Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma
Clinical Stage IV Cutaneous Melanoma AJCC v8, Locally Advanced Melanoma, Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
About this trial
This is an interventional treatment trial for Clinical Stage IV Cutaneous Melanoma AJCC v8
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
Sites / Locations
- Anchorage Associates in Radiation Medicine
- Anchorage Radiation Therapy Center
- Alaska Breast Care and Surgery LLC
- Alaska Oncology and Hematology LLC
- Alaska Women's Cancer Care
- Anchorage Oncology Centre
- Katmai Oncology Group
- Providence Alaska Medical Center
- Cancer Center at Saint Joseph's
- Mayo Clinic Hospital in Arizona
- Mayo Clinic in Arizona
- Mercy Hospital Fort Smith
- CHI Saint Vincent Cancer Center Hot Springs
- Mission Hope Medical Oncology - Arroyo Grande
- Providence Saint Joseph Medical Center/Disney Family Cancer Center
- Cedars Sinai Medical Center
- Pacific Central Coast Health Center-San Luis Obispo
- Mission Hope Medical Oncology - Santa Maria
- Penrose-Saint Francis Healthcare
- Rocky Mountain Cancer Centers-Penrose
- Saint Francis Cancer Center
- Porter Adventist Hospital
- Mercy Medical Center
- Southwest Oncology PC
- Saint Anthony Hospital
- Littleton Adventist Hospital
- Longmont United Hospital
- Rocky Mountain Cancer Centers-Longmont
- Parker Adventist Hospital
- Saint Mary Corwin Medical Center
- Beebe South Coastal Health Campus
- Beebe Medical Center
- Delaware Clinical and Laboratory Physicians PA
- Helen F Graham Cancer Center
- Medical Oncology Hematology Consultants PA
- Christiana Care Health System-Christiana Hospital
- Beebe Health Campus
- TidalHealth Nanticoke / Allen Cancer Center
- Christiana Care Health System-Wilmington Hospital
- MedStar Georgetown University Hospital
- UM Sylvester Comprehensive Cancer Center at Aventura
- UM Sylvester Comprehensive Cancer Center at Coral Gables
- UM Sylvester Comprehensive Cancer Center at Deerfield Beach
- University of Miami Miller School of Medicine-Sylvester Cancer Center
- UM Sylvester Comprehensive Cancer Center at Kendall
- UM Sylvester Comprehensive Cancer Center at Plantation
- Saint Luke's Cancer Institute - Boise
- Saint Luke's Cancer Institute - Fruitland
- Saint Luke's Cancer Institute - Meridian
- Saint Luke's Cancer Institute - Nampa
- Saint Luke's Cancer Institute - Twin Falls
- Saint Anthony's Health
- Rush - Copley Medical Center
- Loyola Center for Health at Burr Ridge
- Carle on Vermilion
- Carle Physician Group-Effingham
- Loyola Medicine Homer Glen
- Carle Physician Group-Mattoon/Charleston
- Loyola University Medical Center
- Marjorie Weinberg Cancer Center at Loyola-Gottlieb
- Good Samaritan Regional Health Center
- Carle Cancer Center
- The Carle Foundation Hospital
- Rush-Copley Healthcare Center
- Reid Health
- Mary Greeley Medical Center
- McFarland Clinic PC - Ames
- McFarland Clinic PC-Boone
- Saint Anthony Regional Hospital
- Medical Oncology and Hematology Associates-West Des Moines
- Mercy Cancer Center-West Lakes
- Alegent Health Mercy Hospital
- Greater Regional Medical Center
- Iowa Methodist Medical Center
- Medical Oncology and Hematology Associates-Des Moines
- Broadlawns Medical Center
- Mercy Medical Center - Des Moines
- Mission Cancer and Blood - Laurel
- Iowa Lutheran Hospital
- McFarland Clinic PC-Trinity Cancer Center
- Trinity Regional Medical Center
- McFarland Clinic PC-Jefferson
- McFarland Clinic PC-Marshalltown
- Methodist West Hospital
- Mercy Medical Center-West Lakes
- Central Care Cancer Center - Garden City
- Central Care Cancer Center - Great Bend
- Flaget Memorial Hospital
- Commonwealth Cancer Center-Corbin
- Saint Joseph Radiation Oncology Resource Center
- Saint Joseph Hospital East
- Saint Joseph London
- Jewish Hospital
- Saints Mary and Elizabeth Hospital
- UofL Health Medical Center Northeast
- Jewish Hospital Medical Center South
- MedStar Franklin Square Medical Center/Weinberg Cancer Institute
- Mayo Clinic in Rochester
