A study to assess the safety and tolerability of AZD1390 given with radiation therapy in patients with brain cancer.

Study identifier:D6940C00002

ClinicalTrials.gov identifier:NCT03423628

EudraCT identifier:2017-002451-28

CTIS identifier:N/A

Recruiting

Official Title

A Phase I, Multicentre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending Doses of AZD1390 in Combination with Radiation Therapy in Patients with Glioblastoma Multiforme and Brain Metastases from Solid Tumors.

Medical condition

Recurrent Glioblastoma Multiforme

Phase

Phase 1

Healthy volunteers

Study drug

AZD1390

Sex

All

Estimated Enrollment

180

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 02 Apr 2018

Estimated Primary Completion Date: 16 Sept 2026

Estimated Study Completion Date: 16 Sept 2026

Study design

Allocation: N/A
Endpoint Classification: -
Intervention Model: Single Group Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Oct 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

• Provision of formalin-fixed paraffin embedded tissue sample from primary or metastatic disease
• Karnofsky Performance Score of ≥60.
• Additional Inclusion Criteria Specific for Arm A and Japan:
o Histologically proven diagnosis of GBM. Patients who have had RT for low-grade glioma (LGG) or grade 3 glioma and have subsequently relapsed to histologically confirmed GBM can be considered
o A radiological diagnosis of recurrent/relapsed or progressive disease according to RANO criteria.
o Completion of first-line radiation at least 6 months prior to Cycle 1 Day 1.
o Patients with tumor-induced seizures must be well controlled on a stable anti-epileptic treatment
o Willing to receive anti-epileptic prophylaxis for the duration of study drug administration.
• Additional Inclusion Criteria Specific for Arm B:
**Arm B has now closed to recruitment**
o Histologically proven diagnosis of solid tumor malignancy and Magnetic Resonance (MR) imaging documenting brain lesions.
o Not eligible for Stereotactic Radiosurgery (SRS) treatment of brain tumor.
o Patient has not received any previous brain RT to the area that is to be irradiated. Prior PBRT may be allowed if there is not significant overlap between the prior and new radiation fields.
o Non-CNS malignant disease must be sufficiently controlled so that patients can be without additional systemic therapy for the required washout period before starting therapy until 5 days after the end of RT. Required washout period before starting the first dose of AZD1390 (Cycle 1) is 28 days for immune checkpoint inhibitors and 7 days for all other agents
o Not received radiation to the lung fields within the past 8 weeks.
o No history of seizures related to the brain metastases or LMD.
o Receiving PBRT (rather than WBRT) during Cycle 1 as standard of care for brain metastases
• Additional Inclusion Criteria Specific for Arm C:
o Histologically proven primary diagnosis of GBM with unmethylated O6-methylguanine-DNA methyltransferase (MGMT). Grade 4 astrocytoma or histology with molecular features of GBM can be considered.
o Determination of MGMT promoter status by methylation-specific polymerase chain reaction (PCR) or pyrosequencing per local institutional guidelines is required to assess eligibility for this Arm.
o Patients will have to undergo mutational testing for Isocitrate dehydrogenase 1 (IDH1) on a tumor specimen before entering study. Patients are eligible for Arm C regardless of their IDH1 mutational status.
o No history of uncontrolled seizures after surgery for primary GBM (despite adequate antiepileptic therapy) or with need for concurrent administration of more than 2 antiepileptic drugs.
o Willing to receive anti-epileptic prophylaxis for the duration of study drug administration
Additional Inclusion criteria for Food Effect Assessment (Arm A) (Not applicable for Japan part):
• For the fed assessment portion: fast overnight (for at least 10 hours) prior to consuming a high-fat meal consisting of approximately 800 to 1000 calories, with around 54% of the calories coming from fat.
• For the fasted assessment portion: fast overnight (for at least 10 hours prior to dosing) and until 4 hours after dosing.
*Note: the optional food effect assessment is currently not open to enrolment*

