study, and on Day 1 and Day 3 in Part B. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part A or B) included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail or metabolites (Part A only), or adavosertib (Part A or B), collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.
Adavosertib Single Dose: Part B, Day 1	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally in the morning of Day 1 in Part B.
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Adavosertib Single Dose: Part B, Day 1	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	16	17	15
Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12) for adavosertib: Part A and Part B [units: nM*h] Geometric Mean (Geometric Coefficient of Variation)	12170 (31.94%)	4940 (39.48%)	10810 (34.15%)

Statistical Analysis 1 for Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12) for adavosertib: Part A and Part B

Groups^[1]	Adavosertib Single Dose: Part B, Day 1, Adavosertib Multiple Dose: Part B, Day 3
Other^[5]	230.76
90% Confidence Interval	( 200.31 to 265.83 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	To assess the extent of accumulation of adavosertib in Part B, a linear mixed-effects model using the natural log transformed AUC0-12 as the response variable, day as a fixed effect and patient as a random effect was performed.
[5]	Other relevant estimation information:
	Day 3 compared to Day 1 (Part B)

Statistical Analysis 2 for Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12) for adavosertib: Part A and Part B

Groups^[1]	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2), Adavosertib Multiple Dose: Part B, Day 3
Other^[5]	107.75
90% Confidence Interval	( 103.59 to 112.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	To assess the potential effects of the cocktail on adavosertib exposure, a linear mixed-effects model using the natural log transformed AUC0-12 as the response variable, study part (A or B) as a fixed effect and patient as a random effect was performed.
[5]	Other relevant estimation information:
	Part A, Day 3 compared to Part B, Day 3

18. Secondary Outcome Measure: Cmax for adavosertib: Part A and Part B [ Time Frame: Blood samples were collected on Day 3 in Part A of the study, and on Day 1 and Day 3 in Part B. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B). ]

Measure Type	Secondary
Measure Name	Cmax for adavosertib: Part A and Part B
Measure Description	Assessment of Cmax for adavosertib in Part A following administration of the cocktail in combination with adavosertib at steady state, and in Part B following administration of adavosertib alone. Cmax was calculated over the 12-h dosing interval, obtained directly from the observed concentration versus time data.
Time Frame	Blood samples were collected on Day 3 in Part A of the study, and on Day 1 and Day 3 in Part B. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part A or B) included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail or metabolites (Part A only), or adavosertib (Part A or B), collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.
Adavosertib Single Dose: Part B, Day 1	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally in the morning of Day 1 in Part B.
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Adavosertib Single Dose: Part B, Day 1	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	16	18	14
Cmax for adavosertib: Part A and Part B [units: nM] Geometric Mean (Geometric Coefficient of Variation)	1437 (29.00%)	712.8 (44.97%)	1462 (23.95%)

Statistical Analysis 1 for Cmax for adavosertib: Part A and Part B

Groups^[1]	Adavosertib Single Dose: Part B, Day 1, Adavosertib Multiple Dose: Part B, Day 3
Other^[5]	206.65
90% Confidence Interval	( 170.47 to 250.50 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	To assess the extent of accumulation of adavosertib in Part B, a linear mixed-effects model using the natural log transformed Cmax as the response variable, day as a fixed effect and patient as a random effect was performed.
[5]	Other relevant estimation information:
	Day 3 compared to Day 1 (Part B)

Statistical Analysis 2 for Cmax for adavosertib: Part A and Part B

Groups^[1]	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2), Adavosertib Multiple Dose: Part B, Day 3
Other^[5]	97.41
90% Confidence Interval	( 90.70 to 104.61 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	To assess the potential effects of the cocktail on adavosertib exposure, a linear mixed-effects model using the natural log transformed Cmax as the response variable, study part (A or B) as a fixed effect and patient as a random effect was performed.
[5]	Other relevant estimation information:
	Part A, Day 3 compared to Part B, Day 3

19. Secondary Outcome Measure: tmax for adavosertib: Part A and Part B [ Time Frame: Blood samples were collected on Day 3 in Part A of the study, and on Day 1 and Day 3 in Part B. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B). ]

