Last updated on December 2019

Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma


Brief description of study

This randomized phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as BRAFV600 and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

Detailed Study Description

PRIMARY OBJECTIVE:

I. To determine whether initial treatment with either combination ipilimumab + nivolumab (with subsequent dabrafenib mesylate [dabrafenib] in combination with trametinib dimethyl sulfoxide [trametinib]) or dabrafenib in combination with trametinib (with subsequent ipilimumab + nivolumab) significantly improves 2 year overall survival (OS) in patients with unresectable stage III or stage IV BRAFV600 mutant melanoma.

SECONDARY CLINICAL OBJECTIVES:

I. To evaluate the impact of initial treatment on median OS and hazard ratio for death.

II. To determine whether initial treatment choice significantly improves 3 year OS.

III. To evaluate the anti-tumor activities (Response Evaluation Criteria in Solid Tumors [RECIST]-defined response rate, median progression-free survival [PFS]) and safety profiles of ipilimumab + nivolumab and dabrafenib-trametinib in a Cooperative Group trial of patients with V600 mutant melanoma.

IV. To evaluate the activity (RECIST-defined response rate, median PFS) and safety of dabrafenib + trametinib in patients who have had disease progression on ipilimumab + nivolumab and in comparison to its activity and safety in ipilimumab + nivolumab naive patients.

V. To evaluate the activity of ipilimumab + nivolumab (RECIST-defined response rate, median PFS) and safety in patients who have had disease progression on dabrafenib + trametinib and in comparison to its activity and safety in dabrafenib + trametinib naive patients.

VI. To assess the feasibility of crossover to the alternative treatment strategy (percentage of patients who are able to crossover from one arm to the other and complete at least an initial course [12 weeks] of treatment after cross-over without intervening symptomatic disease progression or treatment limiting toxicity).

SECONDARY LABORATORY OBJECTIVES:

I. Association of inherited variation with immune mediated adverse events and response to ipilimumab + nivolumab.

Ia. To determine the association of inherited genetic variation and immune-associated adverse events in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines, cytokine receptors and within the major histocompatibility complex (MHC) region and an agnostic genome-wide single nucleotide polymorphism (SNP)-based approach.

Ib. To investigate the association between inherited genetics and survival in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines profile, cytokine receptors and within the MHC region and an agnostic genome-wide SNP-based approach.

Ic. To replicate genomic markers identified in the above aims in an independent sample set of patients treated with ipilimumab containing regimens and preliminarily characterize their potential functional role by completing replication of variation as associated with immune-related adverse events (irAEs) and survival and bio-informatic assessment of genomic markers.

II. To determine the utility of circulating BRAF levels in determining the response and resistance to either BRAF/MEK directed and/or combination immunotherapy in patients with BRAF mutant melanoma.

IIa. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600 mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and resistance to combination BRAF/MEK directed therapy.

IIb. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600 mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and resistance to combination immunotherapy.

IIc. To compare the kinetics of peripheral blood BRAFV600 levels during response and resistance in groups of patients receiving BRAF targeted therapy or combination immunotherapy as initial therapy.

IId. To compare the kinetics of peripheral blood BRAFV600 levels during response and resistance to combination BRAF targeted therapy or combination immunotherapy in individual patients (initial treatment vs crossover treatment).

SECONDARY PATIENT REPORTED OUTCOMES OBJECTIVES:

I. To evaluate differences in overall health between initial treatment arms (dabrafenib + trametinib vs. ipilimumab + nivolumab immunotherapy) at 2 years, accounting for toxicities and overall survival. (Primary) II. To assess differences in overall function over 2 years between initial treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab. (Secondary) III. To document the effects of treatment crossover and treatment administration sequence on symptom burden and overall function. (Secondary) IIIa. To compare differences in function and symptoms by treatment sequence for ipilimumab + nivolumab (arm A vs. D), and dabrafenib + trametinib, (arm B vs. C) at baseline, 6 weeks, 12 weeks, and 6 months after the initiation of each treatment.

