Triple Therapy for Brain Cancer
Recruiting in Palo Alto (17 mi)
+10 other locations
Overseen byThomas Kaley, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: CYP3A inhibitors, CYP3A inducers
Disqualifiers: Intracranial hemorrhage, Immunodeficiency, Autoimmune, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This study will test the safety and effectiveness of a combination of pembrolizumab, olaparib, and temozolomide to see how well these drugs work when given together in people with a glioma that either did not respond to previous treatment or came back after treatment.
Will I have to stop taking my current medications?
The trial does not specify if you must stop all current medications, but you cannot use certain strong CYP3A inhibitors or inducers. Additionally, there are specific time requirements since your last cancer treatments before starting the trial.
What evidence supports the effectiveness of the drug combination Olaparib, Pembrolizumab, and Temozolomide for brain cancer?
A study showed that combining Olaparib and Temozolomide was somewhat effective for certain types of brain tumors, like IDH-mutant grade 2-3 gliomas, with some patients showing tumor shrinkage. However, it was not effective for more aggressive tumors like grade 4 astrocytomas or IDH-wildtype gliomas.
12345Is the combination of Olaparib, Pembrolizumab, and Temozolomide generally safe for humans?
The combination of Olaparib and Temozolomide has been studied for brain cancer, and common side effects include fatigue, gastrointestinal issues, and blood-related problems. Some patients needed to reduce their dose or stop treatment due to these side effects. Safety data for Pembrolizumab in combination with these drugs is not provided in the available research.
12367What makes the triple therapy for brain cancer unique?
The triple therapy for brain cancer is unique because it combines olaparib, a drug that targets DNA repair in cancer cells, with pembrolizumab, an immune system booster, and temozolomide, a chemotherapy drug, offering a multi-faceted approach that targets cancer cells in different ways.
89101112Eligibility Criteria
Adults with a glioma brain tumor that's come back or didn't respond to treatment can join. They must be in good physical condition, able to take oral meds, and have no major organ issues. Pregnant women can't participate, and those who can have children must use birth control.Inclusion Criteria
My glioma has returned after surgery and radiation.
A woman of childbearing potential (WOCBP) must not have a positive urine pregnancy test within 72 hours prior to allocation.Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 12 months after the last dose of the study therapy.
You are expected to live for at least 12 more weeks.
+27 more
Exclusion Criteria
I haven't needed treatment for an autoimmune disease in the last 2 years.
I do not have a history of lung inflammation not caused by infection.
I do not have any active cancer except for certain skin cancers or in situ cervical cancer that has been treated.
+14 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Initial Treatment
Participants receive pembrolizumab for two cycles
6 weeks
Combination Treatment
Participants receive combination therapy with olaparib and temozolomide added to pembrolizumab from cycle 3 to cycle 11
27 weeks
Maintenance Treatment
Participants continue on pembrolizumab maintenance for a maximum of 35 cycles or until progression of disease or unacceptable toxicity
up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
up to 2 years
Participant Groups
The trial is testing how safe and effective the combination of pembrolizumab, olaparib, and temozolomide is for treating recurrent gliomas. Participants will receive all three drugs to see if they work better together.
2Treatment groups
Experimental Treatment
Group I: Recurrent enhancing grade II and III IDH-mutated gliomas that have failed previous therapyExperimental Treatment2 Interventions
All patients will receive pembrolizumab for two cycles prior to the addition of olaparib and temozolomide. Combination olaparib and temozolomide will be added in cycle 3. Combination therapy will continue through cycle 11 (cycles 3-11 = 27 weeks or approximately 6 months). Patients will then continue on pembrolizumab maintenance for a maximum of 35 cycles (two years) or until progression of disease or unacceptable toxicity.