Measure Type	Secondary
Measure Name	tmax for adavosertib: Part A and Part B
Measure Description	Assessment of tmax for adavosertib in Part A following administration of the cocktail in combination with adavosertib at steady state, and in Part B following administration of adavosertib alone. tmax was obtained directly from the observed concentration versus time data.
Time Frame	Blood samples were collected on Day 3 in Part A of the study, and on Day 1 and Day 3 in Part B. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part A or B) included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail or metabolites (Part A only), or adavosertib (Part A or B), collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.
Adavosertib Single Dose: Part B, Day 1	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally in the morning of Day 1 in Part B.
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Adavosertib Single Dose: Part B, Day 1	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	16	18	14
tmax for adavosertib: Part A and Part B [units: h] Median (Full Range)	3.00 (0.75 to 6.00)	2.97 (1.02 to 5.97)	2.50 (1.00 to 3.08)

No statistical analysis provided for tmax for adavosertib: Part A and Part B

20. Secondary Outcome Measure: Minimum Plasma Drug Concentration (Cmin) for adavosertib: Part A and Part B [ Time Frame: Blood samples were collected on Day 3 in Part A and Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Minimum Plasma Drug Concentration (Cmin) for adavosertib: Part A and Part B
Measure Description	Assessment of Cmin for adavosertib in Part A following administration of the cocktail in combination with adavosertib at steady state, and in Part B following administration of adavosertib alone. Cmin was obtained directly from the observed concentration versus time data.
Time Frame	Blood samples were collected on Day 3 in Part A and Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part A or B) included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail or metabolites (Part A only), or adavosertib (Part A or B), collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	16	15
Minimum Plasma Drug Concentration (Cmin) for adavosertib: Part A and Part B [units: nM] Geometric Mean (Geometric Coefficient of Variation)	566.7 (36.66%)	410.4 (136.1%)

No statistical analysis provided for Minimum Plasma Drug Concentration (Cmin) for adavosertib: Part A and Part B

21. Secondary Outcome Measure: Apparent Clearance at Steady State (CLss/F) for adavosertib: Part A and Part B [ Time Frame: Blood samples were collected on Day 3 in Part A and Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose. ]

Measure Type	Secondary
Measure Name	Apparent Clearance at Steady State (CLss/F) for adavosertib: Part A and Part B
Measure Description	Assessment of CLss/F for adavosertib in Part A following administration of the cocktail in combination with adavosertib at steady state, and in Part B following administration of adavosertib alone. CLss/F was calculated as dose divided by AUC0-12.
Time Frame	Blood samples were collected on Day 3 in Part A and Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part A or B) included all dosed patients who had at least 1 quantifiable plasma concentration for any of the cocktail or metabolites (Part A only), or adavosertib (Part A or B), collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once on Day 3 (total of 5 doses in Part A). In addition, patients received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) in combination with the last dose of adavosertib in the morning of Day 3.
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose + Cocktail: Part A, Day 3 (Period 2)	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	16	15
Apparent Clearance at Steady State (CLss/F) for adavosertib: Part A and Part B [units: L/h] Mean (Standard Deviation)	37.99 (12.11)	43.19 (16.82)

No statistical analysis provided for Apparent Clearance at Steady State (CLss/F) for adavosertib: Part A and Part B

22. Secondary Outcome Measure: Accumulation Ratio for AUC0-12(RAUC0-12) for adavosertib: Part B [ Time Frame: Blood samples were collected on Day 1 and Day 3 in Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B). ]

Measure Type	Secondary
Measure Name	Accumulation Ratio for AUC0-12(RAUC0-12) for adavosertib: Part B
Measure Description	Assessment of RAUC0-12 in Part B following administration of adavosertib alone. RAUC0-12 (Day 3/Day 1) was calculated as AUC0-12 Day 3 divided by AUC0-12 Day 1.
Time Frame	Blood samples were collected on Day 1 and Day 3 in Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part B) included all dosed patients who had at least 1 quantifiable plasma concentration for adavosertib in Part B collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	13
Accumulation Ratio for AUC0-12(RAUC0-12) for adavosertib: Part B [units: ratio] Geometric Mean (Geometric Coefficient of Variation)	2.372 (28.46%)

No statistical analysis provided for Accumulation Ratio for AUC0-12(RAUC0-12) for adavosertib: Part B

23. Secondary Outcome Measure: Accumulation Ratio for Cmax (RCmax) for adavosertib: Part B [ Time Frame: Blood samples were collected on Day 1 and Day 3 in Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B). ]

