Hydroxychloroquine in Patients With Stage III or Stage IV Melanoma That Can Be Removed by Surgery

A Phase 0 Trial of Hydroxychloroquine, an Inhibitor of Autophagy, in Patients With Stage III or IV Resectable Melanoma

RATIONALE: Studying samples of blood, tumor tissue, and skin in the laboratory from patients with melanoma receiving hydroxychloroquine may help doctors understand the effect of hydroxychloroquine on biomarkers.

PURPOSE: This early phase I trial is studying hydroxychloroquine in patients with stage III or stage IV melanoma that can be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Melanoma (Skin)
• Intervention / Treatment: Drug: hydroxychloroquine

Detailed Description

OBJECTIVES:

Primary

• To characterize the effects of hydroxychloroquine (HCQ) on the modulation of markers of autophagy, as measured by p62, Beclin1, LC3, and GRp170 expression, in pre- and post-treatment tumor biopsy samples, skin samples, and peripheral blood mononuclear cell samples from patients with stage III or IV melanoma undergoing palliative or curative surgery.

Secondary

• To determine whether the steady-state plasma concentration of HCQ correlates with observed trends in induced markers of autophagy.
• To determine the potential mechanisms of antitumor effect of HCQ, as measured by a reduction in tumor cell proliferation (Ki-67 and mitotic rate) or an increase in apoptosis (activated caspase-3 and TUNEL assays) in melanoma specimens.

OUTLINE: Patients receive oral hydroxychloroquine twice daily for 14 days in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.

Blood, tumor tissue, and skin samples are collected for pharmacokinetic and correlative laboratory studies. Expression of p62, Beclin1, LC3, and GRp170 (autophagy markers) is analyzed.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed melanoma

  • Stage III or IV disease
  • Has ≥ 2 resectable tumors OR tumor large enough to undergo pre-treatment core needle biopsy
• Must be a candidate for curative or palliative surgical resection of disease
• Brain metastases allowed provided they were previously treated and have been stable for > 2 weeks

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute granulocyte count > 1,500/mm³
• Platelet count > 100,000/mm³
• SGOT and SGPT < 2.5 times upper limit of normal (ULN)
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of any social or medical condition that, in the opinion of the investigator, may interfere with the patient's ability to comply with the study or pose additional or unacceptable risk to the patient
• No concurrent serious systemic disorder that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study
• No active clinically significant infection requiring antibiotics
• No hypertension that cannot be controlled by medication (i.e., diastolic blood pressure > 100 mm Hg despite optimal medical therapy)
• No pre-existing thyroid abnormality with thyroid-stimulating hormone that cannot be maintained in the normal range with medication
• No known HIV positivity
• No psoriasis or porphyria
• No known hypersensitivity to 4-aminoquinoline compounds
• No retinal or visual field changes from prior 4-aminoquinoline compound use
• No known G-6P deficiency
• No known gastrointestinal pathology that would interfere with drug bioavailability
• No known prior hypersensitivity to hydroxychloroquine or any of its components
• No clinically significant bleeding or clotting disorder that would preclude curative or palliative surgery

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• More than 2 weeks since prior cytotoxic or biologic agents (6 weeks for mitomycin or nitrosoureas)
• At least 2 weeks since prior surgery, radiotherapy, hormonal therapy, or other drug therapy for melanoma
• No concurrent treatment for rheumatoid arthritis or systemic lupus erythematosus
• No concurrent disease-modifying anti-rheumatic drugs
• No concurrent hydroxychloroquine for treatment or prophylaxis of malaria
• No concurrent aurothioglucose or antimalarial agents
• No other concurrent chemotherapy, immunotherapy, hormonal therapy, radiotherapy, or surgery for cancer
• No other concurrent investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hydroxychloroquine; Patients must have tumor accessible for pre-treatment biopsy (see 5.1.2). Patients will be enrolled on the trial, undergo biopsy of their tumors if no banked tumor is available, and then begin an oral dose of HCQ at the dose of 200 mg twice daily. At the end of two weeks the patients will undergo resection of their tumors. HCQ will be given to the patients up to the day of the operation but not resumed postoperatively.

Drug: hydroxychloroquine; 200 mg twice daily in the first ten patients. If the first ten patients tolerate this dosage schedule (200 mg bid) without significant side effects (Grade 3 or greater gastrointestinal upset, skin toxicity, myopathy or any visual disturbances whatsoever), the second ten patients will be enrolled at a dose of 400 mg bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Modulation of markers of autophagy by hydroxychloroquine (HCQ), as measured by p62, Beclin1, LC3, and GRp170 expression	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlation of steady-state plasma concentration of HCQ with observed trends in induced markers of autophagy	1 year
Potential mechanisms of antitumor effect of HCQ, as measured by a reduction in tumor cell proliferation or an increase in apoptosis	1 year

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Cancer Institute (NCI); Rutgers Cancer Institute of New Jersey
• Investigators: Principal Investigator: Janice M. Mehnert, MD, Rutgers Cancer Institute of New Jersey

Publications and helpful links

Helpful Links

• Clinical trial summary from the National Cancer Institute's PDQ® database

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): May 30, 2013
• Study Completion (Actual): May 30, 2013

Study Registration Dates

• First Submitted: August 19, 2009
• First Submitted That Met QC Criteria: August 19, 2009
• First Posted (Estimate): August 20, 2009

Study Record Updates

• Last Update Posted (Actual): September 7, 2022
• Last Update Submitted That Met QC Criteria: September 1, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: stage IV melanoma; stage III melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 0220090117; P30CA072720 (U.S. NIH Grant/Contract); CDR0000648156 (Other Identifier: NIH); NCI-2011-03324 (Other Identifier: CTRP (Clinical Trials Reporting System)); 090901 (Other Identifier: Rutgers Cancer Institute of New Jersey)