Exclusion Criteria

• Administration of chemotherapy or any investigational drug in the 28 days or carmustine (CCNU) or lomustine (BCNU) in the 6 weeks prior to receiving the first dose of treatment in Arms A and C. Administration of checkpoint inhibitors within 28 days prior to first dose of treatment and any other agent within 7 days of beginning study treatment in Arm B. Hormonal therapies are allowed during study treatment for patients in Arm B.
• History of severe brain-injury or stroke.
• Patient not eligible for sequential MRI evaluations are not eligible for this study.
• History of epileptic disorder or any seizure history unrelated to tumor
• Treatment with Strong inhibitors or inducers of CYP3A4 within 2 weeks prior to receiving study drug
• Concurrent therapy with other seizurogenic medications.
• Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD).
• Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past year. If prior therapy in lifetime, then excluded if history of pulmonary toxicities from administration. Patients who have received treatment with nitrosoureas (e.g., carmustine, lomustine) in the year before study entry without experiencing lung toxicity are allowed on study.
• History or presence of myopathy or raised creatine kinase (CK) >5 x upper limit of normal (ULN) on 2 occasions at screening.
• Cardiac dysfunction defined as: Myocardial infarction within six months of study entry, NYHA (New York Heart Association) Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias
• Evidence of severe pulmonary infections, as judged by the investigator (For Japan part only this includes active infection including tuberculosis, chronic active or uncontrolled Hep B or Hep C)
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.03) Grade 1 at the time of starting study treatment and patients with chronic Grade 2 unresolved toxicities may be eligible
Additional exclusion criteria for Arm A and Japan Part
• Has previously received ATM inhibitor with concurrent RT
Additional Exclusion criteria for Food Effect Assessment (Arm A) (Not applicable for the Japan Part):
• Diabetes Type I, Type II, or steroid-induced diabetes.
• Undergoing systemic steroid treatment
*Note: the optional food effect assessment is currently not open to enrolment*

Sort by status

No locations available

Arms	Assigned Interventions
Experimental: AZD1390 + Radiation Therapy AZD1390 + Radiation Therapy	Radiation: Radiation Therapy Arm A: 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks) Arm B: 30 Gy of whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT) administered at daily fractions of 3 Gy over 10 fractions (2 weeks). Arm B has now closed to recruitment Arm C: 60 Gy of intensity-modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks) Other Name: Radiotherapy Other Name: Radiation treatment Other Name: RT Drug: AZD1390 AZD1390 Administered in 3 Cycles depending on arm: Cycle 0 (arms A and C): 1 dose prior to Radiation Therapy. For optional food effect assessment in Arm A, 2 doses prior to RT under both fed and fasted conditions. Note: the optional food effect assessment is currently not open to recruitment. Cycle 1 (all arms): Intermittent or continuous dosing during Radiation Therapy (except for first 2 cohorts of Arm A). Cycle 2 (arms A and C): 2 weeks adjuvant treatment after Radiation Therapy. Other Name: ATM inhibitor

Arms

Assigned Interventions

Experimental: AZD1390 + Radiation Therapy
AZD1390 + Radiation Therapy

Radiation: Radiation Therapy
Arm A: 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks) Arm B: 30 Gy of whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT) administered at daily fractions of 3 Gy over 10 fractions (2 weeks). **Arm B has now closed to recruitment** Arm C: 60 Gy of intensity-modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)

Other Name: Radiotherapy

Other Name: Radiation treatment

Other Name: RT

Drug: AZD1390
AZD1390 Administered in 3 Cycles depending on arm: Cycle 0 (arms A and C): 1 dose prior to Radiation Therapy. For optional food effect assessment in Arm A, 2 doses prior to RT under both fed and fasted conditions. *Note: the optional food effect assessment is currently not open to recruitment*. Cycle 1 (all arms): Intermittent or continuous dosing during Radiation Therapy (except for first 2 cohorts of Arm A). Cycle 2 (arms A and C): 2 weeks adjuvant treatment after Radiation Therapy.

Other Name: ATM inhibitor

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Investigators

Principal Investigator

Patrick Wen

Dana-Farber Cancer Institute