- Saint Louis Cancer and Breast Institute-Ballwin
- Central Care Cancer Center - Bolivar
- Cox Cancer Center Branson
- Freeman Health System
- Mercy Hospital Joplin
- Delbert Day Cancer Institute at PCRMC
- Mercy Clinic-Rolla-Cancer and Hematology
- Heartland Regional Medical Center
- Saint Louis Cancer and Breast Institute-South City
- Mercy Hospital South
- Mercy Hospital Saint Louis
- Mercy Hospital Springfield
- CoxHealth South Hospital
- Mercy Hospital Washington
- Saint Patrick Hospital - Community Hospital
- CHI Health Saint Francis
- CHI Health Good Samaritan
- Saint Elizabeth Regional Medical Center
- Alegent Health Immanuel Medical Center
- Alegent Health Bergan Mercy Medical Center
- Alegent Health Lakeside Hospital
- Creighton University Medical Center
- Midlands Community Hospital
- Laura and Isaac Perlmutter Cancer Center at NYU Langone
- Indu and Raj Soin Medical Center
- Saint Elizabeth Boardman Hospital
- Dayton Physicians LLC-Miami Valley South
- Miami Valley Hospital South
- Good Samaritan Hospital - Cincinnati
- Oncology Hematology Care Inc-Kenwood
- Bethesda North Hospital
- TriHealth Cancer Institute-Westside
- TriHealth Cancer Institute-Anderson
- Miami Valley Hospital
- Dayton Physician LLC-Miami Valley Hospital North
- Miami Valley Hospital North
- Armes Family Cancer Center
- Blanchard Valley Hospital
- Orion Cancer Care
- Atrium Medical Center-Middletown Regional Hospital
- Dayton Physicians LLC-Atrium
- Dayton Physicians LLC-Wayne
- Wayne Hospital
- Greater Dayton Cancer Center
- Kettering Medical Center
- Springfield Regional Cancer Center
- Springfield Regional Medical Center
- Dayton Physicians LLC-Upper Valley
- Upper Valley Medical Center
- Saint Joseph Warren Hospital
- Saint Elizabeth Youngstown Hospital
- Mercy Hospital Oklahoma City
- Saint Charles Health System
- Clackamas Radiation Oncology Center
- Providence Cancer Institute Clackamas Clinic
- Bay Area Hospital
- Providence Newberg Medical Center
- Providence Portland Medical Center
- Providence Saint Vincent Medical Center
- Saint Charles Health System-Redmond
- Christiana Care Health System-Concord Health Center
- University of Pennsylvania/Abramson Cancer Center
- University of Pittsburgh Cancer Institute (UPCI)
- Saint Joseph Regional Cancer Center
- Huntsman Cancer Institute/University of Utah
- Providence Regional Cancer System-Aberdeen
- PeaceHealth Saint Joseph Medical Center
- Harrison HealthPartners Hematology and Oncology-Bremerton
- Harrison Medical Center
- Highline Medical Center-Main Campus
- Providence Regional Cancer System-Centralia
- Swedish Cancer Institute-Edmonds
- Saint Elizabeth Hospital
- Providence Regional Cancer Partnership
- Saint Francis Hospital
- Swedish Cancer Institute-Issaquah
- Kadlec Clinic Hematology and Oncology
- Providence Regional Cancer System-Lacey
- Saint Clare Hospital
- PeaceHealth Saint John Medical Center
- Harrison HealthPartners Hematology and Oncology-Poulsbo
- Pacific Gynecology Specialists
- Swedish Medical Center-Ballard Campus
- Swedish Medical Center-Cherry Hill
- Swedish Medical Center-First Hill
- PeaceHealth United General Medical Center
- Providence Regional Cancer System-Shelton
- Franciscan Research Center-Northwest Medical Plaza
- PeaceHealth Southwest Medical Center
- Providence Saint Mary Regional Cancer Center
- Providence Regional Cancer System-Yelm
- Marshfield Clinic-Chippewa Center
- Marshfield Medical Center-EC Cancer Center
- Marshfield Clinic - Ladysmith Center
- Marshfield Medical Center-Marshfield
- Marshfield Clinic-Minocqua Center
- Marshfield Medical Center-Rice Lake
- Marshfield Medical Center-River Region at Stevens Point
- Marshfield Clinic-Wausau Center
- Marshfield Medical Center - Weston
- Marshfield Clinic - Wisconsin Rapids Center
Arms of the Study
Arm 1
Arm 2
Experimental
Active Comparator
Arm A (dabrafenib, trametinib, hydroxychloroquine)
Arm B (dabrafenib, trametinib, placebo)
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.
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.