Pembrolizumab +/- Bevacizumab for Recurrent GBM

Study Overview
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Brief Summary
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In this research study, the investigators are looking to determine the effectiveness of Pembrolizumab (MK-3475) when given with bevacizumab or when given alone for the treatment of recurrent glioblastoma multiforme (GBM). This study will also test the safety and tolerability of Pembrolizumab (MK-3475) when given alone or with bevacizumab.

Detailed Description
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Pembrolizumab (MK-3475) is a humanized monoclonal antibody. An antibody is a common type of protein made in the body in response to a foreign substance. Antibodies attack foreign substances and protect against infection. Antibodies can also be produced in the laboratory for use in treating patients, an antibody that is made in the lab is also known as a humanized monoclonal antibody. There are now several approved antibodies for the therapy of cancer and other disease. Pembrolizumab (MK-3475) has been studied in lab experiments and in other types of cancer. Information from these studies suggests that Pembrolizumab (MK-3475) may be beneficial in your type of cancer. Bevacizumab, also known as Avastin, is approved by the FDA for treating recurrent GBM. Bevacizumab is an anti-angiogenic medicine, which means it blocks blood vessels from forming that could supply the tumor with nutrients and oxygen. There is a safety lead-in to evaluate pembrolizumab in combination of with bevacizumab (cohort A) expected to enroll up to 18 participants. Three dose levels (DL) are evaluated for pembrolizumab administered at 200 mg (flat dosing) under various dose intervals: every 3 (DL 0), 4 (DL -1) or 6 (DL -2) weeks. A standard 3+3 design is used starting at DL 0. De-escalation may occur depending on observation of dose-limiting toxicity (DLT). At least 6 participants will be evaluated for DLT at DL 0. The Phase II study randomizes participants to cohort A: pembrolizumab (using the MTD determined in the safety lead-in) and bevacizumab or cohort B: pembrolizumab monotherapy (using the MTD determined in the safety lead-in). Accrual goals are established for each cohort: A n=50 and B n=30 participants. The two cohorts are evaluated independently against a historical control and not compared. All participants treated at the safety lead-in established MTD dose level will be rolled into the Phase II cohort.