Measure Type	Secondary
Measure Name	Accumulation Ratio for Cmax (RCmax) for adavosertib: Part B
Measure Description	Assessment of RCmax for adavosertib in Part B following administration of adavosertib alone. RCmax (Day 3/Day 1) was calculated as Cmax Day 3 divided by Cmax Day 1.
Time Frame	Blood samples were collected on Day 1 and Day 3 in Part B of the study. PK sampling at pre-dose, and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dose (no 24-h post-dose for Day 1 in Part B).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set (Part B) included all dosed patients who had at least 1 quantifiable plasma concentration for adavosertib in Part B collected post-dose without protocol deviations or events that would affect the PK analysis. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Adavosertib Multiple Dose: Part B, Day 3	Patients received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (total of 5 doses in Part B).

Measured Values

	Adavosertib Multiple Dose: Part B, Day 3
Number of Participants Analyzed [units:participants]	13
Accumulation Ratio for Cmax (RCmax) for adavosertib: Part B [units: ratio] Geometric Mean (Geometric Coefficient of Variation)	2.098 (44.30%)

No statistical analysis provided for Accumulation Ratio for Cmax (RCmax) for adavosertib: Part B

Serious Adverse Events

Time Frame

Treatment-emergent adverse event (TEAE) data was reported from the first dose of study treatment up to and including 30 days after the last dose of study treatment, or until enrolment into the open-label continued access (CA) study D6014C00007.

Additional Description

Part A: TEAEs were captured from first dose of cocktail on Day -8 up to and including 30 days after last dose of adavosertib in Part A, or until enrolment into the open label CA study, D6014C00007, if sooner. Part B: TEAEs were captured from first dose of adavosertib on Day 1 in Part B up to and including the End of Study (EoS) visit (for patients not enrolling in the open-label CA study) or End of Treatment (EoT) visit (for patients who did enrol in the open-label CA study).

Reporting Groups

	Description
Cocktail Alone: Part A	Patient had received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A of the study. The TEAE was counted if onset was after first administration of cocktail on Day -8 and prior to first administration of adavosertib on Day 1 and up to and including 30 days after the last administration if the patient discontinued before first administration of adavosertib (or until enrolment into the open-label CA study, if sooner).
Adavosertib Multiple Dose: Part A	Patient had received adavosertib in Part A of the study. Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once in the morning on Day 3. The TEAE was counted if onset was after first administration of adavosertib on Day 1 and prior to second administration of cocktail on Day 3 or up to and including 30 days post the last administration where the patient did not receive second administration of cocktail (or until enrolment into the open-label CA study, if sooner).
Adavosertib Multiple Dose + Cocktail: Part A	Patient had received adavosertib and cocktail in Part A of the study. Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3. The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered in combination with the last dose of adavosertib in the morning of Day 3. The TEAE was counted if onset was after second administration of cocktail on Day 3 but prior to the first administration of adavosertib in Part B, or up to and including 30 days post the last administration where the patient did not enter Part B (or until enrolment into the open-label CA study, if sooner).
Total Adavosertib: Part A	Patient had received adavosertib and cocktail in Part A of the study. Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3. The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered in combination with the last dose of adavosertib in the morning of Day 3. The TEAE was counted if onset was after first administration of adavosertib on Day 1 up to and including 30 days after the last dose date (of adavosertib) in Part A or until enrolment into the open-label CA study, if sooner.
Adavosertib: Part B	Patient had received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (Part B). The TEAE was counted if onset was after first administration of adavosertib on Day 1 in Part B up to and including the EoS visit (for patients who did not enrol in the open-label CA study) or EoT visit (for patients who did enrol in the open-label CA study).
All Adavosertib: Part A and Part B	Patient had received adavosertib and cocktail in Part A of the study and adavosertib in Part B. Part A: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3 in Part A of the study. The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered in combination with the last dose of adavosertib in the morning of Day 3. Part B: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3 in Part B of the study.

