Clinical Stage III Cutaneous Melanoma AJCC v8Phase 3NCT02224781
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
A Phase 3 study testing Biospecimen Collection, Computed Tomography and Dabrafenib Mesylate in people with Clinical Stage III Cutaneous Melanoma AJCC v8 and Clinical Stage IV Cutaneous Melanoma AJCC v8, run by National Cancer Institute (NCI) at 838 sites in United States.
Trial summary
This 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma
- What is being tested?
- Biospecimen Collection, Computed Tomography and Dabrafenib Mesylate
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 267 participants
- Where
- 838 sitesUnited States
- Study dates
- 8 Sep 2015to 19 Dec 2026
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- STEP 1
- Age >= 18 years. Because no dosing or adverse event data are currently available on the use of dabrafenib or dabrafenib + trametinib or nivolumab or nivolumab + ipilimumab therapy in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
- Women must not be pregnant or breast-feeding, as the effects of ipilimumab + nivolumab or dabrafenib + trametinib on the developing human fetus are unknown
- All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy
- A female of childbearing potential is anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Show all 61Show fewer
- The effects of dabrafenib and trametinib or ipilimumab and nivolumab on the developing human fetus are unknown; furthermore, dabrafenib has been reported to interfere with the effect of hormone based oral contraceptives; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and sexually active males must agree to use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; women of child-bearing potential must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 5 months after the last dose of nivolumab and/or ipilimumab. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
- Patients must have unresectable stage III or stage IV disease
- Patients must have measurable disease; all sites of disease must be evaluated within 4 weeks prior to randomization
- Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive
- NOTE: Any patient with BRAF V600 mutant melanoma (whether cutaneous, acral or mucosal primary) who meets the eligibility criteria is eligible for participation in this trial; patients with uveal melanoma are not eligible for this trial
- Patients must have BRAF V600 mutation, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Act (CLIA)-certified lab; if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test, Foundation Medicine); prompt information on tumor BRAF mutation status can also be obtained via Novartis "knowNow" Program
- Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor. Also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease
- Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting >= 4 weeks prior to entering the study and recovered from adverse events due to those agents; mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study; patients must have discontinued radiation therapy >= 1 week prior to entering the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration and patients must be fully recovered from post-surgical complications
- Patients must not receive any other investigational agents while on study or within four weeks prior to registration
- Patients are ineligible if they have any currently known active and definitive central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible; patients must not have taken any steroids =< 10 days prior to randomization for the purpose of managing their brain metastases; repeat imaging after SRS or surgical resection is not required so long as baseline magnetic resonance imaging (MRI) is within 4 weeks of registration; patients with multiple brain metastases treated with SRS (with [w] or without [w/o] whole-brain radiotherapy [WBRT]), are not an exclusion; patients with definitive CNS metastases treated with only WBRT are ineligible; patients with potential CNS metastases that are too small for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain etiology are potentially eligible, but need to be discussed with and approved by the study principal investigator (PI)
- Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for > 2 years prior to the time of registration
- White blood count >= 3,000/uL (obtained within 4 weeks prior to randomization)
- Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 4 weeks prior to randomization)
- Platelet count >= 100,000/uL (obtained within 4 weeks prior to randomization)
- Hemoglobin > 8 g/dL (obtained within 4 weeks prior to randomization)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min (obtained within 4 weeks prior to randomization)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN for patients with documented liver metastases) (obtained within 4 weeks prior to randomization)
- Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement) (obtained within 4 weeks prior to randomization)
- Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert's syndrome (obtained within 4 weeks prior to randomization)
- Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, or psychiatric illness/social situations that would limit compliance with study requirements, interfere with subject's safety, or obtaining informed consent; therapeutic level dosing of warfarin can be used with close monitoring of prothrombin time (PT)/international normalized ratio (INR) by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency
- Patients must not have a history of or evidence of cardiovascular risks including any of the following:
- QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480 msec. at baseline
- History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration
