Triple Therapy for Brain Cancer

Recruiting at 10 trial locations

Overseen By Lauren Schaff, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Intracranial hemorrhage, Immunodeficiency, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

57 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 6 7}

What 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. ^{8 9 10 11 12}

Research Team

Lauren Schaff, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility 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.

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.

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

Treatment Details

Interventions

• Olaparib
• Pembrolizumab
• Temozolomide

Trial Overview 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.

Participant Groups

Group I: Recurrent enhancing grade II and III IDH-mutated gliomas that have failed previous therapy Experimental Treatment 2 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 Treatment 2 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

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a study of 20 patients with various types of glioma, the combination of olaparib and temozolomide (TMZ) showed a 50% objective radiographic response rate in patients with recurrent IDH-mutant grade 2-3 gliomas, indicating potential efficacy for this specific group.

While the treatment was generally manageable, common side effects included fatigue and gastrointestinal issues, with 30% of patients requiring dose adjustments due to toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. Schaff, LR., Kushnirsky, M., Lin, AL., et al.[2023]

Temozolomide (TMZ) chemotherapy shows a 24% objective response rate in patients with recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), with a median progression-free survival of 8.0 months based on a study of 72 patients.

TMZ is recommended as a salvage therapy for recurrent AO/AOA, particularly for patients previously treated with other chemotherapy, as it has an acceptable toxicity profile with severe side effects occurring in only 13% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide salvage chemotherapy for recurrent anaplastic oligodendroglioma and oligo-astrocytoma. Gwak, HS., Yee, GT., Park, CK., et al.[2021]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

In a phase II trial involving 38 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a high response rate, with 52.6% of patients showing a complete or partial response, indicating its efficacy as a first-line chemotherapy.

TMZ was generally well tolerated, with hematologic side effects being the most common, and only one patient discontinuing treatment due to toxicity, suggesting a favorable safety profile for chemotherapy-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. van den Bent, MJ., Taphoorn, MJ., Brandes, AA., et al.[2022]

Temozolomide (TMZ) is an effective oral treatment for recurrent glioblastoma multiforme, showing nearly 100% bioavailability and a favorable safety profile, making it a promising option for patients with this aggressive brain cancer.

Research is ongoing to enhance the efficacy of TMZ by combining it with other treatments like chemotherapy, radiation, and immunotherapy, as well as exploring alternative dosing strategies to overcome resistance in gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of malignant gliomas with temozolomide. Prados, MD.[2018]

Olaparib effectively penetrated recurrent glioblastoma tumors in patients, with measurable concentrations found in all tumor core and margin specimens, indicating its potential for therapeutic use.

The combination of olaparib with low-dose temozolomide (TMZ) was associated with increased hematological toxicity, leading to the need for intermittent dosing, but showed promising efficacy with 36% of patients remaining progression-free at 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Hanna, C., Kurian, KM., Williams, K., et al.[2022]

In a Phase I study involving 23 patients with metastatic melanoma, the combination of temozolomide (TMZ) and interferon alpha-2b (IFN-alpha2b) was found to be safe, with most adverse events being mild to moderate, and the primary dose-limiting toxicity being thrombocytopenia.

The treatment showed clinical activity, with 17% of patients achieving objective responses and a median survival of 9 months, suggesting that this regimen could be effective and warrants further research, especially regarding its impact on brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study. Agarwala, SS., Kirkwood, JM.[2018]

Niraparib, a PARP inhibitor, significantly increased median survival and reduced tumor burden in a specific BRCA-mutant TNBC mouse model (MDA-MB-436), demonstrating its potential efficacy against brain metastases of triple-negative breast cancer.

The study found that combining RAD51 inhibition with PARP inhibition could enhance the sensitivity of various TNBC cell lines to treatment, suggesting a promising strategy for improving therapeutic outcomes in this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models. Sambade, MJ., Van Swearingen, AED., McClure, MB., et al.[2022]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

In a trial involving 35 patients with triple negative breast cancer (TNBC), olaparib showed promising early responses, with 16 patients achieving partial clinical responses and 15 showing radiometabolic responses after just 3 weeks of treatment, including significant responses in 40.7% of gBRCA-wild-type patients.

The study suggests that olaparib may be effective in early-stage TNBC regardless of gBRCA mutation status, highlighting the need for future trials to explore biomarkers like tumor-infiltrating lymphocytes (TILs) and PD-L1 to better identify patients who could benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial. Schettini, F., Corona, SP., Giudici, F., et al.[2023]

In a phase II trial involving 50 patients with early triple-negative breast cancer, 66% achieved a pathological complete response (pCR) after treatment with nab-paclitaxel and pembrolizumab, indicating a promising efficacy of this combination therapy.

The treatment was associated with manageable side effects, with fatigue, peripheral sensory neuropathy, and neutropenia being the most common adverse events, suggesting that this regimen could be a viable alternative to platinum-based chemotherapy for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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). Fasching, PA., Hein, A., Kolberg, HC., et al.[2023]

The OLTRE trial is a Phase II study evaluating the effectiveness of olaparib in treating locally advanced triple-negative breast cancer, focusing on identifying predictive markers of response based on gene and protein expression profiles.

This trial aims to establish surrogate markers that could indicate how well olaparib works in patients with triple-negative breast cancer compared to other breast cancer subtypes with BRCA mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II study of olaparib in breast cancer patients: biological evaluation from a 'window of opportunity' trial. Roviello, G., Milani, M., Gobbi, A., et al.[2017]

References

1. United States pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Temozolomide salvage chemotherapy for recurrent anaplastic oligodendroglioma and oligo-astrocytoma. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

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]

5. United States pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of malignant gliomas with temozolomide. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial. [2023]

11. England pubmed.ncbi.nlm.nih.gov

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]

12. England pubmed.ncbi.nlm.nih.gov

A Phase II study of olaparib in breast cancer patients: biological evaluation from a 'window of opportunity' trial. [2017]