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Testing the Combination of Dabrafenib and Trametinib with or without Hydroxychloroquine in Patients with Stage IIIC or IV BRAF V600E / K Melanoma with Elevated LDH

Trial Status: Active

This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E / K melanoma with elevated lactate dehydrogenase (LDH). Hydroxychloroquine may cause cell death in tumor cells that rely on a process called "autophagy" for survival. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with dabrafenib and trametinib may work better than dabrafenib and trametinib alone to shrink and stabilize the cancer.

Inclusion Criteria

  • 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
  • Patient must have serum LDH > upper limit of normal per institution standards
  • Patient must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Baseline measurements of sites of disease must be obtained within 3 weeks prior to study randomization
  • Patient must have been treated with prior immune checkpoint inhibitor therapy (anti PD-1 antibody, anti-CTLA-4 antibody or a combination regimen including either or both agents) either in the adjuvant or metastatic setting. Patient may have received investigational agents in combination with standard therapy, as long as it was adhering to the timeframes * Patient must have discontinued active immunotherapy (IL-2, interferon, anti-CTLA-4 antibody, anti-PD-1 antibody etc.) or chemotherapy at least 4 weeks prior to randomization * Patient must have discontinued any oral targeted therapy at least 2 weeks prior to randomization * Patients must not receive any other investigational anticancer therapy during the period on study or the 4 weeks prior to randomization
  • Patient may have been treated with prior adjuvant therapy including combined BRAF and MEK inhibitor therapy. Patients will be eligible if they tolerated this therapy and did not discontinue the therapy due to toxicity AND >= 6 months have elapsed since the end of adjuvant BRAF and MEK inhibition. If patients received BRAF and MEK inhibitor therapy in the metastatic setting, they are not eligible
  • Patient may have been treated with prior chemotherapy or radiation therapy
  • Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or abstaining from sexual intercourse for the duration of their participation in the study and for 4 months after the last dose of protocol treatment
  • Patient must have recovered from clinically significant reversible toxicities from previous treatment prior to randomization. Abnormal laboratory values may be grade 1, as long as they meet the eligibility criteria
  • Patient 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
  • Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
  • Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to protocol randomization)
  • Platelets >= 100,000/mcL (obtained =< 14 days prior to protocol randomization)
  • Total bilirubin =< institutional upper limit of normal (ULN) (obtained =< 14 days prior to protocol randomization)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN (obtained =< 14 days prior to protocol randomization)
  • Creatinine =< 1.5 x institutional ULN (obtained =< 14 days prior to protocol randomization)
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patient with asymptomatic new or progressive brain metastases (active brain metastases) are eligible if the treating physician determines that CNS specific treatment is not required * NOTE: Patient with treated brain metastases are eligible. No brain imaging is required, however, 1 week must elapse after gamma knife therapy. Patient treated with whole brain radiation that have been stable for 2 months are eligible. Patient are excluded if they have leptomeningeal disease or metastases causing spinal cord compression that are symptomatic or untreated or not stable (documented by imaging) for at least 3 months or requiring corticosteroids. Patients on a stable dose of corticosteroids for at least 1 month or who have been off of corticosteroids for at least 1 week are eligible

Exclusion Criteria

  • Patients who are known to be experiencing an objective partial response to immunotherapy at the time of study enrollment are not eligible
  • Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All females of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Patient must not have a history of interstitial lung disease (ILD) or chronic pneumonitis * NOTE: If there is radiographic evidence of ILD that is clinically insignificant and asymptomatic, the patient would be eligible
  • Patient must not have porphyria or psoriasis due to risk of disease exacerbation 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
  • Patient must not have a previously documented retinal vein occlusion
  • Patient must not have a history or evidence of increased cardiovascular risk including: * Left ventricular ejection fraction (LVEF) < institutional lower limit of normal measured within 14 days prior to randomization * A QT interval corrected for heart rate using the Bazett‘s formula >= 480 msec * Current clinically significant uncontrolled arrhythmias. Exception: Patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible * Acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization * Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram unless a cardiologist concludes the valve abnormality is not clinically significant. Patients with grade 1 abnormalities (i.e., mild regurgitation/stenosis) are eligible * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • 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
  • Patient must not be receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents). Radiotherapy delivered to palliate pain is allowed as long as it is not targeting a lesion that meets RECIST criteria for progression. Radiation therapy to the surgical bed with gamma knife radiotherapy while on treatment during the first cycle is allowed for small volume surgically resected brain metastases. Gamma knife radiotherapy for known active, asymptomatic small volume central nervous system (CNS) lesions may be performed during the first cycle while on study. Radiotherapy for new CNS lesions identified beyond the first cycle is not allowed on study
  • Patient must not have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)
  • Patient must not have received cytochrome P450 enzyme –inducing anticonvulsant drugs (extended-interval aminoglycoside dosing [EIADs]) (i.e. phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine) within 4 weeks prior to randomization
  • Patient must not have a current use of a prohibited medication

Alaska

Anchorage
Alaska Breast Care and Surgery LLC
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Alaska Oncology and Hematology LLC
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Alaska Women's Cancer Care
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Anchorage Associates in Radiation Medicine
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Anchorage Oncology Centre
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Anchorage Radiation Therapy Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Katmai Oncology Group
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871
Providence Alaska Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 907-212-6871

Arkansas

Ft. Smith
Mercy Hospital Fort Smith
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-378-9373

California

Burbank
Providence Saint Joseph Medical Center / Disney Family Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 818-847-4793
Los Angeles
Cedars Sinai Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 310-423-8965

Florida

Aventura
UM Sylvester Comprehensive Cancer Center at Aventura
Status: ACTIVE
Contact: Site Public Contact
Phone: 954-461-2180
Coral Gables
UM Sylvester Comprehensive Cancer Center at Coral Gables
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Deerfield Beach
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Miami
UM Sylvester Comprehensive Cancer Center at Kendall
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Plantation
UM Sylvester Comprehensive Cancer Center at Plantation
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647

Idaho

Boise
Saint Luke's Cancer Institute - Boise
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774
Fruitland
Saint Luke's Cancer Institute - Fruitland
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774
Meridian
Saint Luke's Cancer Institute - Meridian
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774
Nampa
Saint Luke's Cancer Institute - Nampa
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774
Twin Falls
Saint Luke's Cancer Institute - Twin Falls
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774

Illinois

Aurora
Rush - Copley Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 630-978-6212
Danville
Carle on Vermilion
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Effingham
Carle Physician Group-Effingham
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Mattoon
Carle Physician Group-Mattoon / Charleston
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Mount Vernon
Good Samaritan Regional Health Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 618-242-4600
Urbana
Carle Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
The Carle Foundation Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Yorkville
Rush-Copley Healthcare Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 630-978-6212

Iowa

Ames
Mary Greeley Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-956-4132
McFarland Clinic PC - Ames
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-239-4734
Boone
McFarland Clinic PC-Boone
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-956-4132
Des Moines
Broadlawns Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-282-2200
Iowa Lutheran Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-241-8704
Iowa Methodist Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-241-6727
Medical Oncology and Hematology Associates-Des Moines
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-282-2921
Fort Dodge
McFarland Clinic PC-Trinity Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-956-4132
Trinity Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-574-8302
Jefferson
McFarland Clinic PC-Jefferson
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-956-4132
Marshalltown
McFarland Clinic PC-Marshalltown
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-956-4132
West Des Moines
Methodist West Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-343-1000

Missouri

Ballwin
Saint Louis Cancer and Breast Institute-Ballwin
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-251-7058
Joplin
Freeman Health System
Status: ACTIVE
Contact: Site Public Contact
Phone: 417-347-4030
Mercy Hospital Joplin
Status: ACTIVE
Contact: Site Public Contact
Phone: 417-556-3074
Rolla
Delbert Day Cancer Institute at PCRMC
Status: ACTIVE
Contact: Site Public Contact
Phone: 573-458-8776
Mercy Clinic-Rolla-Cancer and Hematology
Status: ACTIVE
Contact: Site Public Contact
Phone: 573-458-6379
Saint Joseph
Heartland Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 816-271-7937
Saint Louis
Mercy Hospital Saint Louis
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-251-7066
Mercy Hospital South
Status: ACTIVE
Contact: Site Public Contact
Saint Louis Cancer and Breast Institute-South City
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-353-1870
Springfield
CoxHealth South Hospital
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Contact: Site Public Contact
Phone: 417-269-4520
Mercy Hospital Springfield
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Phone: 417-269-4520
Washington
Mercy Hospital Washington
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Phone: 636-390-1600

