Nivolumab +/- Ipilimumab for Ovarian Cancer

Recruiting at 3 trial locations

Overseen By Roxanne Wood, BA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Don Dizon

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Brain metastases, Autoimmune disease, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 12

Duration: Varies by arm (2-6 weeks per cycle)

46 Participants Needed

Trial Summary

What is the purpose of this trial?

Preclinical and early-phase clinical data suggest that immune modulation represents a treatment strategy that is worthy of further investigation in relapsed epithelial ovarian cancer. One method by which tumor cells may evade immune surveillance is by activation of the programmed cell death (PD-1) pathway, mediated by expression of PD-1 on the surface of T lymphocytes, which conveys an inhibitory signal after binding to its ligand PD-L1 on the surface of tumor cells. Nivolumab and Ipilimumab have shown activity as monotherapies in solid tumors and very early data suggest that nivolumab may be particularly active for ovarian clear cell carcinoma.(Hamanishi et al., 2015). Given the uniformly poor prognosis for patients with clear cell carcinoma in general, we are interested in formally evaluating this agent in all extra-renal clear cell carcinomas.

Will I have to stop taking my current medications?

The trial requires that you stop any chemotherapy or radiotherapy at least 4 weeks before starting, and endocrine therapy must be stopped 7 days prior. If you are on systemic corticosteroids or other immunosuppressive medications, you need to stop them 14 days before starting the trial.

What data supports the effectiveness of the drug combination Nivolumab and Ipilimumab for ovarian cancer?

The combination of Nivolumab and Ipilimumab has shown durable and long-term effectiveness in treating advanced non-small cell lung cancer, suggesting potential benefits in other cancers. However, single-agent PD-1 blockade, like Nivolumab alone, has shown limited effectiveness in ovarian cancer, indicating that combining it with Ipilimumab might enhance its efficacy. ^{1 2 3 4 5}

What safety information is available for Nivolumab and Ipilimumab in ovarian cancer treatment?

Nivolumab and Ipilimumab, used in treating ovarian cancer, can cause immune-related side effects, which are different from those seen with traditional chemotherapy. It's important to recognize and manage these side effects early to ensure patient safety. ^{1 3 6 7 8}

How is the drug combination of Nivolumab and Ipilimumab different from other treatments for ovarian cancer?

The combination of Nivolumab and Ipilimumab is unique because it uses two immune checkpoint inhibitors to enhance the body's immune response against ovarian cancer, which is different from traditional chemotherapy that directly targets cancer cells. This approach aims to overcome the limited effectiveness of single-agent PD-1 blockade in ovarian cancer. ^{1 3 9 10 11}

Research Team

Don Dizon, MD

Principal Investigator

Brown University Oncology Research Group (BrUOG) & Lifespan Cancer Institute

Eligibility Criteria

This trial is for adults with clear cell carcinoma of ovarian, fallopian tube, primary peritoneal, or extra-renal origin who have progressed after prior treatments. They must have good organ function and performance status, no history of certain immune diseases or severe allergies to monoclonal antibodies, not be pregnant or breastfeeding, and agree to use effective contraception.

Inclusion Criteria

My ovarian, fallopian, or peritoneal cancer worsened after platinum and taxane treatment.

My clear cell cancer has worsened after at least one treatment for its advanced stage.

leukocytes ≥3,000/mcL

Exclusion Criteria

You have had a serious allergic reaction to any type of medication called monoclonal antibodies.

I haven't taken high-dose steroids or other immune-weakening drugs in the last 14 days.

I have previously received treatments targeting the immune system for cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Nivolumab 240 mg every 2 weeks or Nivolumab 240 mg with Ipilimumab 1mg/kg every 6 weeks

Varies by arm (2-6 weeks per cycle)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 12 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The study is testing the effectiveness of Nivolumab alone or in combination with Ipilimumab in treating clear cell carcinomas. These drugs are designed to help the immune system recognize and attack cancer cells by blocking pathways that cancer uses to hide from immune cells.

Participant Groups

Group I: Arm 2 Nivolumab and Ipilimumab Ovarian Experimental Treatment 2 Interventions

Nivolumab 240 mg every 2 weeks Ipilimumab 1mg/kg day 1 Cycle=6 weeks

Group II: Arm 2 Nivolumab and Ipilimumab Extra-renal Experimental Treatment 2 Interventions