Serious Adverse Events

Cocktail Alone: Part A

Adavosertib Multiple Dose: Part A

Adavosertib Multiple Dose + Cocktail: Part A

Total Adavosertib: Part A

Adavosertib: Part B

All Adavosertib: Part A and Part B

Total, serious adverse events

# participants affected / at risk

1/33 (3.03%)

3/30 (10.00%)

1/26 (3.85%)

4/30 (13.33%)

1/21 (4.76%)

5/30 (16.67%)

Gastrointestinal disorders

Pancreatitis¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

0/26 (0.00%)

1/30 (3.33%)

0/21 (0.00%)

1/30 (3.33%)

# events

Gastrointestinal disorders

Small intestinal obstruction¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

0/26 (0.00%)

1/30 (3.33%)

0/21 (0.00%)

1/30 (3.33%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/33 (0.00%)

0/30 (0.00%)

0/26 (0.00%)

0/30 (0.00%)

1/21 (4.76%)

1/30 (3.33%)

# events

Infections and infestations

Necrotising soft tissue infection¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

0/26 (0.00%)

1/30 (3.33%)

0/21 (0.00%)

1/30 (3.33%)

# events

Infections and infestations

Pneumonia bacterial¹,^†

# participants affected / at risk

1/33 (3.03%)

0/30 (0.00%)

0/26 (0.00%)

0/30 (0.00%)

0/21 (0.00%)

0/30 (0.00%)

# events

Renal and urinary disorders

Acute kidney injury¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

0/26 (0.00%)

1/30 (3.33%)

0/21 (0.00%)

1/30 (3.33%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

0/33 (0.00%)

0/30 (0.00%)

1/26 (3.85%)

1/30 (3.33%)

0/21 (0.00%)

1/30 (3.33%)

# events

Vascular disorders

Deep vein thrombosis¹,^†

# participants affected / at risk

1/33 (3.03%)

0/30 (0.00%)

0/26 (0.00%)

0/30 (0.00%)

0/21 (0.00%)

0/30 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.1

Other Adverse Events

Time Frame

Additional Description

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Cocktail Alone: Part A	Patient had received a single oral dose of the cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) alone on Day -8 in Part A of the study. The TEAE was counted if onset was after first administration of cocktail on Day -8 and prior to first administration of adavosertib on Day 1 and up to and including 30 days after the last administration if the patient discontinued before first administration of adavosertib (or until enrolment into the open-label CA study, if sooner).
Adavosertib Multiple Dose: Part A	Patient had received adavosertib in Part A of the study. Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once in the morning on Day 3. The TEAE was counted if onset was after first administration of adavosertib on Day 1 and prior to second administration of cocktail on Day 3 or up to and including 30 days post the last administration where the patient did not receive second administration of cocktail (or until enrolment into the open-label CA study, if sooner).
Adavosertib Multiple Dose + Cocktail: Part A	Patient had received adavosertib and cocktail in Part A of the study. Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3. The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered in combination with the last dose of adavosertib in the morning of Day 3. The TEAE was counted if onset was after second administration of cocktail on Day 3 but prior to the first administration of adavosertib in Part B, or up to and including 30 days post the last administration where the patient did not enter Part B (or until enrolment into the open-label CA study, if sooner).
Total Adavosertib: Part A	Patient had received adavosertib and cocktail in Part A of the study. Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3. The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered in combination with the last dose of adavosertib in the morning of Day 3. The TEAE was counted if onset was after first administration of adavosertib on Day 1 up to and including 30 days after the last dose date (of adavosertib) in Part A or until enrolment into the open-label CA study, if sooner.
Adavosertib: Part B	Patient had received adavosertib 225 mg (3 x 75 mg capsules) orally BID on Days 1 and 2 and once in the morning on Day 3 (Part B). The TEAE was counted if onset was after first administration of adavosertib on Day 1 in Part B up to and including the EoS visit (for patients who did not enrol in the open-label CA study) or EoT visit (for patients who did enrol in the open-label CA study).
All Adavosertib: Part A and Part B	Patient had received adavosertib and cocktail in Part A of the study and adavosertib in Part B. Part A: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3 in Part A of the study. The cocktail containing caffeine (200 mg tablet), omeprazole (20 mg capsule) and midazolam (1 mL of 2 mg/mL syrup formulation) was administered in combination with the last dose of adavosertib in the morning of Day 3. Part B: Adavosertib 225 mg (3 x 75 mg capsules) was administered orally BID on Days 1 and 2 and once on Day 3 in Part B of the study.

