Melanoma Clinical Trial
Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma
Summary
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. 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.
Full Description
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.
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.
Eligibility Criteria
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 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
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There are 168 Locations for this study
Anchorage Alaska, 98508, United States
Anchorage Alaska, 99504, United States
Anchorage Alaska, 99508, United States
Anchorage Alaska, 99508, United States
Anchorage Alaska, 99508, United States
Anchorage Alaska, 99508, United States
Anchorage Alaska, 99508, United States
Anchorage Alaska, 99508, United States
Phoenix Arizona, 85004, United States
Phoenix Arizona, 85054, United States
Scottsdale Arizona, 85259, United States
Fort Smith Arkansas, 72903, United States
Hot Springs Arkansas, 71913, United States
Arroyo Grande California, 93420, United States
Burbank California, 91505, United States
Los Angeles California, 90048, United States
San Luis Obispo California, 93401, United States
Santa Maria California, 93444, United States
Colorado Springs Colorado, 80907, United States
Colorado Springs Colorado, 80907, United States
Colorado Springs Colorado, 80923, United States
Denver Colorado, 80210, United States
Durango Colorado, 81301, United States
Durango Colorado, 81301, United States
Lakewood Colorado, 80228, United States
Littleton Colorado, 80122, United States
Longmont Colorado, 80501, United States
Longmont Colorado, 80501, United States
Parker Colorado, 80138, United States
Pueblo Colorado, 81004, United States
Frankford Delaware, 19945, United States
Lewes Delaware, 19958, United States
Newark Delaware, 19713, United States
Newark Delaware, 19713, United States
Newark Delaware, 19713, United States
Newark Delaware, 19718, United States
Rehoboth Beach Delaware, 19971, United States
Seaford Delaware, 19973, United States
Wilmington Delaware, 19801, United States
Washington District of Columbia, 20007, United States
Aventura Florida, 33180, United States
Coral Gables Florida, 33146, United States
Deerfield Beach Florida, 33442, United States
Miami Florida, 33136, United States
Miami Florida, 33176, United States
Plantation Florida, 33324, United States
Boise Idaho, 83712, United States
Fruitland Idaho, 83619, United States
Meridian Idaho, 83642, United States
Nampa Idaho, 83686, United States
Twin Falls Idaho, 83301, United States
Alton Illinois, 62002, United States
Aurora Illinois, 60504, United States
Burr Ridge Illinois, 60527, United States
Danville Illinois, 61832, United States
Effingham Illinois, 62401, United States
Homer Glen Illinois, 60491, United States
Mattoon Illinois, 61938, United States
Maywood Illinois, 60153, United States
Melrose Park Illinois, 60160, United States
Mount Vernon Illinois, 62864, United States
Urbana Illinois, 61801, United States
Urbana Illinois, 61801, United States
Yorkville Illinois, 60560, United States
Richmond Indiana, 47374, United States
Ames Iowa, 50010, United States
Ames Iowa, 50010, United States
Boone Iowa, 50036, United States
Carroll Iowa, 51401, United States
Clive Iowa, 50325, United States
Clive Iowa, 50325, United States
Council Bluffs Iowa, 51503, United States
Creston Iowa, 50801, United States
Des Moines Iowa, 50309, United States
Des Moines Iowa, 50309, United States
Des Moines Iowa, 50314, United States
Des Moines Iowa, 50314, United States
Des Moines Iowa, 50314, United States
Des Moines Iowa, 50316, United States
Fort Dodge Iowa, 50501, United States
Fort Dodge Iowa, 50501, United States
Jefferson Iowa, 50129, United States
Marshalltown Iowa, 50158, United States
West Des Moines Iowa, 50266, United States
West Des Moines Iowa, 50266, United States
Garden City Kansas, 67846, United States
Great Bend Kansas, 67530, United States
Bardstown Kentucky, 40004, United States
Corbin Kentucky, 40701, United States
Lexington Kentucky, 40504, United States
Lexington Kentucky, 40509, United States
London Kentucky, 40741, United States
Louisville Kentucky, 40202, United States
Louisville Kentucky, 40215, United States