Nivolumab 240 mg every 2 weeks Ipilimumab 1mg/kg day 1 Cycle=6 weeks

Group III: Arm 1 Nivolumab Ovarian Experimental Treatment 1 Intervention

Nivolumab 240 mg Day 1 Cycle = 2 weeks

Group IV: Arm 1 Nivolumab Extra-renal Experimental Treatment 1 Intervention

Nivolumab 240 mg Day 1 Cycle = 2 weeks

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Don Dizon

Lead Sponsor

Trials

3

Recruited

50+

Brown University

Lead Sponsor

Trials

480

Recruited

724,000+

The Miriam Hospital

Collaborator

Trials

252

Recruited

39,200+

Women and Infants Hospital of Rhode Island

Collaborator

Trials

119

Recruited

59,200+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Rhode Island Hospital

Collaborator

Trials

275

Recruited

71,400+

Findings from Research

In a study of 100 women with recurrent epithelial ovarian cancer, the combination of ipilimumab and nivolumab resulted in a significantly higher response rate (31.4%) compared to nivolumab alone (12.2%), indicating improved efficacy of the combination therapy.

The median progression-free survival was also longer for the combination group (3.9 months) compared to nivolumab alone (2 months), although both treatments had similar rates of severe adverse events, suggesting that the combination therapy is relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. Zamarin, D., Burger, RA., Sill, MW., et al.[2021]

Intra-tumoral immune cell density is a significant prognostic factor in epithelial ovarian cancer, suggesting that the immune environment plays a crucial role in disease outcomes.

Despite the rationale for using PD1/PD-L1 inhibitors in treating relapsed ovarian cancer, clinical trials have not shown promising results, leading to the exploration of combination therapies and earlier intervention strategies to improve efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors in ovarian cancer: where do we stand? Leary, A., Tan, D., Ledermann, J.[2021]

In a study of 44 women with recurrent ovarian cancer treated with immune checkpoint inhibitors, the overall response rate was 14.2%, with a notable correlation between platinum sensitivity and response in high-grade serous ovarian cancer (HGSOC) patients.

Severe immune-related adverse events (irAEs) occurred in 47.7% of patients, with elevated hepatic or pancreatic enzymes being the most common, and a higher number of gene mutations appeared to protect against these specific adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics and outcomes of patients with recurrent ovarian cancer undergoing early phase immune checkpoint inhibitor clinical trials. Hinchcliff, E., Hong, D., Le, H., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Epithelial ovarian cancer (EOC) has a high recurrence rate of about 70% after standard treatment, highlighting the urgent need for new therapies to improve patient survival.

Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, are being explored as potential treatments for EOC due to the cancer's strong immunogenicity, but further research is necessary to understand their effectiveness and identify which patients may benefit most.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer? Mittica, G., Genta, S., Aglietta, M., et al.[2022]

Immune checkpoint inhibitors, which target specific proteins like CTLA-4 and PD-1, have significantly improved survival rates for patients with advanced solid tumors, including ovarian cancer.

The report emphasizes the need for early recognition and management of immune-related adverse events, which differ from those seen with traditional chemotherapy, highlighting the unique challenges of immunotherapy in treating gynecologic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis and Management of Immune Checkpoint Inhibitor-related Toxicities in Ovarian Cancer: A Series of Case Vignettes. Johnson, C., Jazaeri, AA.[2019]

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]

In a phase III study involving 316 patients with platinum-resistant ovarian cancer, nivolumab did not improve overall survival compared to chemotherapy (gemcitabine or pegylated liposomal doxorubicin), with median overall survival of 10.1 months for nivolumab versus 12.1 months for chemotherapy.

Nivolumab was associated with fewer treatment-related adverse events (61.5% vs. 98.1% for chemotherapy), indicating it may be better tolerated, but it also showed worse progression-free survival (2.0 months vs. 3.8 months for chemotherapy).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA). Hamanishi, J., Takeshima, N., Katsumata, N., et al.[2023]

The combination of the FRα vaccine TPIV200 and the PD-L1 inhibitor durvalumab was well tolerated in 27 patients with advanced platinum-resistant ovarian cancer, showing a low grade 3 toxicity rate of 18.5%.

While the overall response rate was low (3.7% partial response and 33.3% stable disease), the median overall survival was notably long at 21 months, suggesting potential benefits from this immunotherapy approach in a heavily pretreated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial. Zamarin, D., Walderich, S., Holland, A., et al.[2021]

References

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

Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. [2021]

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

Immune checkpoint inhibitors in ovarian cancer: where do we stand? [2021]

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

Characteristics and outcomes of patients with recurrent ovarian cancer undergoing early phase immune checkpoint inhibitor clinical trials. [2023]

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer? [2022]

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

Diagnosis and Management of Immune Checkpoint Inhibitor-related Toxicities in Ovarian Cancer: A Series of Case Vignettes. [2019]

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

The role of immune checkpoint inhibition in the treatment of ovarian cancer. [2022]

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

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

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

Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. [2022]

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

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA). [2023]

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

Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial. [2021]