Group II: Recurrent IDH-wildtype gliomas and homologous recombination deficiency (HRD).Experimental Treatment2 Interventions
Five patients will receive pembrolizumab for two cycles prior to the addition of olaparib and temozolomide. Combination olaparib and temozolomide will be added in cycle 3. Combination therapy will continue through cycle 11 (cycles 3-11 = 27 weeks or approximately 6 months). Patients will then continue on pembrolizumab maintenance for a maximum of 35 cycles (two years) or until progression of disease or unacceptable toxicity. This cohort will be analyzed descriptively.
Olaparib is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Lynparza for:
- Breast cancer
- Ovarian cancer
- Fallopian tube cancer
- Peritoneal cancer
- Pancreatic cancer
- Prostate cancer
- Endometrial cancer
🇺🇸 Approved in United States as Lynparza for:
- Ovarian, fallopian tube, and primary peritoneal cancer
- Breast cancer
- Prostate cancer
- Pancreatic cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hartford Healthcare Alliance (Data Collection Only)Hartford, CT
Memorial Sloan Kettering Westchester (Limited Protocol Activities)West Harrison, NY
Lehigh Valley Health Network (Data Collection Only)Allentown, PA
BAPTIST ALLIANCE - MCI (Data Collection Only)Miami, FL
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]Label="OBJECTIVES" NlmCategory="OBJECTIVE">To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma METHODS: Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021 RESULTS: Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively.
Temozolomide salvage chemotherapy for recurrent anaplastic oligodendroglioma and oligo-astrocytoma. [2021]To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA).
Future directions for temozolomide therapy. [2019]Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.
Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. [2022]Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy.
Future directions in the treatment of malignant gliomas with temozolomide. [2018]Temozolomide (TMZ) is a new, orally administered, second-generation imidazotetrazine prodrug with essentially 100% oral bioavailability that has demonstrated meaningful efficacy and an acceptable safety profile in the treatment of patients with recurrent glioblastoma multiforme. Because of its unique properties and broad spectrum of anticancer activity, preliminary studies are being conducted to evaluate the efficacy of TMZ in combination with other chemotherapeutic agents, radiation, or immunotherapy. The presence of de novo or acquired resistance to alkylating agents exhibited by malignant gliomas represents a serious impediment in the treatment of these tumors. This review discusses the mechanism of action of TMZ and strategies for overcoming pathways of resistance to this promising agent, including the use of TMZ in combination with other chemotherapeutic agents or radiation therapy, and exploration of alternate dosing schedules. Studies that have evaluated some of these strategies indicate that TMZ is a useful therapeutic option in patients with high-grade gliomas. Alternative approaches, including the use of high-dose TMZ with bone marrow transplantation and in combination with gene therapy, will also be discussed.
Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. [2022]The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.
Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study. [2018]Metastatic melanoma (MM) is associated with a high risk of central nervous system (CNS) metastases, and current chemotherapy does not adequately treat or protect patients with MM against CNS metastases. Therefore, the authors initiated a Phase I study to determine the pharmacokinetics and safety profile of temozolomide (TMZ), a novel oral alkylating agent known to cross the blood-brain barrier, in combination with interferon alpha-2b (IFN-alpha2b).
Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">Despite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)-mutant TNBC.
Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy.
Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial. [2023]Label="INTRODUCTION" NlmCategory="BACKGROUND">Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.
Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer - A single-arm phase II trial (NeoImmunoboost, AGO-B-041). [2023]Pembrolizumab is approved for the neoadjuvant/adjuvant treatment of early triple-negative breast cancer (TNBC) patients in combination with chemotherapy. The Keynote-522 trial used platinum chemotherapy. As neoadjuvant nab-paclitaxel (nP) is also highly effective in triple-negative breast cancer patients, this study investigates the response to nP-containing neoadjuvant chemotherapy in combination with pembrolizumab.
A Phase II study of olaparib in breast cancer patients: biological evaluation from a 'window of opportunity' trial. [2017]The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, 'window of opportunity' Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib. The OLTRE trial is expected to identify the surrogate markers of the biological activity of olaparib in the treatment of patients with triple-negative breast cancer.