Montana

Missoula
Saint Patrick Hospital - Community Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 406-327-3118

Oklahoma

Oklahoma City
Mercy Hospital Oklahoma City
Status: ACTIVE
Contact: Site Public Contact
Phone: 405-752-3402

Oregon

Bend
Saint Charles Health System
Status: ACTIVE
Contact: Site Public Contact
Phone: 541-706-2909
Clackamas
Clackamas Radiation Oncology Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 503-215-2614
Providence Cancer Institute Clackamas Clinic
Status: ACTIVE
Contact: Site Public Contact
Phone: 503-215-2614
Coos Bay
Bay Area Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 541-269-8392
Newberg
Providence Newberg Medical Center
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Contact: Site Public Contact
Phone: 503-215-2614
Portland
Providence Portland Medical Center
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Phone: 503-215-2614
Providence Saint Vincent Medical Center
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Phone: 503-215-2614
Redmond
Saint Charles Health System-Redmond
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Phone: 541-706-2909

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-647-8073

Washington

Aberdeen
Providence Regional Cancer System-Aberdeen
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-412-8958
Bellingham
PeaceHealth Saint Joseph Medical Center
Status: ACTIVE
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Phone: 360-788-8238
Centralia
Providence Regional Cancer System-Centralia
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-412-8958
Edmonds
Swedish Cancer Institute-Edmonds
Status: ACTIVE
Contact: Site Public Contact
Phone: 206-215-3086
Everett
Providence Regional Cancer Partnership
Status: ACTIVE
Contact: Site Public Contact
Phone: 425-261-3529
Issaquah
Swedish Cancer Institute-Issaquah
Status: ACTIVE
Contact: Site Public Contact
Phone: 206-215-3086
Kennewick
Kadlec Clinic Hematology and Oncology
Status: ACTIVE
Contact: Site Public Contact
Phone: 509-783-4637
Lacey
Providence Regional Cancer System-Lacey
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-412-8958
Longview
PeaceHealth Saint John Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-514-2016
Seattle
Pacific Gynecology Specialists
Status: ACTIVE
Contact: Site Public Contact
Phone: 206-215-3086
Swedish Medical Center-Ballard Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 206-215-3086
Swedish Medical Center-Cherry Hill
Status: ACTIVE
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Phone: 206-215-3086
Swedish Medical Center-First Hill
Status: ACTIVE
Contact: Site Public Contact
Phone: 206-215-3086
Sedro-Woolley
PeaceHealth United General Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-788-8238
Shelton
Providence Regional Cancer System-Shelton
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-412-8958
Vancouver
PeaceHealth Southwest Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-514-3940
Walla Walla
Providence Saint Mary Regional Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 509-897-5993
Yelm
Providence Regional Cancer System-Yelm
Status: ACTIVE
Contact: Site Public Contact
Phone: 360-412-8958

PRIMARY OBJECTIVE:

I. To determine the rate of one year progression-free survival (PFS) when hydroxychloroquine sulfate (hydroxychloroquine) or placebo is added to dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) in advanced BRAFV600E/K melanoma with elevated LDH.

SECONDARY OBJECTIVES:

I. To compare the PFS of both arms.

II. To evaluate the best overall response rate by treatment arm.

III. To evaluate the complete response (CR) rate by treatment arm.

IV. To evaluate the adverse event rate by treatment arm.

V. To evaluate overall survival (OS) by treatment arm.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive dabrafenib mesylate orally (PO) twice daily (BID), trametinib dimethyl sulfoxide PO once daily (QD), and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: 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.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Ravi Amaravadi

  • Primary ID EA6191
  • Secondary IDs NCI-2020-04552
  • Clinicaltrials.gov ID NCT04527549