Official Title
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Phase II Study of Pembrolizumab (MK-3475) With and Without Bevacizumab for Recurrent Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically confirmed World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma). Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made. Previous first line therapy with at least radiotherapy and temozolomide Be at first or second relapse. Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan. CT or MRI within 14 days prior to start of study drug. An interval of at least 4 weeks (to start of study agent) between prior surgical resection or one week for stereotactic biopsy. An interval of at least 12 weeks from the completion of radiation therapy to start of study drug unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field or there is unequivocal histologic confirmation of tumor progression Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide). From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. Exclusion Criteria: Current or planned participation in a study of an investigational agent or using an investigational device. Has a diagnosis of immunodeficiency. Has tumor primarily localized to the brainstem or spinal cord. Has presence of diffuse leptomeningeal disease or extracranial disease. Has received systemic immunosuppressive treatments within 6 months of start of study drug Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of study drug. Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery. Requires therapeutic anticoagulation with warfarin at baseline; patients must be off warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting study drug; however, therapeutic or prophylactic therapy with low-molecular weight heparin is allowed. Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive MRI scans. Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within 6 months of start of study drug. Has a known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. 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. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial Has a known history of HIV Has known active Hepatitis B or Hepatitis C Has received a live vaccine within 30 days prior to the first dose of study drug. Has a known hypersensitivity to any of the study therapy products. Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc) Has a history of non-healing wounds or ulcers, or bone refractures within 3 months of fracture Has a history of arterial thromboembolism within 12 months of start of study drug. Has inadequately controlled hypertension Has a history of hypertensive crisis or hypertensive encephalopathy Has had clinically significant cardiovascular disease within 12 months of start of study drug Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to start of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There is a safety lead-in before the start of the randomized phase 2 study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A Safety Lead-In: Pembrolizumab (DL 0) + Bevacizumab<br>Pembrolizumab (Dose Level 0): 200 mg administered intravenously on days 1 and 22 of each 42 day cycle Bevacizumab: 10 mg/kg administered Intravenously on days 1, 15 and 29 of each 42 day cycle Participants were treated until disease progression or unacceptable toxicity up to 16 cycles. | Drug: Pembrolizumab<br> <br> * Other names: SCH 900475;|
| Experimental: Cohort A: Pembrolizumab + Bevacizumab<br>Pembrolizumab: 200 mg administered intravenously on days 1 and 22 of each 42 day cycle Bevacizumab: 10 mg/kg administered Intravenously on days 1, 15 and 29 of each 42 day cycle Participants were treated until disease progression or unacceptable toxicity up to 16 cycles. | Drug: Pembrolizumab<br> <br> * Other names: SCH 900475;Drug: Bevacizumab<br> <br> * Other names: Avastin;|
| Experimental: Cohort B: Pembrolizumab<br>Pembrolizumab: 200 mg administered intravenously on days 1 and 22 of each 42 day cycle Participants were treated until disease progression or unacceptable toxicity up to 16 cycles. | Drug: Pembrolizumab<br> <br> * Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pembrolizumab Maximum Tolerated Dose (MTD) [Cohort A Safety Lead-In] | The MTD of pembrolizumab in combination with bevacizumab 10 mg/kg intravenously (IV) on days 1, 15 and 29 of each 42 day cycle is determined by the number of participants who experience a dose limiting toxicity (DLT) at the various regimens of dosing frequency of pembrolizumab 200 mg IV administered under evaluation. See subsequent primary outcome measure for the DLT definition. The MTD is defined as the pembrolizumab dose frequency regimen at which fewer than one-third of participants experience a DLT. If de-escalation does not occur per design, then the starting dose is the Recommended Phase II Dose (RP2D). | one cycle/42 days | 
| Pembrolizumab Dose Limiting Toxicity (DLT) [Cohort A Safety Lead-In] | A DLT is defined as an adverse event (AE) that (a) is >= grade 3 and related to the pembrolizumab with an attribution of possible, probably or definite, and (b) occurs during and/or begins during the first 42 days of study treatment, and (c) does not meet any of the following exception criteria: grade 3 immune-related AE that downgrades to <= grade 2 within 5 days, or <= grade 1/baseline within 14 days of onset; grade 3 asymptomatic endocrinopathy; grade 3 inflammatory reaction attribution to anti-tumor response; grade 3 pneumonitis, neurologic event, or uveitis that downgrades to <=grade 1 within 3 days; liver transaminase elevation <= 8 times institutional upper limit of normal (ULN); total bilirubin <= 5 times institutional ULN; any pre-existing lab abnormality that deteriorates to grade 3/4 and determine not clinically significant by Investigator, Overall Principal Investigator and Sponsor. | The evaluation for MTD occurred continuously through one cycle of treatment (42 days). | 
| 6-Month Progression-Free Survival (PFS6) | PFS6 is the proportion of patients remaining alive and progression-free at 6-months from study entry. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria. PD is a >25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition. | Disease was assessed radiographically for response every cycle on treatment. Treatment duration in cycles (cycle=42 days) was a mean (SD) of 4.5 (4.4) for Cohort A and 2.5 (2.7) for Cohort B. Assessment at week 72/cycle 12 pertains to the 6-month PFS. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS based on Kaplan-Meier is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the date of last disease assessment. Per Response Assessment in Neuro-Oncology (RANO) criteria, PD is a >25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition. | Disease was assessed radiographically for response every cycle on treatment and every 6 weeks long-term. Median PFS follow-up (months) was 25 for Cohort A and 26 for Cohort B. | 
| Overall Survival (OS) | OS based on Kaplan-Meier is defined as the time from study entry to death or date last known alive. | Participants were followed long-term for survival every 3 months from the end of treatment until death or lost to follow-up. Median survival follow-up was 25 months for each cohort. | 
| Overall Radiographic Response (ORR) | ORR was established based on Response Assessment in Neuro-Oncology (RANO) criteria. RANO criteria has 5 potential categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive disease (PD) and Unknown. CR: disappearance of all enhancing lesions, stable or improved non-enhancing lesions, and stable or improved clinically. PR: >= 50% decrease in sum of perpendicular diameters of all measurable enhancing lesions, no progression of non-measurable disease, stable or improved non-enhancing lesions, and stable or improved clinically. PD: >25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition. SD: does not qualify for CR, PR or PD. | Disease was assessed radiographically for response every cycle on treatment. Treatment duration in cycles (each cycle=42 days) was a mean (SD) of 4.5 (4.4) for Cohort A and 2.5 (2.7) for Cohort B. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent