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Dabrafenib, Trametinib and Hydroxychloroquine in Treating Patients with Stage IV Metastatic Melanoma

Trial Status: Active

This phase I / II trial studies the side effects and best dose of hydroxychloroquine when given together with dabrafenib and trametinib and to see how well they work in treating patients with stage IV melanoma that has spread to other places in the body. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sometimes when dabrafenib and trametinib are given, the tumor cells activate a stress response called autophagy. Autophagy provides resistance to dabrafenib and trametinib treatment over time making them less effective. Giving hydroxychloroquine with dabrafenib and trametinib may reduce drug resistance and allow more tumor cells to be killed.

Inclusion Criteria

  • Patients must have histologically confirmed diagnosis of stage IV metastatic melanoma positive for BRAF V600E by a Clinical Laboratory Improvement Amendments (CLIA) approved assay
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count (ANC) >= 1.2 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelet count >= 100 x 10^9/L
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x upper limit of normal (ULN); subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization
  • Total bilirubin =< 1.5 x ULN; except subjects with known Gilbert’s syndrome
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Serum creatinine =< 1.5 mg/dL; if serum creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft-Gault formula; creatinine clearance must be >= 50 mL/min to be eligible
  • Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by echocardiogram (ECHO); ECHO scans must be used throughout the study when indicated
  • Patients must be able to provide written informed consent
  • Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women; women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for >= 1 year; women must use an effective method of contraception from 14 days prior to randomization, throughout the treatment period, and for at least 6 months after the last dose of study treatment as directed by their physician; effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, or intra-uterine devices); at the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance; (periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception); hormonal-based methods (e.g., oral contraceptives) are NOT permitted as contraception
  • Patients with brain metastases treated with whole brain radiation that have been stable for 2 months are eligible; patients with brain metastases treated with gamma knife or surgery are allowed to participate after 3 weeks have elapsed since their procedure; demonstration of brain stability by an imaging study after the procedure is required for gamma knife or central nervous system (CNS) surgery patients; subjects are excluded if they have leptomeningeal or metastases causing spinal cord compression that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 1 week can be enrolled with approval of the medical monitor
  • Any number and type of prior anticancer therapies are allowed except BRAF or mitogen-activated protein kinase kinase (MEK) inhibitors
  • Patients must have discontinued active immunotherapy (interleukin [IL]-2, interferon, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], etc.) or chemotherapy at least 4 weeks prior to entering the study and oral targeted therapy at least 2 weeks prior to entering the study; patients must not receive any other investigational anticancer therapy during the period on study or the four weeks prior to entry
  • All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed above) must be =< grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03, 2009) at the time of starting treatment
  • Patient much have measurable disease as defined by RECIST 1.1
  • Patients must be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

Exclusion Criteria

  • Patients with known serious concurrent infection or medical illness, including psychiatric disorders
  • Patients who are pregnant or breast-feeding
  • Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents)
  • Patients who are known to be experiencing an objective partial response to immunotherapy at the time of study enrollment
  • History of malignancy other than disease under study within 3 years of study enrollment with exceptions below: * Exception: subjects with a history of completely resected non-melanoma skin cancer, or subjects with indolent second malignancies are eligible
  • History of malignancy with confirmed activating RAS mutation at any time; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
  • History of interstitial lung disease or chronic pneumonitis
  • Patients with porphyria or psoriasis are ineligible unless the disease is well controlled and they are under the care of a specialist for the disorder who agrees to monitor the patient for exacerbations
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)
  • Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (EIADs) (i.e. phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of the start of the study treatment
  • Current use of a prohibited medication
  • Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted)
  • Patients with a previously documented retinal vein occlusion
  • History or evidence of increased cardiovascular risk including any of the following: * Left ventricular ejection fraction (LVEF) < institutional lower limit of normal * A QT interval corrected for heart rate using the Bazett’s formula >= 480 msec * Current clinically significant uncontrolled arrhythmias ** Exception: subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization * Current >= class II congestive heart failure as defined by New York Heart Association * Patients with intra-cardiac defibrillators * Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study

Illinois

Chicago
Northwestern University
Status: ACTIVE
Contact: Sunandana Chandra

Missouri

Saint Louis
Washington University School of Medicine
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION
Contact: Leonel F. Hernandez-Aya
Phone: 314-454-8313

New Jersey

New Brunswick
Rutgers University Medical School
Status: ACTIVE
Contact: Janice M. Mehnert
Phone: 732-235-8675

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: ACTIVE
Contact: Ravi Amaravadi
Phone: 215-662-7402

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and preliminary safety of hydroxychloroquine (HCQ) when administered in conjunction with oral dabrafenib and trametinib (D+T) in patients with advanced B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutant melanoma. (Phase I)

II. To assess the clinical efficacy of HCQ+D+T by 1 year progression-free survival (PFS) rate. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate the toxicity rates of oral HCQ when administered in conjunction with oral D+T.

II. To measure the response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and 1-year survival.

III. To determine the rate of squamous cell carcinoma of the skin, arthralgias, and pyrexia in patients treated with D+T and HCQ.

IV. To determine the type and frequency of ocular toxicities with this regimen.

TERTIARY OBJECTIVES:

I. To establish a population pharmacokinetic (PK) model for HCQ and its metabolites in combination with D+T.

II. To use the population PK model to estimate the exposure of HCQ in individual patients.

III. To compare PK parameters for HCQ and D+T in combination to data from published dabrafenib and trametinib single agent and combination studies.

IV. To measure the change in median number of autophagic vesicles/cell (mAV/cell) in serially collected tumor tissue with D+T alone and with D+T + HCQ and correlate these changes with HCQ exposure.

V. To determine if markers of T cell immunity are increased or decreased in D+T and D+T + HCQ treated tumor compared to baseline.

VI. To characterize changes in gene expression within the tumor microenvironment with D+T+ HCQ treatment in patients.

VII. To evaluate whether or not treatment results in modulation of systemic immunity by assessing peripheral cytokine levels.

VIII. To determine if blood based candidate biomarkers of autophagy modulation reflect autophagy dynamics in tumors of patients treated with this combination.

OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine, followed by a phase II study.

Patients receive dabrafenib orally (PO) twice daily (BID) (approximately every 12 hours) and trametinib PO once daily (QD) on days 1-28. Beginning week 2 patients also receive hydroxychloroquine PO BID every 12 hours on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 6 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Ravi Amaravadi

  • Primary ID UPCC 02614
  • Secondary IDs NCI-2015-00364, UPCC# 02614, 819986
  • Clinicaltrials.gov ID NCT02257424