Other Adverse Events

Cocktail Alone: Part A

Adavosertib Multiple Dose: Part A

Adavosertib Multiple Dose + Cocktail: Part A

Total Adavosertib: Part A

Adavosertib: Part B

All Adavosertib: Part A and Part B

Total, other (not including serious) adverse events

# participants affected / at risk

1/33 (3.03%)

14/30 (46.67%)

13/26 (50.00%)

22/30 (73.33%)

13/21 (61.90%)

27/30 (90.00%)

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

0/33 (0.00%)

0/30 (0.00%)

2/26 (7.69%)

2/30 (6.67%)

1/21 (4.76%)

2/30 (6.67%)

# events

Blood and lymphatic system disorders

Thrombocytopenia¹,^†

# participants affected / at risk

0/33 (0.00%)

2/30 (6.67%)

1/26 (3.85%)

3/30 (10.00%)

0/21 (0.00%)

3/30 (10.00%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

0/33 (0.00%)

0/30 (0.00%)

2/26 (7.69%)

2/30 (6.67%)

1/21 (4.76%)

3/30 (10.00%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

0/26 (0.00%)

1/30 (3.33%)

3/21 (14.29%)

3/30 (10.00%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/33 (0.00%)

11/30 (36.67%)

5/26 (19.23%)

16/30 (53.33%)

7/21 (33.33%)

21/30 (70.00%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

0/33 (0.00%)

5/30 (16.67%)

4/26 (15.38%)

8/30 (26.67%)

7/21 (33.33%)

14/30 (46.67%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/33 (0.00%)

8/30 (26.67%)

1/26 (3.85%)

9/30 (30.00%)

5/21 (23.81%)

12/30 (40.00%)

# events

General disorders and administration site conditions

Fatigue¹,^†

# participants affected / at risk

0/33 (0.00%)

0/30 (0.00%)

3/26 (11.54%)

3/30 (10.00%)

1/21 (4.76%)

4/30 (13.33%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

0/33 (0.00%)

2/30 (6.67%)

2/26 (7.69%)

4/30 (13.33%)

0/21 (0.00%)

4/30 (13.33%)

# events

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

2/26 (7.69%)

3/30 (10.00%)

1/21 (4.76%)

4/30 (13.33%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/33 (3.03%)

1/30 (3.33%)

2/26 (7.69%)

3/30 (10.00%)

0/21 (0.00%)

3/30 (10.00%)

# events

Psychiatric disorders

Insomnia¹,^†

# participants affected / at risk

0/33 (0.00%)

2/30 (6.67%)

1/26 (3.85%)

3/30 (10.00%)

0/21 (0.00%)

3/30 (10.00%)

# events

Blood and lymphatic system disorders

Neutropenia¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

1/26 (3.85%)

2/30 (6.67%)

0/21 (0.00%)

2/30 (6.67%)

# events

Investigations

Blood creatinine increased¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

1/26 (3.85%)

2/30 (6.67%)

0/21 (0.00%)

2/30 (6.67%)

# events

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

0/33 (0.00%)

0/30 (0.00%)

1/26 (3.85%)

1/30 (3.33%)

1/21 (4.76%)

2/30 (6.67%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

1/26 (3.85%)

2/30 (6.67%)

0/21 (0.00%)

2/30 (6.67%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

0/26 (0.00%)

1/30 (3.33%)

1/21 (4.76%)

2/30 (6.67%)

# events

Skin and subcutaneous tissue disorders

Dermatitis contact¹,^†

# participants affected / at risk

0/33 (0.00%)

1/30 (3.33%)

1/26 (3.85%)

2/30 (6.67%)

1/21 (4.76%)

2/30 (6.67%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Investigator shall provide the Sponsor with copies of any materials intended for publication, submission or presentation, at least 30 days in advance. At the request of the Sponsor, the Investigator shall not include in or shall remove from any proposed publication any Confidential Information, errors or inaccuracies; and shall withhold publication or presentation for a period of 90 days to allow the Sponsor to preserve its proprietary rights and/or protect its Confidential Information.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
In Part A, paraxanthine AUC was only reliably characterised in 10 patients in Period 1 and 1 patient in Period 2. Hence, the treatment comparison for AUC is not considered scientifically meaningful.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	+1 877 240 9479
E-mail:	[email protected]

Documents available

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D6014C00006&attachmentIdentifier=06c01c81-32a4-4007-b3f2-29abeec67eb5&fileName=d6014c00006-csp-v3_redacted.pdf&versionIdentifier=
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Lone Ottesen

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site