Nivolumab + Hydroxychloroquine / Ipilimumab for Melanoma

(LIMIT Trial)

Overseen By Lydia Giles, BSN, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

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

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

Compensation: Varies

Number of Visits: 11

94 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a drug combination for people with advanced melanoma, a type of skin cancer. The study examines hydroxychloroquine (HCQ) with two other drugs, nivolumab and ipilimumab, to assess their combined and separate efficacy. Different groups in the trial test unique combinations of these treatments. People with advanced-stage melanoma who do not respond to current treatments might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this combination therapy.

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.

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

Research shows that the treatment combining nivolumab and ipilimumab, with or without hydroxychloroquine (HCQ), has been studied for safety in patients with melanoma, a type of skin cancer. Nivolumab and ipilimumab are established cancer treatments, often used together for advanced melanoma. Previous studies indicate that this combination can cause severe side effects in about 59% of patients.

Hydroxychloroquine, a drug commonly used for malaria and rheumatoid arthritis, is being tested to see if it can enhance cancer treatment. Researchers are working to find the best dose and check for safety concerns when combined with nivolumab. The early phase of this study focuses on finding the highest dose of hydroxychloroquine that patients can tolerate when used with nivolumab, which helps understand how patients can manage this treatment.

Overall, while evidence shows severe side effects in some patients, researchers are carefully monitoring these treatments to ensure safety and find the most effective dosing. Participants should discuss potential risks and benefits with their healthcare provider before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine existing immunotherapies, nivolumab and ipilimumab, with hydroxychloroquine (HCQ) to potentially enhance effectiveness against melanoma. Unlike standard treatments, which typically rely on either nivolumab or ipilimumab alone, this combination approach aims to leverage HCQ's ability to modulate the immune system. By adding HCQ, these treatments may better inhibit tumor growth by disrupting autophagy, a process cancer cells use to survive. This novel combination could offer a new avenue for patients, particularly those who haven't responded well to current options.

What evidence suggests that this trial's treatments could be effective for melanoma?

Studies have shown that using nivolumab with ipilimumab effectively treats advanced melanoma, a type of skin cancer. In one study, 43% of patients who received these two drugs were still alive ten years later. Another study found that among patients who were alive and cancer-free after three years, 96% survived for ten years. This trial will explore one treatment arm combining nivolumab, ipilimumab, and hydroxychloroquine. Another arm will study nivolumab and hydroxychloroquine without ipilimumab. Nivolumab alone has led to tumor shrinkage in 31% of advanced melanoma patients. Researchers are investigating whether adding hydroxychloroquine, which may help boost the immune system, can enhance the effectiveness of these treatments. ^{2 6 7 8 9}

Who Is on the Research Team?

Ravi Amaravadi, MD

Principal Investigator

Abramson Cancer Center at Penn Medicine

Are You a Good Fit for This Trial?

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 cancer that did not respond to previous anti-PD-1 therapy.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Hydroxychloroquine
• Ipilimumab
• Nivolumab

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.

How Is the Trial Designed?

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.

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?

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

Published Research Related to This Trial

In a phase 3 trial with patients suffering from advanced melanoma, the combination of nivolumab and ipilimumab resulted in significantly longer overall survival rates (58% at 3 years) compared to ipilimumab alone (34%).

The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse events, indicating that while effective, the combination therapy has a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok, JD., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

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]

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]

In a study of 945 patients with untreated metastatic melanoma, the combination of nivolumab and ipilimumab significantly improved progression-free survival to a median of 11.5 months compared to just 2.9 months with ipilimumab alone.

For patients with PD-L1-negative tumors, the combination therapy was particularly effective, showing a progression-free survival of 11.2 months compared to 5.3 months with nivolumab alone, highlighting the potential of dual checkpoint inhibition in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-00960

Nivolumab and Hydroxychloroquine or ... This phase I/II trial studies the best dose and effect of hydroxychloroquine when given together with nivolumab or nivolumab and ipilimumab in treating ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04464759/a-study-of-nivolumab-and-hydroxychloroquine-or-nivolumab-ipilimumab-and-hydroxychloroquine-in-advanced-melanoma

A Study of Nivolumab and Hydroxychloroquine or ... This study will evaluate the safety, tolerability and efficacy (objective response rate) of using hydroxychloroquine (HCQ) in combination ...

3. opdivohcp.com opdivohcp.com/efficacy/melanoma

Efficacy Data for Melanoma | OPDIVO® (nivolumab) In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4778791/

Clinical utility of nivolumab in the treatment of advanced ... Long-term follow-up of 107 patients with advanced melanoma from this trial showed a similar ORR of 31% (33/107), with median response duration of 2 years as ...

5. trials.braintumor.org trials.braintumor.org/trials/NCT04464759

A Study of Nivolumab and Hydroxychloroquine or Nivolumab ... This study will evaluate the safety, tolerability and efficacy (objective response rate) of using hydroxychloroquine (HCQ) in combination with nivolumab and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04464759

NCT04464759 | A Study of Nivolumab and ... This study will evaluate the safety, tolerability and efficacy (objective response rate) of using hydroxychloroquine (HCQ) in combination with nivolumab and ...

7. app.trialscreen.org app.trialscreen.org/trials/phase-1-2-melanoma-nivolumab-hydroxychloroquine-or-ipilimumab-advanced-trial-nct04464759

A Study of Nivolumab and Hydroxychloroquine or ... A Phase 1/2 study of Nivolumab and Hydroxychloroquine in Advanced Melanoma. A Clinical Trial Evaluating the Safety and Efficacy of Combining Nivolumab and ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9439759/

Safety and efficacy of nivolumab compared with other ... Nivolumab monotherapy yields high progression-free survival rates and has the same efficacy when combined with ipilimumab in a 1-year OS.

9. withpower.com withpower.com/trial/phase-2-melanoma-9-2020-6bd0c

Nivolumab + Hydroxychloroquine / Ipilimumab for Melanoma The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse ...