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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
University of California, Los Angeles
Los Angeles, California, United States
University of California, San Francisco
San Francisco, California, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
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).
Time frame: 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.
Time frame: 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.
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Boston, Massachusetts, United States
Memorial Sloan-Kettering Cancer
New York, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
UT, MD Anderson Cancer Center
Houston, Texas, United States
Huntsman Cancer Institute
Salt Lake City, Utah, United States
Time frame: 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.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.