A Phase I, Multicenter 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
Overview
- Phase
- Phase 1
- Intervention
- Radiation Therapy
- Conditions
- Recurrent Glioblastoma Multiforme
- Sponsor
- AstraZeneca
- Enrollment
- 180
- Locations
- 1
- Primary Endpoint
- Incidence of dose-limiting toxicities (DLTs)
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This study will test an investigational drug called AZD1390 in combination with radiation therapy for the treatment of brain tumors. This is the first time AZD1390 is being given to patients. This study will test safety, tolerability and PK (how the drug is absorbed, distributed and eliminated) of ascending doses of AZD1390 in combination with distinct regimens of radiation therapy
Detailed Description
This first time-in patients (FTIP), open-label, multicentre study of AZD1390 will be conducted in the United States, the United Kingdom and Japan. It consists of three treatment arms: Arm A, B, C. The Japan dose confirmation part (Japan part) is a sub-study of Arm A. Sites from Japan will only participate in the Japan part. This Phase 1 study will assess safety and tolerability of AZD1390 in combination with radiation therapy (RT) in brain malignancies. The combination cohorts have been designed to assess escalating cumulative doses of AZD1390 in settings with 3 different radiation treatment regimens: * Arm A: 35 Gy over 2 weeks with intensity-modulated radiation therapy (IMRT) in patients with recurrent Glioblastoma Multiforme (GBM). Arm A will also include the food effect cohort * Arms B: 30 Gy over two weeks with whole brain radiation therapy (WBRT)/ partial brain radiation therapy (PBRT) in patients with brain metastases. \*\*Arm B has now closed to recruitment\*\* * Arm C: 60 Gy over 6 weeks (IMRT) in patients with primary GBM Each arm provides standard of care RT for the disease setting indicated with the experimental agent being administered in dose escalating cohorts.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of formalin-fixed paraffin embedded tissue sample from primary or metastatic disease
- •Karnofsky Performance Score of ≥
- •Additional Inclusion Criteria Specific for Arm A and Japan:
- •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
- •A radiological diagnosis of recurrent/relapsed or progressive disease according to RANO criteria.
- •Completion of first-line radiation at least 6 months prior to Cycle 1 Day
- •Patients with tumor-induced seizures must be well controlled on a stable anti-epileptic treatment
- •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\*\*
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.
Arms & Interventions
Arm A: AZD1390 + Radiation Therapy
AZD1390 administration plus 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks)
Intervention: Radiation Therapy
Arm A: AZD1390 + Radiation Therapy
AZD1390 administration plus 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks)
Intervention: AZD1390
Arm B: AZD1390 + Radiation Therapy
AZD1390 administration plus 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).
Intervention: Radiation Therapy
Arm B: AZD1390 + Radiation Therapy
AZD1390 administration plus 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).
Intervention: AZD1390
Arm C: AZD1390 + Radiation Therapy
AZD1390 administration plus 60 Gy of intensity- modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)
Intervention: Radiation Therapy
Arm C: AZD1390 + Radiation Therapy
AZD1390 administration plus 60 Gy of intensity- modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)
Intervention: AZD1390
Outcomes
Primary Outcomes
Incidence of dose-limiting toxicities (DLTs)
Time Frame: From the start of treatment until the end of the DLT period (approximately 6 weeks for Arm A, 3 weeks for Arm B and 10 weeks for Arm C)
DLTs will be used to calculate the maximum tolerated dose (MTD). In each arm, the MTD of AZD1390 is the highest dose at which the predicted probability of a DLT is less than 25% in that specific RT setting
Incidence of adverse events (AEs) and serious adverse events (SAEs)
Time Frame: From the start of treatment until the end of the study (approximately 9 months after the last patient has started treatment)
For each adverse event CTCAE grade and causality (related to AZD1390 or radiotherapy) will be collected.
Secondary Outcomes
- Event free survival (EFS) for Arms A and C only(From the start of treatment until the patient is off study (approximately 9 months after the last patient has started treatment))
- Objective response rate defined by RANO criteria for Arms A and C only(Every 8 weeks starting from 4 weeks after RT until the end of the study (approximately 9 months after the last patient has started treatment))
- Objective response rate defined by RANO-BM criteria for Arm B only. **Arm B has now closed to recruitment**(From screening until the patient is off study, approximately 8 weeks)
- Objective response rate defined by RECIST 1.1 criteria for Arm B only. **Arm B has now closed to recruitment**(From screening until the patient is off study, approximately 8 weeks)
- Maximum Observed Plasma Concentration (Cmax) of AZD1390(At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C))
- Time to observed Cmax (Tmax) for AZD1390(At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C))
- Area under the plasma concentration-time curve (AUC) for AZD1390(At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C))
- Overall survival for Arms A and C only(From start of treatment until the patient dies, withdraws or the end of study is reached (approximately 9 months after the last patient has started treatment))
- Assessment of the food effect of AZD1390 at the MTD for Arm A (if conducted)(At two predefined intervals during cycle 0 (at least 5 days apart))