What side effects are associated with this type of intervention?

Common treatments for cutaneous melanoma, particularly those involving enzyme inhibitors like dabrafenib and trametinib, often include side effects such as fever, fatigue, nausea, rash, and diarrhea. Hydroxychloroquine, which inhibits autophagy, can cause gastrointestinal disturbances, headache, dizziness, and in rare cases, retinal toxicity. When combined, these treatments may also lead to more complex side effects, including increased risk of skin reactions and potential liver toxicity.

What prior FDA approvals exist?

The FDA has approved several treatments for cutaneous melanoma, particularly for patients with BRAF V600 mutations. Dabrafenib and Trametinib, both enzyme inhibitors, have been approved for use in combination to improve recurrence-free survival (RFS) and overall survival (OS) in patients with high-risk melanoma. These drugs target the BRAF and MEK pathways, respectively, to inhibit tumor growth. Additionally, the combination of these inhibitors with immunotherapy agents like pembrolizumab has shown promise in clinical trials. While Hydroxychloroquine, an autophagy inhibitor, is being studied in combination with Dabrafenib and Trametinib to overcome resistance and delay disease progression, it is not yet FDA-approved for this specific use in melanoma.

What other types of research exist?

Promising novel alternatives for Cutaneous Melanoma patients include: 1) Selective RET inhibitors such as selpercatinib and pralsetinib, which target specific mutations and have shown efficacy in tumor shrinkage and disease stabilization. 2) Anti-PD-1 and anti-PD-L1 therapies like pembrolizumab and nivolumab, which have demonstrated improved survival rates and durable responses in metastatic melanoma. 3) Combination therapies involving BRAF/MEK inhibitors with immunotherapies, such as the combination of talimogene laherparepvec (T-VEC) with pembrolizumab, which has shown promising results in clinical trials.

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Kinase Inhibitor

Dabrafenib + Trametinib +/- Hydroxychloroquine for Melanoma

Phase 2

Waitlist Available

Led By Ravi Amaravadi

Research Sponsored by ECOG-ACRIN Cancer Research Group

Eligibility Criteria Checklist

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

Must have

Patient must have locally advanced unresectable stage IIIC or stage IV melanoma

Patient must have BRAF V600E or BRAF V600K tumor genotype based on a Clinical Laboratory Improvement Act (CLIA) approved assay

Must not have

Patient must not have a current use of a prohibited medication

Patient with known serious concurrent infection or medical illness, including psychiatric disorders, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety are not eligible

Timeline

Screening 3 weeks

Treatment Varies

Follow Up assessed every 4 weeks while on treatment and for 30 days after the end of treatment, up to 3 years

Summary

This trial tests if adding a new drug to existing cancer treatments can better control cancer. It targets patients with advanced melanoma. The new drug may help kill cancer cells, while the existing treatments prevent cell growth. The existing treatments have been shown to improve survival in patients with a specific type of advanced melanoma.

Who is the study for?

This trial is for adults with advanced melanoma (stage IIIC or IV) that has a specific mutation (BRAF V600E/K). Participants must have previously tried immunotherapy, be able to take oral medication, and not be pregnant or breastfeeding. They should not have other serious medical conditions or infections, and cannot join if they've had certain heart issues or are on drugs that could interact poorly with the study medications.

What is being tested?

The study tests whether adding hydroxychloroquine to standard treatment with dabrafenib and trametinib helps overcome resistance in melanoma. Patients will either receive this combination or just dabrafenib and trametinib without hydroxychloroquine to see which works better at controlling cancer growth.

What are the potential side effects?

Possible side effects include digestive issues, vision changes, liver enzyme changes, skin reactions, heart problems like irregular heartbeat or low ejection fraction, muscle pain, fatigue, and increased risk of infection due to immune system suppression.

Eligibility Criteria

Inclusion Criteria

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

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My melanoma is at an advanced stage and cannot be surgically removed.

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My tumor has the BRAF V600E or V600K mutation.

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My hepatitis B virus load is undetectable with treatment.

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I had hepatitis C but am cured, or I'm being treated with no detectable virus.

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I am fully active or can carry out light work.

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

Exclusion Criteria

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

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I am not currently taking any medications that are not allowed.

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

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I have never had interstitial lung disease or chronic pneumonitis.

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I haven't taken certain seizure medications in the last 4 weeks.

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I do not have a history of heart problems.

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My heart function is classified as class 2B or better according to NYHA.

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I am not currently having a partial response to immunotherapy.

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I have never had a blockage in the blood vessels of my eye.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ assessed every 4 weeks while on treatment and for 30 days after the end of treatment, up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~assessed every 4 weeks while on treatment and for 30 days after the end of treatment, up to 3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and assessed every 4 weeks while on treatment and for 30 days after the end of treatment, up to 3 years for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

One-year Progression-free Survival Rate

Secondary study objectives

Adverse Event Rate

Overall Survival

Progression-free Survival

+2 more

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Arm A (dabrafenib, trametinib, hydroxychloroquine)Experimental Treatment3 Interventions

Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (dabrafenib, trametinib, placebo)Active Control3 Interventions

Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Hydroxychloroquine

2017

Completed Phase 4

~5360

0 / 14Eligibility 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

Common treatments for Cutaneous Melanoma, such as Hydroxychloroquine, Dabrafenib, and Trametinib, work by targeting specific cellular processes. Hydroxychloroquine inhibits autophagy, a survival mechanism in cancer cells, leading to cell death. Dabrafenib and Trametinib inhibit the BRAF and MEK enzymes, respectively, which are part of a pathway that drives tumor growth. By blocking this pathway, these drugs can reduce tumor proliferation. Understanding these mechanisms helps patients grasp how these treatments can control melanoma progression and improve their prognosis.