Chemotherapy + Pembrolizumab/Olaparib for Ovarian Cancer

Recruiting at 226 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: BRCA mutation, Pneumonitis, Autoimmune disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 15 weeks for initial cycles, up to 105 weeks for pembrolizumab cycles

1367 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the efficacy and safety of treatment with carboplatin/paclitaxel\* PLUS pembrolizumab (MK-3475) and maintenance olaparib (MK-7339) in women with epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal cancer. The primary study hypotheses are that the combination of pembrolizumab plus carboplatin/paclitaxel\* followed by continued pembrolizumab and maintenance olaparib is superior to carboplatin/paclitaxel alone with respect to Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in participants with programmed death-ligand 1 (PD-L1)-positive tumors (Combined Positive Score \[CPS\]≥10) and in all participants, and that the combination of pembrolizumab plus carboplatin/paclitaxel followed by continued pembrolizumab is superior to carboplatin/paclitaxel alone with respect to PFS per RECIST 1.1 in participants with PD-L1-positive tumors (CPS≥10) and in all participants.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking certain strong or moderate inhibitors or inducers of CYP3A4 that cannot be stopped for the study duration.

What data supports the effectiveness of the drug combination of chemotherapy, pembrolizumab, and olaparib for ovarian cancer?

Research shows that combining olaparib with chemotherapy drugs like carboplatin and paclitaxel can help control ovarian cancer. In some studies, this combination has shown clinical benefits, such as partial responses and stable disease in patients who have been heavily treated before. ^{1 2 3 4 5}

Is the combination of chemotherapy, pembrolizumab, and olaparib generally safe for humans?

Olaparib, when used in combination with chemotherapy drugs like carboplatin and paclitaxel, has been shown to be generally safe in humans, with common side effects including fatigue, nausea, and vomiting, which are usually mild and temporary. In studies, some patients experienced more severe side effects, but these were less common, and the treatment was generally well-tolerated. ^{1 6 7 8 9}

What makes the chemotherapy plus pembrolizumab/olaparib treatment for ovarian cancer unique?

This treatment combines chemotherapy with pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, and olaparib, a drug that targets cancer cells with specific genetic defects. This combination aims to enhance the effectiveness of treatment by using different mechanisms to control the disease. ^{1 3 10 11 12}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. They should be candidates for specific chemotherapy, have adequate organ function, and not be pregnant or breastfeeding. Women must use effective contraception and provide a biopsy before randomization.

Inclusion Criteria

I am not pregnant or breastfeeding and follow the required contraceptive guidelines.

My cancer is advanced ovarian, peritoneal, or fallopian tube cancer.

I can provide a recent biopsy for BRCA1/2 and PD-L1 testing.

Exclusion Criteria

I have or had hepatitis B or C.

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

I had major surgery less than 3 weeks ago or am still recovering from one.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

Participants receive a single 3-week cycle of carboplatin/paclitaxel

3 weeks

Treatment

Participants receive up to 5 cycles of carboplatin/paclitaxel with pembrolizumab or placebo, followed by maintenance with olaparib or placebo

15 weeks for initial cycles, up to 105 weeks for pembrolizumab cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 6 years

Treatment Details

Interventions

• Carboplatin
• Olaparib
• Paclitaxel
• Pembrolizumab

Trial Overview The study tests if adding pembrolizumab to carboplatin/paclitaxel chemotherapy followed by olaparib maintenance improves progression-free survival in these patients compared to chemotherapy alone. It's specifically for those without BRCA mutations but with PD-L1-positive tumors.

Participant Groups

Group I: Pembrolizumab + Placebo for Olaparib Experimental Treatment 6 Interventions

Participants receive carboplatin/paclitaxel via IV infusion for five 3-week cycles starting in Cycle 1 PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles PLUS placebo for olaparib via oral tablet BID, starting with Cycle 7. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m\^2 Q3W) plus carboplatin AUC 5 Q3W after Sponsor consultation. Participants may also receive bevacizumab via IV infusion on Day 1 of each 3-week cycle at the Investigator's discretion.

Group II: Pembrolizumab + Olaparib Experimental Treatment 6 Interventions

Participants receive carboplatin/paclitaxel via intravenous (IV) infusion for five 3-week cycles PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles PLUS olaparib 300 mg via oral tablet twice each day (BID), starting with Cycle 7. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m\^2 Q3W) plus carboplatin AUC 5 Q3W after Sponsor consultation. Participants may also receive bevacizumab via IV infusion on Day 1 of each 3-week cycle at the Investigator's discretion.

Group III: Placebo for Pembrolizumab + Placebo for Olaparib Active Control 6 Interventions

Participants receive carboplatin/paclitaxel via IV infusion for five 3-week cycles PLUS placebo for pembrolizumab (normal saline or dextrose) via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles PLUS placebo for olaparib via oral tablet BID, starting with Cycle 7. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m\^2 Q3W) plus carboplatin AUC 5 Q3W after Sponsor consultation. Participants may also receive bevacizumab via IV infusion on Day 1 of each 3-week cycle at the Investigator's discretion.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

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

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

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

Merck Sharp & Dohme LLC

Lead 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

Gynecologic Oncology Group

Collaborator

Trials

251

Recruited

65,400+

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Collaborator

Trials

41

Recruited

19,200+

Findings from Research

In a study of 120 ovarian cancer patients, the combination of olaparib with paclitaxel and carboplatin significantly improved the objective remission rate and disease control rate compared to the standard treatment with paclitaxel and carboplatin alone.

