Pembro + Olaparib with TMZ for Recurrent Glioblastoma

Recruiting at 3 trial locations

Overseen By Luis N Gonzalez Castro, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Patrick Wen, MD

Must not be taking: PARP inhibitors, Anti-VEGF agents

Disqualifiers: IDH mutation, Brainstem tumor, 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: 3

Duration: Up to 24 months

78 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications before starting the study. Specifically, you must stop using enzyme-inducing anti-epileptic drugs, strong inhibitors or inducers of CYP3A, certain herbal medications, and coumadin-derivative anticoagulants at least 7 to 14 days before the study. High-dose systemic corticosteroids and systemic immunosuppressive treatments must also be stopped within specified timeframes.

What data supports the effectiveness of the drug combination of Pembro, Olaparib, and Temozolomide for recurrent glioblastoma?

Research shows that Temozolomide (TMZ) is effective in treating glioblastoma and other brain tumors, with some studies indicating prolonged survival when used before radiotherapy. Additionally, Olaparib combined with TMZ has shown some effectiveness in certain types of gliomas, although responses in more aggressive forms like grade 4 astrocytomas were not observed. ^{1 2 3 4 5}

Is the combination of Pembro, Olaparib, and TMZ generally safe for humans?

The combination of Olaparib and Temozolomide (TMZ) has shown common side effects like fatigue, gastrointestinal issues, and blood-related toxicity. In some cases, patients needed to reduce the dose or stop treatment due to these side effects. ^{1 4 6 7 8}

How is the drug combination of Pembro, Olaparib, and TMZ unique for treating recurrent glioblastoma?

This drug combination is unique because it combines Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with Olaparib, a PARP inhibitor that prevents cancer cells from repairing their DNA, and Temozolomide, a chemotherapy drug that can cross the blood-brain barrier. This multi-faceted approach aims to enhance treatment effectiveness by targeting the cancer through different mechanisms. ^{1 2 3 9 10}

What is the purpose of this trial?

This trial is testing a combination of three drugs to treat brain tumors that have come back after previous treatments. The drugs help the immune system attack the tumor, stop the tumor cells from repairing themselves, and prevent them from growing. About 66-78 people will participate in this study.

Research Team

Luis N Gonzalez Castro, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with recurrent glioblastoma, a type of brain tumor. They must be in good physical condition (KPS ≥ 70), not pregnant or breastfeeding, able to swallow pills, and have adequate organ function. Patients should be at their first or second relapse and haven't had certain prior treatments like anti-PD-1 or PARP inhibitors.

Inclusion Criteria

I have enough tissue from a previous surgery for glioblastoma available for study.

It has been enough time since my last cancer treatment to start a new one.

I am among the first 10 in Arm A and have both types of tumor tissue for removal.

Exclusion Criteria

I had major surgery less than 4 weeks ago or am still dealing with its side effects.

I have a history of lung inflammation not caused by an infection.

I have had viral therapy or vaccines for my brain tumor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab, olaparib, and temozolomide before and after surgery. Pembrolizumab is administered on Day 1 of every other 21-day cycle, olaparib and temozolomide are administered on Days 1-7 of each 21-day cycle.

Up to 24 months

Every 3 weeks (in-person)

Surgery

Surgery to obtain tumor tissue for analysis, occurring 14 days +/- 5 days after initiation of treatment.

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of tumor infiltrating lymphocytes and gene expression profiling.

24 months

Treatment Details

Interventions

• Olaparib
• Pembrolizumab
• Surgical Treatment
• Temozolomide

Trial Overview The study tests a combination therapy using Pembrolizumab, Olaparib, and Temozolomide as potential treatments for recurrent glioblastoma. It aims to see if this mix can stop the tumor from growing after previous treatment has failed.

Participant Groups

Group I: Cohort 2 (Surgical Cohort): Arm B - Pembrolizumab monotherapy Experimental Treatment 1 Intervention

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).

Group II: Cohort 2 (Surgical Cohort): Arm A - Pembrolizumab plus olaparib and temozolomide Experimental Treatment 3 Interventions

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).

Group III: Cohort 1 (Safety Lead In): pembrolizumab plus olaparib and temozolomide Experimental Treatment 3 Interventions

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).

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?

Patrick Wen, MD

Lead Sponsor

Trials

3

Recruited

600+

L. Nicolas Gonzalez Castro, MD, PhD

Lead Sponsor

Trials

1

Recruited

80+

Patrick Y. Wen, MD

Lead Sponsor

Trials

10

Recruited

990+

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]

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

In a study of 151 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma, temozolomide (TMZ) demonstrated significantly better progression-free survival (78.87%) compared to semustine (Me-CCNU) (55.88%), indicating its superior efficacy.

TMZ also had a lower rate of adverse events (29.11%) compared to Me-CCNU (45.15%), suggesting that TMZ is not only more effective but also has a better safety profile for treating these types of brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Multicenter randomized controlled study of temozolomide versus semustine in the treatment of recurrent malignant glioma]. Sun, J., Yang, XJ., Yang, SY.[2018]

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]

In a study of 80 patients with recurrent glioma who were rechallenged with temozolomide (TMZ), the progression-free survival at 6 months was 48% for anaplastic glioma (AG) patients and 27.7% for glioblastoma (GBM) patients, indicating that rechallenging can be effective.

TMZ was generally well tolerated, with only 22 out of 90 rechallenges showing significant hematological toxicity, suggesting that this treatment strategy is safe and merits further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rechallenge with temozolomide in patients with recurrent gliomas. Wick, A., Pascher, C., Wick, W., et al.[2022]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

In a phase 2 trial involving 50 patients with newly diagnosed glioblastoma, the neoadjuvant use of temozolomide (TMZ) followed by hypofractionated accelerated radiation therapy (HART) showed promising long-term survival outcomes, with a median overall survival of 22.3 months.

The treatment was generally well-tolerated, with acceptable toxicity levels, although some patients experienced serious side effects like grade 5 pancytopenia and grade 4 hepatotoxicity, indicating that while the regimen is promising, careful monitoring is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma. Shenouda, G., Souhami, L., Petrecca, K., et al.[2022]

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]

The study of 100 glioma patients (50 with anaplastic astrocytoma and 50 with glioblastoma multiforme) found that the 1236C>T polymorphism in the MDR1 gene significantly affects plasma levels of temozolomide (TMZ), an important drug for treating malignant glioma.

Patients with the TT genotype had poorer survival outcomes compared to those with CT or CC genotypes, indicating that genotyping the MDR1 polymorphism could help predict the effectiveness of TMZ therapy in glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population. Munisamy, M., Munisamy, S., Kumar, JP., et al.[2023]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. [2018]

3. China pubmed.ncbi.nlm.nih.gov

[Multicenter randomized controlled study of temozolomide versus semustine in the treatment of recurrent malignant glioma]. [2018]

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. Germany pubmed.ncbi.nlm.nih.gov

Rechallenge with temozolomide in patients with recurrent gliomas. [2022]

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

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. [2023]

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

A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma. [2022]

8. 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]

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

Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]