Nivolumab + Hydroxychloroquine / Ipilimumab for Melanoma

(LIMIT Trial)

Overseen by Ravi Amaravadi, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Ravi Amaravadi, MD

Must be taking: Nivolumab, Hydroxychloroquine

Must not be taking: Anticonvulsants, Immunosuppressants

Disqualifiers: Pregnancy, Severe autoimmune, Brain metastases, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of hydroxychloroquine with two immune-boosting drugs, nivolumab and ipilimumab, in patients with advanced skin cancer. The goal is to see if these combinations are safe and effective. Hydroxychloroquine helps the immune system, while nivolumab and ipilimumab help the body attack cancer cells. Nivolumab and ipilimumab have been used together to treat various cancers, including advanced melanoma, with improved response rates.

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

You will need to stop any active immunotherapy, chemotherapy, or investigational anticancer therapy at least 4 weeks before joining the study, and any oral targeted therapy at least 2 weeks before. If you are taking certain anticonvulsant drugs or medications that might interact with the study drugs, you may also need to stop those.

What data supports the effectiveness of the drug combination of Nivolumab, Ipilimumab, and Hydroxychloroquine for treating melanoma?

Research shows that combining Nivolumab and Ipilimumab improves survival and response rates in advanced melanoma compared to using Ipilimumab alone. However, there is no specific data on the addition of Hydroxychloroquine to this combination for melanoma. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for treating melanoma?

The combination of Nivolumab and Ipilimumab for melanoma can lead to increased risk of immune-related side effects, which can be severe and affect multiple organs. While these treatments can be effective, they often require careful monitoring and management of side effects. ^{6 7 8 9 10}

What makes the drug combination of Nivolumab and Ipilimumab unique for treating melanoma?

The combination of Nivolumab and Ipilimumab is unique because it uses two different types of immune checkpoint inhibitors that work together to enhance the body's immune response against melanoma. This combination has shown improved response rates and longer progression-free survival compared to using Ipilimumab alone, although it may also lead to more immune-related side effects. ^{1 3 11 12 13}

Research Team

Ravi Amaravadi, MD

Principal Investigator

Abramson Cancer Center at Penn Medicine

Eligibility Criteria

This trial is for adults with advanced melanoma, either Stage III not removable by surgery or Stage IV. They can have any genetic makeup and PD-L1 status, may or may not have had previous treatments, and must be physically well enough to participate (ECOG 0-1). Women must not be pregnant and should test negative for pregnancy. Participants need at least one measurable disease site that hasn't been treated with radiation before.

Inclusion Criteria

I have a cancer spot that can be measured and hasn't been treated with radiation.

I can take pills and don’t have major stomach or bowel issues affecting drug absorption.

I have or haven't had previous treatments before considering nivolumab + HCQ.

Exclusion Criteria

I do not have any serious infections, illnesses, or psychiatric conditions that would make treatment unsafe for me.

My cancer is partially responding to my current immunotherapy treatment.

I don't have untreated or unstable brain or spinal cord tumors, and I'm not on high doses of steroids.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Treatment

Identify the maximum tolerated dose (MTD) and preliminary safety of combination hydroxychloroquine and nivolumab therapy

16-32 weeks

Every 4 weeks

Phase 1b Treatment

Identify the MTD and preliminary safety of hydroxychloroquine administered in conjunction with nivolumab and ipilimumab therapy

16-32 weeks

Every 3 weeks for 4 cycles, then every 4 weeks

Phase 2 Treatment

Assess the clinical efficacy of combination hydroxychloroquine and nivolumab therapy

Up to 24 months

Every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Hydroxychloroquine (Other)
• Ipilimumab (Checkpoint Inhibitor)
• Nivolumab (Checkpoint Inhibitor)

Trial Overview The study tests the combination of hydroxychloroquine with nivolumab alone or together with ipilimumab in patients with advanced melanoma. It aims to assess how safe this mix is, if it's tolerable for patients, and how effective it is at fighting cancer cells.

Participant Groups

Group I: Phase 2: Nivolumab and Hydroxychloroquine (HCQ) Experimental Treatment 2 Interventions

HCQ 400-600 mg (maximum tolerated dose from Phase 1a) orally every 12 hours and nivolumab 480 mg IV every 4 weeks Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.

Group II: Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ) Experimental Treatment 3 Interventions

HCQ 400-600 mg orally every 12 hours and nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg IV every 3 weeks x4 cycles Then 6 weeks after the last dose of ipilimumab/nivolumab begin maintenance nivolumab 480 mg IV every 4 weeks Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.

Group III: Phase 1a: Nivolumab and Hydroxychloroquine (HCQ) Experimental Treatment 2 Interventions

Dose escalation: Dose Level 1: HCQ 400 mg orally every 12 hours and nivolumab 480 mg IV every 4 weeks Dose Level 2: HCQ 600 mg orally every 12 hours and nivolumab 480 mg IV every 4 weeks Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.

Who Is Running the Clinical Trial?

Ravi Amaravadi, MD

Lead Sponsor

Trials

2

Recruited

270+

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

Findings from Research

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

The combination of ipilimumab and nivolumab is more effective in treating advanced melanoma compared to ipilimumab alone, leading to better patient responses.

However, this two-drug combination significantly increases the likelihood of side effects compared to using ipilimumab as a single treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab + ipilimumab ups melanoma response. [2018]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

A patient with advanced melanoma experienced severe immune-related adverse events (irAEs) after receiving a single treatment of combined immunotherapy with ipilimumab and nivolumab, which are known to block PD-1 and CTLA-4 checkpoints.

Despite the severe irAEs leading to early discontinuation of therapy, the patient achieved a durable complete response, suggesting that irAEs may be associated with better long-term outcomes in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report. Matull, J., Livingstone, E., Wetter, A., et al.[2020]

Ipilimumab is an immunotherapy that works by inhibiting CTLA-4, leading to enhanced immune system activation, which can effectively treat advanced melanoma and other cancers.

Common side effects of ipilimumab are mostly mild to moderate (grade I or II) and include immune-mediated reactions like inflammatory diarrhea and pruritus, but serious side effects can be managed effectively with corticosteroids or other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a nursing perspective. Ledezma, B.[2017]

Ipilimumab, the first drug to improve survival in advanced melanoma, works by inhibiting CTLA-4 on T cells, but newer PD-1 inhibitors like nivolumab and pembrolizumab have shown better efficacy and safety.

The combination of ipilimumab and nivolumab enhances response rates and progression-free survival in advanced melanoma patients, but it also increases the risk of immune-related toxicities, leading to its FDA approval in 2015 for BRAF wild-type cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? Carlino, MS., Long, GV.[2018]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. [2022]

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

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. [2023]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]

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

Nivolumab + ipilimumab ups melanoma response. [2018]

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

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report. [2020]

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

Ipilimumab for advanced melanoma: a nursing perspective. [2017]

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

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? [2018]

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

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. [2023]

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

Nivolumab: a review of its use in patients with malignant melanoma. [2021]