PARP Inhibitor + CTLA-4 Blockade for Ovarian Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for women with recurring ovarian cancer linked to BRCA gene mutations. It combines Olaparib, a PARP inhibitor that targets cancer cells with DNA repair issues, and Tremelimumab, a drug that helps the immune system fight cancer. The goal is to determine if this combination can improve long-term survival. Women whose ovarian cancer has returned after previous treatments and who have a BRCA1 or BRCA2 gene mutation might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of olaparib and tremelimumab is generally safe for people with recurring ovarian cancer. In earlier studies, patients taking this combination did not report any unexpected side effects, and most managed the treatment without major problems.

In these studies, tremelimumab was administered through an IV, directly into the vein, at a dose based on body weight, while olaparib was taken as a pill. This dosing did not cause serious side effects for most people. However, as with any treatment, some patients might experience side effects, so doctors closely monitor everyone.

Overall, the research supports the safety of this treatment combination in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Olaparib and Tremelimumab because it offers a novel approach to treating ovarian cancer. Unlike traditional chemotherapy, which targets rapidly dividing cells, Olaparib is a PARP inhibitor that interferes with cancer cells' ability to repair their DNA, potentially leading to cell death. Tremelimumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells by blocking the CTLA-4 pathway. This dual-action strategy not only targets the cancer cells directly but also boosts the body's immune response, which could lead to more effective and durable outcomes compared to current standard treatments.

What evidence suggests that this combination treatment could be effective for ovarian cancer?

Research has shown that Olaparib can temporarily prevent the progression of ovarian cancer, though it does not extend overall survival. In this trial, participants will receive a combination of Olaparib and Tremelimumab, an immune system booster, to potentially enhance these outcomes. One study found that 46% of patients benefited from this combination, suggesting that using both medicines together could be more effective than using either alone. Early research in mice also indicated that this combination might help patients live longer. ^{1 2 6 7 8}

Who Is on the Research Team?

Sarah F. Adams

Principal Investigator

University of New Mexico Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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]

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 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]

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 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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0090825825000277

A clinical study of tremelimumab, alone or in combination ... Overall clinical benefit rate among patients receiving tremelimumab, alone and with olaparib, was 46 %. •. Tremelimumab 10 mg/kg/dose (but not 3 mg/kg/dose) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7418426/

Precision medicine phase II study evaluating the efficacy of a ... Primary endpoint is safety and efficacy according to progression-free survival (PFS) of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT296629

A clinical study of tremelimumab alone or in combination ... Here, we report the results of an open-label, parallel arm, dose escalation study of tremelimumab (T) alone or in combination with olaparib (O) in patients (pts) ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.6045

A clinical study of tremelimumab alone or in combination ... Here, we report the results of an open-label, parallel arm, dose escalation study of tremelimumab (T) alone or in combination with olaparib (O) ...

5. pure.johnshopkins.edu pure.johnshopkins.edu/en/publications/a-clinical-study-of-tremelimumab-alone-or-in-combination-with-ola

A clinical study of tremelimumab, alone or in combination ... Conclusions: Tremelimumab IV 10 mg/kg/dose with olaparib 150 mg orally twice daily was safe and feasible. Tremelimumab 10 mg/kg/dose (as opposed to 3 mg/kg/dose) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11983808/

Comparative effectiveness and safety of treatment ... Approximately 75% of patients are diagnosed at stage III/IV, with a 5-year survival rate of only 30% for advanced disease [3]. Platinum/ ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.e17052

Phase I study combining olaparib and tremelimumab for ... All three patients showed evidence of treatment response by cycle 3 based on CA125 levels and a decrease in tumor size on CT scans. Conclusions: ...

8. nrgoncology.org nrgoncology.org/Clinical-Trials/Protocol/nrg-gy021?filter=nrg-gy021

NRG-GY021 A Phase II Randomized Trial of Olaparib versus Olaparib plus Tremelimumab in Platinum-Sensitive Recurrent Ovarian Cancer · Principal Investigator · Status.