A Surgical "Window-of-Opportunity" and Phase II Trial of Pembrolizumab, Olaparib and Temozolomide in Recurrent Glioblastoma
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Glioblastoma
- Sponsor
- L. Nicolas Gonzalez Castro, MD, PhD
- Enrollment
- 78
- Locations
- 8
- Primary Endpoint
- Tumor infiltrating lymphocytes (TIL) Density
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief Summary
This research study is studying a combination therapy as a possible treatment for recurrent glioblastoma (GBM), a brain tumor that is growing or progressing despite earlier treatment.
The names of the study interventions involved in this study are/is:
- Pembrolizumab
- Olaparib
- Temozolomide (Temodar)
Detailed Description
This is an open label, multi-center, phase II trial evaluating the safety and efficacy of olaparib, temozolomide and pembrolizumab in participants with recurrent glioblastoma at their first or second relapse. The U.S. Food and Drug Administration (FDA) has not approved pembrolizumab or olaparib for recurrent glioblastoma, but both have been approved for other uses. Pembrolizumab is an antibody designed to block the action of the receptor, PD-1. PD-1 works to help tumor cells inhibit the immune system's response against a tumor. Olaparib is an inhibitor of PARP (poly \[adenosine diphosphate-ribose\] polymerase) an enzyme found in the cells of the human body that helps cells, including cancer cells, survive and grow by repairing DNA damage in the cells. Olaparib helps kill cancer cells by preventing PARP from repairing their DNA. The U.S. FDA has approved temozolomide as a treatment option for glioblastoma. Temozolomide is a chemotherapy drug that can enter the brain and prevent tumor cells from growing by causing DNA damage. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. It is expected that all participants will receive pembrolizumab for up to 2 years or as long as they do not have serious side effects and their disease does not get worse. It is expected that Cohort 1 and Cohort 2 Arm A participants will receive Olaparib and temozolomide for as long as they do not have serious side effects and their disease does not get worse. It is expected that about 66-78 people will take part in this research study. Merck Sharp \& Dohme Corp., a subsidiary of Merck \& Co., Inc., is supporting this research study by providing funding for the research study and both investigational study drugs, pembrolizumab and olaparib.
Investigators
L. Nicolas Gonzalez Castro, MD, PhD
Sponsor-Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants must be able to understand and willing to sign a written informed consent document.
- •Participants must be able to adhere to the dosing and visit schedules and agree to record medication times accurately and consistently in a daily diary.
- •Participants must be at least 18 years old on day of signing informed consent.
- •Women of childbearing potential are eligible to participate if they are not pregnant or breastfeeding.
- •Participants must have a Karnofsky Performance Status (KPS) ≥ 70 and Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 (see Appendix A).
- •Participants must be able to swallow oral medications. Nature of illness and treatment history
- •Participants must have histologically World Health Organization Grade IV IDH wildtype glioblastoma by IDHR132H immunohistochemistry or variants including gliosarcoma or IDH wildtype diffuse glioma with molecularly features of glioblastoma (EGFR amplification, TERT promoter mutation, or concurrent gain of Chromosome 7 and loss of Chromosome 10) (Brat et al., 2018). IDH mutational status can be established via immunohistochemistry and/or next-generation sequencing.
- •Participants must be at first or second relapse of GBM. First relapse is defined as progression following initial therapy and second relapse is progression following second therapy. The intent therefore is that patients had no more than 2 prior therapies (i.e. radiation +/- chemotherapy if that was used as initial therapy and one additional therapy for first recurrence). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute 1 relapse.
- •Participants must have shown unequivocal evidence for tumor progression by MRI scan per modified RANO criteria (Ellingson et al., 2017).
- •MRI should be obtained within 14 days prior to study registration.
Exclusion Criteria
- •4 weeks or 5 half-lives (whichever is shorter) from any investigational agent;
- •4 weeks from cytotoxic therapy (except 23 days for temozolomide; 6 weeks from nitrosoureas);
- •4 weeks or 5 half-lives (whichever is shorter) from antibodies;
- •4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies.
- •No washout required for tumor treating fields.
- •Clinical labs - Participants should have adequate organ function, in accordance to the studies outlined below. All screening laboratory tests should be performed within 10 days prior to the first dose of the study intervention.
- •Hematology:
- •Leukocytes ≥ 3,000/µL
- •Absolute neutrophil count (ANC) ≥ 1,500/µL
- •Platelet count ≥ 100,000/µL
Arms & Interventions
Cohort 1 (Safety Lead In): pembrolizumab plus olaparib and temozolomide
Following a 3 + 3 dose escalation design 6-18 participants will receive: * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Pembrolizumab
Cohort 1 (Safety Lead In): pembrolizumab plus olaparib and temozolomide
Following a 3 + 3 dose escalation design 6-18 participants will receive: * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Olaparib
Cohort 1 (Safety Lead In): pembrolizumab plus olaparib and temozolomide
Following a 3 + 3 dose escalation design 6-18 participants will receive: * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Temozolomide
Cohort 2 (Surgical Cohort): Arm A - Pembrolizumab plus olaparib and temozolomide
Cohort 2 participants will be randomized into either group a or b (1:1): Group A participants will receive pembrolizumab, olaparib, and temozolomide before and after surgery. * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Pembrolizumab
Cohort 2 (Surgical Cohort): Arm A - Pembrolizumab plus olaparib and temozolomide
Cohort 2 participants will be randomized into either group a or b (1:1): Group A participants will receive pembrolizumab, olaparib, and temozolomide before and after surgery. * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Olaparib
Cohort 2 (Surgical Cohort): Arm A - Pembrolizumab plus olaparib and temozolomide
Cohort 2 participants will be randomized into either group a or b (1:1): Group A participants will receive pembrolizumab, olaparib, and temozolomide before and after surgery. * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Temozolomide
Cohort 2 (Surgical Cohort): Arm B - Pembrolizumab monotherapy
Cohort 2 participants will be randomized into either group a or b (1:1): Group B participants will receive pembrolizumab monotherapy before and after surgery. * Pembrolizumab Before Surgery: Day 1 of the pre-surgical treatment cycle. * Pembrolizumab After Surgery: Day 1 of every other 21-day cycle (once every 6 weeks).
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Tumor infiltrating lymphocytes (TIL) Density
Time Frame: At surgery. Surgery will occur 14 days +/- 5 days after initiation of treatment.
TIL density quantifies anti-tumor immune response. It is measured in tumor tissue from protocol surgery, analyzed by immunohistochemistry and by next generation sequencing.
6-month Progression-Free Survival (PFS6)
Time Frame: 6 months after surgery. Surgery will occur 14 days +/- 5 days after initiation of treatment.
Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. PD defined by modified RANO as well as iRANO criteria, per protocol section 12.
Secondary Outcomes
- Grade 3 or Higher Treatment-Related Toxicity Rate(24 months)
- Objective Response Rate (ORR)(24 months)
- Gene expression profiling (GEP) score(At surgery. Surgery will occur 14 days +/- 5 days after initiation of treatment.)
- Median Overall Survival (OS)(24 months)