IIIb. To describe the frequency and severity of treatment toxicities at baseline, 6 weeks, 12 weeks, and 6 months after initiation of each treatment.

EXPLORATORY TOBACCO USE OBJECTIVES:

I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose modifications).

II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.

III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.

IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.

OUTLINE: Patients are randomized to 1 of 2 treatment arms (Arm A or Arm B).

ARM A:

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab intravenously (IV) over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C.

ARM C: Patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm D.

ARM D:

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Clinical Study Identifier: NCT02224781

Find a site near you

Start Over

Northwest Cancer Clinic

Kennewick, WA United States
  Connect »

Saint Francis Cancer Center

Greenville, SC United States
  Connect »

Kootenai Cancer Center

Post Falls, ID United States
  Connect »

Carle Cancer Center

Urbana, IL United States
  Connect »

MetroHealth Medical Center

Cleveland, OH United States
  Connect »

Marshfield Clinic-Chippewa Center

Chippewa Falls, WI United States
  Connect »

Margaret R Pardee Memorial Hospital

Hendersonville, NC United States
  Connect »

Northside Hospital

Atlanta, GA United States
  Connect »

Ochsner Medical Center Jefferson

New Orleans, LA United States
  Connect »

Deaconess Clinic Downtown

Evansville, IN United States
  Connect »

Presbyterian Kaseman Hospital

Albuquerque, NM United States
  Connect »

SIH Cancer Institute

Carterville, IL United States
  Connect »

Illinois CancerCare-Bloomington

Bloomington, IL United States
  Connect »

Feather River Cancer Center

Paradise, CA United States
  Connect »

University of Virginia Cancer Center

Charlottesville, VA United States
  Connect »

Saint Francis Medical Center

Cape Girardeau, MO United States
  Connect »

Olathe Medical Center

Olathe, KS United States
  Connect »

Mills-Peninsula Medical Center

Burlingame, CA United States
  Connect »

Saint Joseph Mercy Hospital

Ann Arbor, MI United States
  Connect »

Valley Medical Center

Renton, WA United States
  Connect »

Peninsula Cancer Center

Poulsbo, WA United States
  Connect »

Mercy Hospital

Coon Rapids, MN United States
  Connect »

Boulder Community Hospital

Boulder, CO United States
  Connect »

Decatur Memorial Hospital

Decatur, IL United States
  Connect »

Baystate Medical Center

Springfield, MA United States
  Connect »

Katmai Oncology Group

Anchorage, AK United States
  Connect »

Bay Area Hospital

Coos Bay, OR United States
  Connect »

Mercy Health Saint Mary's

Grand Rapids, MI United States
  Connect »

Mary Imogene Bassett Hospital

Cooperstown, NY United States
  Connect »

Dekalb Medical Center

Decatur, GA United States
  Connect »

Kaiser Permanente-Oakland

Oakland, CA United States
  Connect »

Frederick Memorial Hospital

Frederick, MD United States
  Connect »

Vidant Oncology-Kinston

Kinston, NC United States
  Connect »

Cleveland Clinic Foundation

Cleveland, OH United States
  Connect »

Fairbanks Memorial Hospital

Fairbanks, AK United States
  Connect »

Alaska Women's Cancer Care

Anchorage, AK United States
  Connect »

Anchorage Oncology Centre

Anchorage, AK United States
  Connect »

Kaiser Permanente-Anaheim

Anaheim, CA United States
  Connect »

Kaiser Permanente-Baldwin Park

Baldwin Park, CA United States
  Connect »

Kaiser Permanente-Bellflower

Bellflower, CA United States
  Connect »

Kaiser Permanente-Fontana

Fontana, CA United States
  Connect »

Kaiser Permanente-Fresno

Fresno, CA United States
  Connect »

Kaiser Permanente - Harbor City

Harbor City, CA United States
  Connect »

Kaiser Permanente-Irvine

Irvine, CA United States
  Connect »

Kaiser Permanente-Cadillac

Los Angeles, CA United States
  Connect »

Kaiser Permanente-Modesto

Modesto, CA United States
  Connect »

Kaiser Permanente-Ontario

Ontario, CA United States
  Connect »