The addition of olaparib also resulted in lower levels of tumor markers and a reduced rate of tumor metastasis after one year, all without increasing the incidence of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. Zhang, H., Zhang, Y.[2022]

The GEICO1601-ROLANDO trial is a Phase II study investigating the combination of olaparib (a PARP inhibitor) and pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, regardless of BRCA mutation status.

The primary goal of the trial is to assess progression-free survival at 6 months, with additional measures including response rate, disease control rate, quality of life, and overall survival, aiming to improve treatment outcomes in a population with historically low response to PARP inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GEICO1601-ROLANDO: a multicentric single arm Phase II clinical trial to evaluate the combination of olaparib and pegylated liposomal doxorubicin for platinum-resistant ovarian cancer. Perez-Fidalgo, JA., Iglesias, M., Bohn, U., et al.[2020]

Olaparib (OLA) monotherapy showed a similar overall objective response rate (ORR) compared to chemotherapy (CT) in patients with relapsed ovarian cancer, with ORR of 24.3% for OLA and 28.3% for CT, indicating comparable efficacy.

In patients with platinum-resistant ovarian cancer (PROC) who had received more than four prior lines of treatment, OLA demonstrated a higher ORR of 22.9% compared to 0% for CT, suggesting that OLA may be more effective in heavily pretreated cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. Vanderstichele, A., Loverix, L., Busschaert, P., et al.[2022]

The combination of olaparib and carboplatin is tolerable and shows clinical benefit in patients with BRCA wild-type high-grade serous ovarian carcinoma, with a clinical benefit rate of 64% in heavily pretreated patients.

The maximum tolerated dose was established at olaparib 400 mg twice daily with carboplatin AUC4, although significant side effects like neutropenia and thrombocytopenia were observed, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in heavily pretreated recurrent high-grade serous ovarian cancer at low genetic risk. Lampert, EJ., Hays, JL., Kohn, EC., et al.[2023]

Olaparib significantly improves progression-free survival (PFS) in patients with platinum-sensitive BRCA-mutated ovarian cancer, with a hazard ratio of 0.31, indicating a strong benefit compared to placebo or chemotherapy.

The treatment also shows a slight improvement in overall survival (OS) with a hazard ratio of 0.75, while maintaining a manageable safety profile with mostly mild adverse effects like anemia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of olaparib maintenance therapy in platinum-sensitive ovarian cancer patients with BRCA mutations: a meta-analysis on randomized controlled trials. Ma, J., Deng, H., Li, J., et al.[2020]

In the phase 3 SOLO2 trial involving 295 patients with BRCA1/2 mutations and relapsed ovarian cancer, maintenance therapy with olaparib significantly improved progression-free survival compared to placebo, demonstrating its efficacy as a treatment option.

Despite common side effects like fatigue and nausea, olaparib did not negatively impact health-related quality of life, and patients experienced longer durations of good quality of life and quality-adjusted progression-free survival compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial. Friedlander, M., Gebski, V., Gibbs, E., et al.[2021]

In a study of 69 Croatian patients with BRCA1-2 mutated, platinum-sensitive recurrent ovarian cancer, olaparib maintenance therapy demonstrated a median progression-free survival of 21 months, confirming its efficacy in a real-world setting.

The treatment was generally safe, with only 3% of patients discontinuing due to toxicity, although 88% experienced some level of side effects, indicating that while effective, monitoring for adverse effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib Outcomes in Patients with BRCA 1-2 Mutated, Platinum-Sensitive, Recurrent Ovarian Cancer in Croatia: A Retrospective Noninterventional Study. Majić, A., Miše, BP., Matković, V., et al.[2020]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[2022]

In a study involving patients with recurrent platinum-resistant ovarian cancer, the combination of pembrolizumab, cisplatin, and gemcitabine resulted in an overall response rate of 60%, but the duration of response was relatively short at 4.9 months.

The addition of pembrolizumab did not show a significant benefit over chemotherapy alone, leading to the decision to close the trial for further accrual after an interim analysis indicated modest outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. Walsh, CS., Kamrava, M., Rogatko, A., et al.[2022]

A pilot study in Korea is investigating biomarker-driven targeted therapies for 68 patients with platinum-resistant recurrent ovarian cancer, focusing on HRD and PD-L1 status to tailor treatments.

Patients will receive different combinations of treatments based on their biomarker status, with the primary goal of assessing the response rate 6 months after starting treatment, highlighting a personalized approach to cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An umbrella study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG 3045), AMBITION. Lee, JY., Yi, JY., Kim, HS., et al.[2020]

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

References

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

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. [2022]

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

GEICO1601-ROLANDO: a multicentric single arm Phase II clinical trial to evaluate the combination of olaparib and pegylated liposomal doxorubicin for platinum-resistant ovarian cancer. [2020]

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

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. [2022]

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

Phase I/Ib study of olaparib and carboplatin in heavily pretreated recurrent high-grade serous ovarian cancer at low genetic risk. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy and safety of olaparib maintenance therapy in platinum-sensitive ovarian cancer patients with BRCA mutations: a meta-analysis on randomized controlled trials. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial. [2021]

8. Egypt pubmed.ncbi.nlm.nih.gov

Olaparib Outcomes in Patients with BRCA 1-2 Mutated, Platinum-Sensitive, Recurrent Ovarian Cancer in Croatia: A Retrospective Noninterventional Study. [2020]

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

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. [2022]

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

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. [2022]

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

An umbrella study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG 3045), AMBITION. [2020]

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

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. [2019]