Louisville Kentucky, 40245, United States
Shepherdsville Kentucky, 40165, United States
Baltimore Maryland, 21237, United States
Rochester Minnesota, 55905, United States
Ballwin Missouri, 63011, United States
Bolivar Missouri, 65613, United States
Branson Missouri, 65616, United States
Joplin Missouri, 64804, United States
Joplin Missouri, 64804, United States
Rolla Missouri, 65401, United States
Rolla Missouri, 65401, United States
Saint Joseph Missouri, 64506, United States
Saint Louis Missouri, 63109, United States
Saint Louis Missouri, 63128, United States
Saint Louis Missouri, 63141, United States
Springfield Missouri, 65804, United States
Springfield Missouri, 65807, United States
Washington Missouri, 63090, United States
Missoula Montana, 59802, United States
Grand Island Nebraska, 68803, United States
Kearney Nebraska, 68847, United States
Lincoln Nebraska, 68510, United States
Omaha Nebraska, 68122, United States
Omaha Nebraska, 68124, United States
Omaha Nebraska, 68130, United States
Omaha Nebraska, 68131, United States
Papillion Nebraska, 68046, United States
New York New York, 10016, United States
Beavercreek Ohio, 45431, United States
Boardman Ohio, 44512, United States
Centerville Ohio, 45459, United States
Centerville Ohio, 45459, United States
Cincinnati Ohio, 45220, United States
Cincinnati Ohio, 45236, United States
Cincinnati Ohio, 45242, United States
Cincinnati Ohio, 45247, United States
Cincinnati Ohio, 45255, United States
Dayton Ohio, 45409, United States
Dayton Ohio, 45415, United States
Dayton Ohio, 45415, United States
Findlay Ohio, 45840, United States
Findlay Ohio, 45840, United States
Findlay Ohio, 45840, United States
Franklin Ohio, 45005, United States
Franklin Ohio, 45005, United States
Greenville Ohio, 45331, United States
Greenville Ohio, 45331, United States
Kettering Ohio, 45409, United States
Kettering Ohio, 45429, United States
Springfield Ohio, 45504, United States
Springfield Ohio, 45505, United States
Troy Ohio, 45373, United States
Troy Ohio, 45373, United States
Warren Ohio, 44484, United States
Youngstown Ohio, 44501, United States
Oklahoma City Oklahoma, 73120, United States
Bend Oregon, 97701, United States
Clackamas Oregon, 97015, United States
Clackamas Oregon, 97015, United States
Coos Bay Oregon, 97420, United States
Newberg Oregon, 97132, United States
Portland Oregon, 97213, United States
Portland Oregon, 97225, United States
Redmond Oregon, 97756, United States
Chadds Ford Pennsylvania, 19317, United States
Philadelphia Pennsylvania, 19104, United States
Pittsburgh Pennsylvania, 15232, United States
Bryan Texas, 77802, United States
Salt Lake City Utah, 84112, United States
Aberdeen Washington, 98520, United States
Bellingham Washington, 98225, United States
Bremerton Washington, 98310, United States
Bremerton Washington, 98310, United States
Burien Washington, 98166, United States
Centralia Washington, 98531, United States
Edmonds Washington, 98026, United States
Enumclaw Washington, 98022, United States
Everett Washington, 98201, United States
Federal Way Washington, 98003, United States
Issaquah Washington, 98029, United States
Kennewick Washington, 99336, United States
Lacey Washington, 98503, United States
Lakewood Washington, 98499, United States
Longview Washington, 98632, United States
Poulsbo Washington, 98370, United States
Seattle Washington, 98104, United States
Seattle Washington, 98107, United States
Seattle Washington, 98122, United States
Seattle Washington, 98122, United States
Sedro-Woolley Washington, 98284, United States
Shelton Washington, 98584, United States
Tacoma Washington, 98405, United States
Vancouver Washington, 98664, United States
Walla Walla Washington, 99362, United States
Yelm Washington, 98597, United States
Chippewa Falls Wisconsin, 54729, United States
Eau Claire Wisconsin, 54701, United States
Ladysmith Wisconsin, 54848, United States
Marshfield Wisconsin, 54449, United States
Minocqua Wisconsin, 54548, United States
Rice Lake Wisconsin, 54868, United States
Stevens Point Wisconsin, 54482, United States
Wausau Wisconsin, 54401, United States
Weston Wisconsin, 54476, United States
Wisconsin Rapids Wisconsin, 54494, United States
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