PARP Inhibitor + CTLA-4 Blockade for Ovarian Cancer

Recruiting at 4 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: New Mexico Cancer Care Alliance

Must not be taking: CYP3A4 inhibitors, Immunosuppressants

Disqualifiers: Autoimmune disorders, HIV, Heart disease, others

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

Compensation: Varies

Number of Visits: 28

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Of the approximately 21,000 cases of ovarian cancer diagnosed annually in the U.S, ten percent are attributed to hereditary syndromes, most commonly the result of mutations in the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Mutation in these genes results in the inability to repair double-stranded breaks in DNA. Treating these tumors with poly(adenosine diphosphate \[ADP\]-ribose) polymerase (PARP) inhibitors results in the specific killing of BRCA negative cells by blocking a second DNA-repair mechanism. Treatment of ovarian cancer patients with PARP inhibitors has resulted in improved progression free survival (PFS), but not overall survival (OS). It's not completely understood why this is the case, but some preclinical studies using ovarian cancer models in mice have suggested that combining PARP inhibitors with immune system modulators like T cell checkpoint inhibitors improves long-term survival. Therefore, the purpose of this study is to evaluate the safety and efficacy of a combination of a PARP inhibitor (Olaparib) with a T cell checkpoint inhibitor (the anti-CTLA-4 antibody Tremelimumab) in women with recurrent BRCA mutation-associated ovarian cancer.

Will I have to stop taking my current medications?

The trial requires that any cancer treatment medications, including hormonal therapy, chemotherapy, biologic/targeted agents, and immunologic agents, must be stopped at least 1 to 3 weeks before joining the study. Hormone replacement therapy for symptom management is allowed.

What data supports the effectiveness of the drug combination Olaparib, Lynparza, Tremelimumab, Imjudo, and Tremelimumab-actl for ovarian cancer?

Research shows that Olaparib, a PARP inhibitor, has been effective in treating ovarian cancer, especially in patients with certain genetic profiles. Additionally, combining Olaparib with immune therapies like Tremelimumab may enhance the immune system's ability to fight cancer, as seen in studies with similar drug combinations. ^{1 2 3 4 5}

Is the combination of PARP inhibitor and CTLA-4 blockade safe for humans?

Olaparib, a PARP inhibitor, has been tested in various clinical trials for ovarian cancer and is generally considered safe, with its safety profile well-documented in studies involving patients with and without BRCA mutations. However, specific safety data for the combination of PARP inhibitors with CTLA-4 blockade (like Tremelimumab) in humans is not provided in the available research. ^{6 7 8 9 10}

What makes the drug combination of Olaparib and Tremelimumab unique for ovarian cancer?

The combination of Olaparib, a PARP inhibitor that helps prevent cancer cells from repairing their DNA, and Tremelimumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, is unique because it targets both the cancer's ability to repair itself and enhances the body's immune response, offering a novel approach for treating ovarian cancer. ^{6 7 11 12 13}

Research Team

Sarah F. Adams

Principal Investigator

University of New Mexico Comprehensive Cancer Center

Eligibility Criteria

This trial is for women with recurrent ovarian cancer linked to BRCA mutations, who've had platinum-based chemo. They must have good organ function and a performance status of 0-2, indicating they can carry out daily activities with varying degrees of assistance. Participants need measurable disease and cannot be on other cancer treatments or have autoimmune diseases, uncontrolled illnesses, or known allergies to the drugs being tested.

Inclusion Criteria

Patients must meet pre-entry requirements as specified

My organs and bone marrow are functioning well.

My ovarian, fallopian tube, or peritoneal cancer has returned and cannot be cured with standard treatments.

Exclusion Criteria

I stopped my cancer hormone therapy at least a week ago.

You have HIV or other immune system problems.

I stopped all cancer treatments at least 3 weeks ago.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive Olaparib and Tremelimumab to determine the recommended Phase 2 dose based on regimen-limiting toxicity

8 weeks

Every 4 weeks for the first 6 doses

Treatment Phase 2

Participants receive Olaparib and Tremelimumab at doses determined in Phase 1, with monitoring for objective response rate

2 years

Every 12 weeks

Follow-up

Participants are monitored for progression-free survival and overall survival

5 years

Every 12 weeks

Treatment Details

Interventions

• Olaparib
• Tremelimumab

Trial Overview The study tests Olaparib (a PARP inhibitor) combined with Tremelimumab (an anti-CTLA-4 antibody) in treating BRCA mutation-associated ovarian cancer. It aims to see if this combo improves survival rates by targeting DNA repair mechanisms in cancer cells while also stimulating the immune system.

Participant Groups

Group I: Olaparib and Tremelimumab Experimental Treatment 2 Interventions

Each cycle is 28 days: Olaparib at 300 mg, orally, twice daily + Tremelimumab at 10 mg/kg, intravenously, every 4 weeks for the first 6 doses, then every 12 weeks until disease progression or unacceptable toxicity. * If 1 of the first 3 patients experiences a regimen-limiting toxicity (RLT), 3 more patients will be treated with 10 mg/kg Tremelimumab in Phase 1. If 2 or more of 6 patients experience RLT, then 6 mg/kg Tremelimumab will be tested * If at 6 mg/kg, 1 or more of 3 patients experience RLT, 3 patients will be treated at 3 mg/kg Tremelimumab * If at 3 mg/kg, 1 or more patients experience RLT, the study will be discontinued for safety purposes In Phase 2, patients will receive doses of Olaparib and Tremelimumab determined in the Phase 1 portion as described above, based on tolerability.

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?

New Mexico Cancer Care Alliance

Lead Sponsor

Trials

71

Recruited

52,500+

New Mexico Cancer Research Alliance

Lead Sponsor

Trials

71

Recruited

52,500+

Findings from Research

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]

The combination treatment of dostarlimab and niraparib in patients with recurrent platinum-resistant ovarian cancer showed a low objective response rate of only 7.3%, leading to the early termination of the study due to insufficient efficacy.

Despite the treatment being generally safe with no new safety issues identified, 95.1% of patients experienced treatment-related adverse events, and health-related quality of life worsened over time, indicating a need for more effective therapies for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). Randall, LM., O'Malley, DM., Monk, BJ., et al.[2023]

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]

Olaparib, a PARP inhibitor, has received FDA approval as the first treatment of its kind for fourth-line therapy in patients with ovarian cancer that has germline BRCA1/2 mutations, marking a significant advancement in cancer treatment.

The drug works by exploiting the vulnerabilities of cancer cells with DNA repair deficiencies, leading to cell death through a mechanism known as synthetic lethality, particularly effective in high-grade serous ovarian carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer. Tewari, KS., Eskander, RN., Monk, BJ.[2022]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

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]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

The DUETTE trial is investigating the efficacy of combining ceralasertib, an ATR inhibitor, with olaparib, a PARP inhibitor, as a second maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, involving 192 participants.

The primary goal is to determine if this combination therapy can prolong progression-free survival compared to placebo, with the study also assessing tolerability and safety in patients who have previously received PARP inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment. McMullen, M., Karakasis, K., Loembe, B., et al.[2021]

References

1. 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]

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

Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer. [2023]

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

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). [2023]

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

Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study. [2021]

5. 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]

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

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer. [2022]

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

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. [2020]

8. 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]

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

Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. [2022]

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

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. [2016]

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

DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer. [2021]

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

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair. [2022]