Phase I/II Study to Evaluate the Safety and Clinical Efficacy of Atezolizumab (aPDL1) in Combination With Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma (GBM)
Overview
- Phase
- Phase 1
- Intervention
- Atezolizumab
- Conditions
- Glioblastoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Dose-limiting toxicities (DLTs) (Phase I)
- Status
- Completed
- Last Updated
- 7 months ago
Overview
Brief Summary
This phase I/II trial studies the side effects and how well atezolizumab works in combination with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. It is not yet known how well atezolizumab works in combination with temozolomide and radiation therapy in treating patients with glioblastoma.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety of atezolizumab in combination with radiation and temozolomide during the concurrent stage and in combination with temozolomide during the adjuvant stage. (Phase I) II. To evaluate the overall survival (OS) of atezolizumab in combination with radiation and temozolomide and in combination with temozolomide at onset of treatment. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the overall response rate (ORR), duration of response, and progression free survival (PFS) of atezolizumab in combination with radiation and temozolomide during the treatment period. CORRELATIVE OBJECTIVES: I. Profiling tumor immune cell populations (example: immunohistochemistry \[IHC\] analyses of CD4, CD8, programmed death-1 \[PD-1\], programmed death-ligand 1 \[PD-L1\], and PD-L2). II. Profiling of tumor deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microRNA and epigenetic profiling (DNA methylation) and evaluation of whole exome sequencing, RNA sequencing, microRNA sequencing and cell-free circulating tumor DNA (ctDNA). III. Peripheral blood collection for evaluation of circulating chemokines/cytokines. OUTLINE: This is a phase I study followed by a phase II study. PHASE I (CONCURRENT PHASE): Patients receive temozolomide orally (PO) daily on days 1-42 and atezolizumab intravenously (IV) over 30-60 minutes on day 1, 15, 29, and 42. Patients undergo radiation therapy (RT) 5 days per week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity. PHASE II (ADJUVANT PHASE): Patients receive temozolomide PO on days 1-5 and atezolizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed informed consent form (ICF).
- •Ability and willingness to comply with the requirements of the study protocol.
- •Have histologically confirmed World Health Organization grade IV glioma (glioblastoma or gliosarcoma). Archival tissue will be required for diagnosis confirmation. Receipt of archival tissue is not required for the start of treatment.
- •Patients must have undergone surgery and must not have had any further treatment following surgery.
- •Have a performance status of \>= 60 on the Karnofsky performance status (KPS).
- •A baseline brain magnetic resonance imaging (MRI) obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids no greater than 4 mg a day of dexamethasone for at least 5 days.
- •Patients must start treatment within 6 weeks of definitive resection.
- •Absolute neutrophil count (ANC) \>= 1,500 /mcL.
- •Platelets \>= 100,000 /mcL.
- •Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L.
Exclusion Criteria
- •Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery. Prior treatment with Gliadel wafers will be excluded. Prior treatment with the Optune device will be excluded.
- •Is currently participating or has participated in any other newly diagnosed therapeutic trial before or after chemoradiation.
- •Any serious medical condition that interferes with adherence to study procedures.
- •Patients may not receive concomitant chemotherapy, hormonal therapy, immunotherapy, or radiotherapy while patients are on study.
- •Malignancies other than the disease under study within 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0).
- •Has known leptomeningeal disease, gliomatosis cerebri, extracranial disease, or multifocal disease. Subject has multifocal glioblastoma (GBM), defined as discrete sites of contrast enhancing disease without contiguous T2/fluid attenuated inversion recovery (FLAIR) abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted.
- •Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
- •Has an active infection requiring systemic therapy.
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Arms & Interventions
Adjuvant phase (temozolomide, atezolizumab)
Patients receive temozolomide PO on days 1-5 and atezolizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Adjuvant phase (temozolomide, atezolizumab)
Patients receive temozolomide PO on days 1-5 and atezolizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Temozolomide
Concurrent phase (temozolomide, atezolizumab, RT)
Patients receive temozolomide PO daily on days 1-42 and atezolizumab IV over 30-60 minutes on day 1, 15, 29, and 42. Patients undergo RT 5 days per week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Concurrent phase (temozolomide, atezolizumab, RT)
Patients receive temozolomide PO daily on days 1-42 and atezolizumab IV over 30-60 minutes on day 1, 15, 29, and 42. Patients undergo RT 5 days per week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Radiation Therapy
Concurrent phase (temozolomide, atezolizumab, RT)
Patients receive temozolomide PO daily on days 1-42 and atezolizumab IV over 30-60 minutes on day 1, 15, 29, and 42. Patients undergo RT 5 days per week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Temozolomide
Outcomes
Primary Outcomes
Dose-limiting toxicities (DLTs) (Phase I)
Time Frame: Up to 10 weeks
Will monitor time to DLT continuously using a Bayesian method that assumes the median time to DLT follows an Inverse gamma distribution and that the individual times to DLT follow an exponential distribution.
Overall survival (OS) (Phase II)
Time Frame: Up to 3 years
Kaplan-Meier curves will be generated for OS and median times and probabilities estimated with 95% confidence intervals.
Incidence of adverse events
Time Frame: Up to 3 years
The overall toxicity rate will be estimated with exact binomial 95% confidence intervals. Adverse Events will be tabulated by grade and by their relationship to the treatment.
Secondary Outcomes
- Overall response rate(Up to 3 years)
- Duration of response (DoR)(Up to 3 years)
- Progression-free survival (PFS)(Up to 3 years)