Pembrolizumab +/- Bevacizumab for Recurrent GBM

NCT02337491 | Completed Phase 2 Results DMC

• 1 other identifier: 14-477
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Glioblastoma

Keywords

Recurrent

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Progression-Free Survival (PFS)

  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)

  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)

  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.

Study Arms (3)

Cohort A Safety Lead-In: Pembrolizumab (DL 0) + Bevacizumab

EXPERIMENTAL

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

Cohort A: Pembrolizumab + Bevacizumab

EXPERIMENTAL

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; Drug: Bevacizumab

Cohort B: Pembrolizumab

EXPERIMENTAL

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

Interventions

Pembrolizumab DRUG

Also known as: MK-3475, SCH 900475

Cohort A Safety Lead-In: Pembrolizumab (DL 0) + Bevacizumab; Cohort A: Pembrolizumab + Bevacizumab; Cohort B: Pembrolizumab

Bevacizumab DRUG

Also known as: Avastin

Cohort A: Pembrolizumab + Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (8)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

University of California, San Francisco

San Francisco, California, 94143-0372, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02113, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan-Kettering Cancer

New York, New York, 10021, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

UT, MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• de Melo SM, Elias Nunes da Silva ME, Torloni MR, Riera R, De Cicco K, Latorraca CO, Pinto ACPN. Anti-PD-1 and anti-PD-L1 antibodies for glioma. Cochrane Database Syst Rev. 2025 Jan 8;1(1):CD012532. doi: 10.1002/14651858.CD012532.pub2.

  PMID: 39777725 DERIVED

MeSH Terms

Conditions

Glioblastoma; Recurrence

Interventions

pembrolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: David A. Reardon, MD
• Organization: Dana-Farber Cancer Institute

dreardon3@partners.org

617-632-2166

Study Officials

• David Reardon, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: There is a safety lead-in before the start of the randomized phase 2 study.

Study Record Dates

• First Submitted: January 9, 2015
• First Posted: January 13, 2015
• Study Start: February 9, 2015
• Primary Completion: August 28, 2016
• Study Completion: September 14, 2020
• Last Updated: December 22, 2020
• Results First Posted: April 9, 2018

Record last verified: 2020-11

Locations

US (8)