Kaiser Permanente - Panorama City

Panorama City, CA United States
  Connect »

City of Hope Rancho Cucamonga

Rancho Cucamonga, CA United States
  Connect »

Kaiser Permanente-Richmond

Richmond, CA United States
  Connect »

Kaiser Permanente-Riverside

Riverside, CA United States
  Connect »

Kaiser Permanente-Roseville

Roseville, CA United States
  Connect »

Kaiser Permanente - Sacramento

Sacramento, CA United States
  Connect »

Kaiser Permanente San Leandro

San Leandro, CA United States
  Connect »

Kaiser Permanente-San Marcos

San Marcos, CA United States
  Connect »

Kaiser Permanente-Stockton

Stockton, CA United States
  Connect »

Kaiser Permanente-Vallejo

Vallejo, CA United States
  Connect »

Kaiser Permanente-Walnut Creek

Walnut Creek, CA United States
  Connect »

Kaiser Permanente-Woodland Hills

Woodland Hills, CA United States
  Connect »

Penrose-Saint Francis Healthcare

Colorado Springs, CO United States
  Connect »

Rocky Mountain Cancer Centers-Penrose

Colorado Springs, CO United States
  Connect »

Porter Adventist Hospital

Denver, CO United States
  Connect »

Mercy Medical Center

Durango, CO United States
  Connect »

Southwest Oncology PC

Durango, CO United States
  Connect »

Swedish Medical Center

Englewood, CO United States
  Connect »

Grand Valley Oncology

Grand Junction, CO United States
  Connect »

Saint Anthony Hospital

Lakewood, CO United States
  Connect »

Littleton Adventist Hospital

Littleton, CO United States
  Connect »

Longmont United Hospital

Longmont, CO United States
  Connect »

McKee Medical Center

Loveland, CO United States
  Connect »

Parker Adventist Hospital

Parker, CO United States
  Connect »

Mount Sinai Medical Center

Miami Beach, FL United States
  Connect »

Summit Cancer Care-Candler

Savannah, GA United States
  Connect »

Island Urology

Honolulu, HI United States
  Connect »

Queen's Medical Center

Honolulu, HI United States
  Connect »

Kootenai Medical Center

Coeur d'Alene, ID United States
  Connect »

Kootenai Cancer Clinic

Sandpoint, ID United States
  Connect »

Memorial Hospital of Carbondale

Carbondale, IL United States
  Connect »

Illinois CancerCare-Carthage

Carthage, IL United States
  Connect »

Centralia Oncology Clinic

Centralia, IL United States
  Connect »

Northwestern University

Chicago, IL United States
  Connect »

Carle on Vermilion

Danville, IL United States
  Connect »

Crossroads Cancer Center

Effingham, IL United States
  Connect »

Illinois CancerCare-Galesburg

Galesburg, IL United States
  Connect »

Illinois CancerCare-Princeton

Princeton, IL United States
  Connect »

Rush-Copley Healthcare Center

Yorkville, IL United States
  Connect »

Sidney and Lois Eskenazi Hospital

Indianapolis, IN United States
  Connect »

Springmill Medical Center

Indianapolis, IN United States
  Connect »

Woodland Cancer Care Center

Michigan City, IN United States
  Connect »

Alegent Health Mercy Hospital

Council Bluffs, IA United States
  Connect »

Mercy Medical Center-West Lakes

West Des Moines, IA United States
  Connect »

Lawrence Memorial Hospital

Lawrence, KS United States
  Connect »

Associates In Womens Health

Wichita, KS United States
  Connect »

Flaget Memorial Hospital

Bardstown, KY United States
  Connect »

Saint Joseph Hospital East

Lexington, KY United States
  Connect »

Jewish Hospital

Louisville, KY United States
  Connect »

Jewish Hospital Medical Center South

Shepherdsville, KY United States
  Connect »

Mary Bird Perkins Cancer Center

Baton Rouge, LA United States
  Connect »

Ochsner Health Center-Summa

Baton Rouge, LA United States
  Connect »

