What side effects are associated with this type of intervention?

Common side effects of PD-1 inhibitors like Nivolumab include skin reactions, endocrine events, and gastrointestinal issues such as diarrhea. CTLA-4 inhibitors like Ipilimumab can cause immune-related adverse events including colitis, hepatitis, and dermatitis. When used in combination, these drugs can lead to increased frequency and severity of immune-related adverse events, such as pneumonitis, nephritis, and severe skin reactions. Hydroxychloroquine, an autophagy inhibitor, can cause gastrointestinal disturbances, retinopathy, and myopathy. Combining these treatments may enhance anti-tumor efficacy but also increases the risk of compounded side effects, necessitating careful monitoring and management.

What prior FDA approvals exist?

Nivolumab (a PD-1 inhibitor) and Ipilimumab (a CTLA-4 inhibitor) have both received FDA approval for the treatment of advanced melanoma. Nivolumab was first approved in 2014 for unresectable or metastatic melanoma and later for use in combination with Ipilimumab. Ipilimumab was approved in 2011 for similar indications. Hydroxychloroquine, although not specifically approved for melanoma, is being studied for its potential to improve the effectiveness of these immunotherapies by inhibiting autophagy.

What other types of research exist?

Promising alternatives to Hydroxychloroquine in combination with Nivolumab and Ipilimumab for melanoma patients include: 1) Talimogene laherparepvec (T-VEC) combined with Pembrolizumab, which has shown efficacy in advanced melanoma. 2) Combination therapies involving immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors, which are being evaluated in ongoing trials for their potential to increase objective responses and overall survival.

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Checkpoint Inhibitor

Nivolumab + Hydroxychloroquine / Ipilimumab for Melanoma (LIMIT Trial)

Phase 1 & 2

Recruiting

Research Sponsored by Ravi Amaravadi, MD

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Phase 1b nivolumab + ipilimumab + HCQ: anti-PD-1 refractory

At least one measurable site of disease by RECIST 1.1 criteria that has not been previously irradiated

Must not have

Known serious concurrent infection or medical illness, including psychiatric disorders, which would jeopardize the ability to receive the protocol treatment with reasonable safety

Patients known to be experiencing an objective partial response to immunotherapy at the time of study enrollment

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from start of treatment to one year

Awards & highlights

No Placebo-Only Group

Approved for 10 Other Conditions

All Individual Drugs Already Approved

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Possible side effects include immune system reactions affecting organs, skin issues like rash or itching, liver function changes, digestive problems such as nausea or diarrhea, fatigue, muscle aches and pains. The severity of these side effects can vary from person to person.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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

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

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I can provide tissue samples from my cancer for testing.

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I am fully active or have some restrictions but can still care for myself.

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My melanoma cannot be surgically removed and is in Stage III or IV.

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I have had immunotherapy before for my cancer.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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My cancer is partially responding to my current immunotherapy treatment.

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

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All my cancer treatment side effects are mild, except for hair loss.

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I am not taking any medications that are not allowed in the study.

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I have a history of heart problems or am at high risk for them.

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I have a severe autoimmune disease and take medication to suppress my immune system.

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I have a history of lung scarring or inflammation not caused by previous immune treatments.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from start of treatment to one year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from start of treatment to one year

This trial's timeline: 3 weeks for screening, Varies for treatment, and from start of treatment to one year for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Phase 1: Maximum tolerated dose (MTD) - Number of Subjects with Dose-limiting Toxicities

Phase 2: Objective Response Rate (ORR)

Secondary study objectives

1 year survival rate

Progression-free survival

Side effects data

From 2016 Phase 3 trial • 217 Patients • NCT02057250

13%

Upper respiratory tract infection

Neutropenia

Sinusitis

Alanine aminotransferase increased

Urinary tract infection

Injection site erythema

Accidental overdose

Bronchitis

Injection site pruritus

Thrombocytopenia

Nasopharyngitis

Contusion

Arthralgia

Wolff-Parkinson-White syndrome

Coronary artery occlusion

Anaemia

Leukopenia

Lumbar spinal stenosis

Transient ischaemic attack

Vertebrobasilar insufficiency

Chronic obstructive pulmonary disease

Small intestinal obstruction

Nephrolithiasis

Cataract

Thrombophlebitis superficial

Vomiting

Endometrial hyperplasia

Traumatic arthritis

Hypertension

Pneumonia

Pancreatic carcinoma metastatic

Osteoarthritis

Rheumatoid lung

Pharyngitis

Femoral neck fracture

100%

80%

60%

40%

20%

Study treatment Arm

Sarilumab 150 mg by PFS (Extension Phase)

Sarilumab 150 mg by AID (AID Assessment Phase)

Sarilumab 150 mg by PFS (AID Assessment Phase)

Sarilumab 200 mg by PFS (AID Assessment Phase)

Sarilumab 200 mg by AID (AID Assessment Phase)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Approved for 10 Other Conditions

This treatment demonstrated efficacy for 10 other conditions.

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Phase 2: Nivolumab and Hydroxychloroquine (HCQ)Experimental Treatment2 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 Treatment3 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 Treatment2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Hydroxychloroquine

FDA approved

Ipilimumab

FDA approved

Nivolumab

FDA approved

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for melanoma include Hydroxychloroquine, Nivolumab, and Ipilimumab. Hydroxychloroquine inhibits autophagy, a survival mechanism for cancer cells under stress. Nivolumab is a PD-1 inhibitor that blocks the programmed death receptor-1 pathway, preventing cancer cells from evading the immune system. Ipilimumab is a CTLA-4 inhibitor that enhances the immune response by blocking the cytotoxic T-lymphocyte-associated antigen-4. These treatments are significant for melanoma patients as they target different pathways that cancer cells use to grow and evade the immune system, potentially leading to more effective treatment outcomes.