Medical Center of Baton Rouge

Baton Rouge, LA United States
  Connect »

Ochsner High Grove

Baton Rouge, LA United States
  Connect »

Bronson Battle Creek

Battle Creek, MI United States
  Connect »

Saint Joseph Mercy Brighton

Brighton, MI United States
  Connect »

Saint Joseph Mercy Canton

Canton, MI United States
  Connect »

Caro Cancer Center

Caro, MI United States
  Connect »

Saint Joseph Mercy Chelsea

Chelsea, MI United States
  Connect »

Weisberg Cancer Treatment Center

Farmington Hills, MI United States
  Connect »

Hurley Medical Center

Flint, MI United States
  Connect »

Academic Hematology Oncology Specialists

Grosse Pointe Woods, MI United States
  Connect »

Bronson Methodist Hospital

Kalamazoo, MI United States
  Connect »

West Michigan Cancer Center

Kalamazoo, MI United States
  Connect »

Borgess Medical Center

Kalamazoo, MI United States
  Connect »

Sparrow Hospital

Lansing, MI United States
  Connect »

Hope Cancer Clinic

Livonia, MI United States
  Connect »

Saint Mary Mercy Hospital

Livonia, MI United States
  Connect »

Mercy Health Mercy Campus

Muskegon, MI United States
  Connect »

Hope Cancer Center

Pontiac, MI United States
  Connect »

Saint Joseph Mercy Oakland

Pontiac, MI United States
  Connect »

Bhadresh Nayak MD PC-Sterling Heights

Sterling Heights, MI United States
  Connect »

Ascension Saint Joseph Hospital

Tawas City, MI United States
  Connect »

Metro Health Hospital

Wyoming, MI United States
  Connect »

Huron Gastroenterology PC

Ypsilanti, MI United States
  Connect »

Miller-Dwan Hospital

Duluth, MN United States
  Connect »

Essentia Health - Fosston

Fosston, MN United States
  Connect »

Unity Hospital

Fridley, MN United States
  Connect »

Abbott-Northwestern Hospital

Minneapolis, MN United States
  Connect »

Hennepin County Medical Center

Minneapolis, MN United States
  Connect »

Health Partners Inc

Minneapolis, MN United States
  Connect »

Essentia Health - Park Rapids

Park Rapids, MN United States
  Connect »

Regions Hospital

Saint Paul, MN United States
  Connect »

United Hospital

Saint Paul, MN United States
  Connect »

Essentia Health Sandstone

Sandstone, MN United States
  Connect »

Lakeview Hospital

Stillwater, MN United States
  Connect »

Capital Region Southwest Campus

Jefferson City, MO United States
  Connect »

Bozeman Deaconess Hospital

Bozeman, MT United States
  Connect »

CHI Health Saint Francis

Grand Island, NE United States
  Connect »

CHI Health Good Samaritan

Kearney, NE United States
  Connect »

Midlands Community Hospital

Papillion, NE United States
  Connect »

Ann M Wierman MD LTD

Las Vegas, NV United States
  Connect »

Wayne Memorial Hospital

Goldsboro, NC United States
  Connect »

Miami Valley Hospital South

Centerville, OH United States
  Connect »

Bethesda North Hospital

Cincinnati, OH United States
  Connect »

Riverside Methodist Hospital

Columbus, OH United States
  Connect »

Grant Medical Center

Columbus, OH United States
  Connect »

Miami Valley Hospital

Dayton, OH United States
  Connect »

Dayton Physicians LLC-Atrium

Franklin, OH United States
  Connect »

Dayton Physicians LLC-Wayne

Greenville, OH United States
  Connect »

Greater Dayton Cancer Center

Kettering, OH United States
  Connect »

Kettering Medical Center

Kettering, OH United States
  Connect »

Hillcrest Hospital Cancer Center

Mayfield Heights, OH United States
  Connect »

Licking Memorial Hospital

Newark, OH United States
  Connect »

Newark Radiation Oncology

Newark, OH United States
  Connect »

Southern Ohio Medical Center

Portsmouth, OH United States
  Connect »

North Coast Cancer Care

Sandusky, OH United States
  Connect »

South Pointe Hospital

Warrensville Heights, OH United States
  Connect »

Integris Southwest Medical Center

Oklahoma City, OK United States
  Connect »

Geisinger Medical Center

Danville, PA United States
  Connect »

Pocono Medical Center

East Stroudsburg, PA United States
  Connect »

Ephrata Community Hospital

Ephrata, PA United States
  Connect »

Lewistown Hospital

Lewistown, PA United States
  Connect »

Community Medical Center

Scranton, PA United States
  Connect »

Geisinger Medical Group

State College, PA United States
  Connect »

Saint Francis Hospital

Greenville, SC United States
  Connect »

Greenville Memorial Hospital

Greenville, SC United States
  Connect »

Avera Cancer Institute

Sioux Falls, SD United States
  Connect »

Memorial Hospital

Chattanooga, TN United States
  Connect »

Memorial GYN Plus

Ooltewah, TN United States
  Connect »

Harrison Medical Center

Bremerton, WA United States
  Connect »

Saint Elizabeth Hospital

Enumclaw, WA United States
  Connect »

Saint Francis Hospital

Federal Way, WA United States
  Connect »

Saint Clare Hospital

Lakewood, WA United States
  Connect »

United Hospital Center

Bridgeport, WV United States
  Connect »

WVUH-Berkely Medical Center

Martinsburg, WV United States
  Connect »

Camden Clark Medical Center

Parkersburg, WV United States
  Connect »

Duluth Clinic Ashland

Ashland, WI United States
  Connect »

UW Cancer Center Johnson Creek

Johnson Creek, WI United States
  Connect »

HSHS Saint Nicholas Hospital

Sheboygan, WI United States
  Connect »

PCR Oncology

Arroyo Grande, CA United States
  Connect »

Huron Medical Center PC

Port Huron, MI United States
  Connect »

Lake Huron Medical Center

Port Huron, MI United States
  Connect »

Desert West Surgery

Las Vegas, NV United States
  Connect »

Hope Cancer Care of Nevada

Las Vegas, NV United States
  Connect »

OptumCare Cancer Care at Oakey

Las Vegas, NV United States
  Connect »

21st Century Oncology

Las Vegas, NV United States
  Connect »

University Cancer Center

Las Vegas, NV United States
  Connect »

Nebraska Medicine-Bellevue

Bellevue, NE United States
  Connect »

Eden Hospital Medical Center

Castro Valley, CA United States
  Connect »

Memorial Medical Center

Modesto, CA United States
  Connect »

Kaiser Permanente-San Rafael

San Rafael, CA United States
  Connect »

Kaiser San Rafael-Gallinas

San Rafael, CA United States
  Connect »

Menorah Medical Center

Overland Park, KS United States
  Connect »

Research Medical Center

Kansas City, MO United States
  Connect »

Sutter Davis Hospital

Davis, CA United States
  Connect »

Yale University

New Haven, CT United States
  Connect »

Las Vegas Urology - Pebble

Henderson, NV United States
  Connect »

Las Vegas Urology - Pecos

Las Vegas, NV United States
  Connect »

Saint Joseph London

London, KY United States
  Connect »

Cancer Center of Western Wisconsin

New Richmond, WI United States
  Connect »

Chambersburg Hospital

Chambersburg, PA United States
  Connect »

City of Hope Upland

Upland, CA United States
  Connect »

Las Vegas Urology - Sunset

Las Vegas, NV United States
  Connect »

Vidant Oncology-Kenansville

Kenansville, NC United States
  Connect »

Vidant Oncology-Richlands

Richlands, NC United States
  Connect »

UHHS-Westlake Medical Center

Westlake, OH United States
  Connect »

Sandra L Maxwell Cancer Center

Cedar City, UT United States
  Connect »

Logan Regional Hospital

Logan, UT United States
  Connect »

Riverton Hospital

Riverton, UT United States
  Connect »

LDS Hospital

Salt Lake City, UT United States
  Connect »

Holy Family Memorial Hospital

Manitowoc, WI United States
  Connect »