- History prior to registration or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
- Left ventricular ejection fraction (LVEF) =< 45% on cardiac echocardiogram (echo) or multi gated acquisition scan (MUGA)
- Intra-cardiac defibrillator
- Individuals who are known to be human immunodeficiency virus (HIV) infected are ineligible (note: HIV testing is not required for entry into the study)
- Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), should be evaluated for the presence of target organ involvement and potential need for systemic treatment; if no systemic immune suppression is deemed necessary they can be eligible
- The following medications or non-drug therapies are also prohibited while on treatment in this study:
- Other anti-cancer therapies
- Other investigational drugs
- Patients taking any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible
- Patients must not have history of retinal vein occlusion (RVO)
- Patients must not have evidence of interstitial lung disease or pneumonitis
- Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib
- STEP 2 (CROSSOVER ARMS): The patient must have met all eligibility criteria (except as detailed below) at the time of crossover
- RECIST defined measurable disease is not required
- Only prior systemic therapy as part of step 1 is allowed; patients who received allowed systemic therapy in the adjuvant setting prior to Step 1 and were eligible for Step 1 are not excluded from proceeding to Step 2 if they meet other eligibility criteria
- Malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to Arm D (ipilimumab + nivolumab) treatment
- History of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to Arm C (dabrafenib/trametinib) therapy
- Patients crossing over from Arm A (nivolumab/ipilimumab) to Arm C (dabrafenib/trametinib) who underwent surgery or SRS to CNS metastases need not be off of steroids to start treatment
- There is no restriction on serum lactate dehydrogenase (LDH) at crossover
- Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study principal investigator (PI) at time of crossover
- STEP 2 (CROSSOVER ARMS): Patients randomized to Arm A on Step 1 must have melanoma that is metastatic and clearly progressive on Step 1 therapy prior to crossing over to Arm C
- NOTE: Patients should (if possible) be at least 1 week from documented PD on Step 1 of current study. All sites of disease must be evaluated within 4 weeks prior to registration
- STEP 2 (CROSSOVER ARMS): Patients randomized to Arm B on Step 1 may cross over to Arm D at or prior to disease progression
- NOTE: If possible, patients should wait to cross over until after the cycle with the next protocol-required imaging assessment is completed; all sites of disease must be evaluated within 4 weeks prior to Step 2 registration
- NOTE: Patients should start Arm D treatment at least 1 week after stopping dabrafenib and trametinib, unless otherwise clinically indicated
- NOTE: Baseline labs and QOL assessments should be completed, and patients should follow the Arm D schedule
- STEP 2 (CROSSOVER ARMS): Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy; patients with immune related toxicities from ipilimumab + nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less
- STEP 2 (CROSSOVER ARMS): Patients must have discontinued radiation therapy prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications
- STEP 2 (CROSSOVER ARMS): Patients are ineligible if they have any currently active and definitive CNS metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible to proceed; patients crossing over from Arm B (dabrafenib/trametinib) to Arm D (nivolumab [nivo]/ipilimumab [ipi]) must not have taken any steroids =< 10 days prior to Step 2 registration for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases are ineligible; patients with definitive CNS metastases treated with only WBRT are ineligible; patients with potential CNS metastases that are too small for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain etiology are potentially eligible, but need to be discussed with and approved by the study PI
- STEP 2 (CROSSOVER ARMS): Patients must not have other current malignancies
- STEP 2 (CROSSOVER ARMS): Women must not be pregnant or breast-feeding, as the effects of ipilimumab + nivolumab or dabrafenib + trametinib on the developing human fetus are unknown; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to Step 2 crossover to rule out pregnancy; a female of childbearing potential is anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
- STEP 2 (CROSSOVER ARMS): The effects of dabrafenib and trametinib or ipilimumab and nivolumab on the developing human fetus are unknown; furthermore, dabrafenib has been reported to interfere with the effect of hormone based oral contraceptives; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and sexually active males must agree to continue to use the same contraception requirements as on Step 1 of this study (i.e.: use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; women of child-bearing potential must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 5 months after the last dose of nivolumab and/or ipilimumab. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
Who cannot join
None listed.
Trial locations and contacts
838 sites in 1 country.
300 sites in 1 country
United States300 sites
Hawaii Cancer Care - Westridge
‘Aiea, Hawaii, 96701
Pali Momi Medical Center
‘Aiea, Hawaii, 96701
Queen's Cancer Center - Pearlridge
‘Aiea, Hawaii, 96701
Straub Pearlridge Clinic
‘Aiea, Hawaii, 96701
The Cancer Center of Hawaii-Pali Momi
‘Aiea, Hawaii, 96701
The Queen's Medical Center - West Oahu
‘Ewa Beach, Hawaii, 96706
Providence Regional Cancer System-Aberdeen
Aberdeen, Washington, 98520
Hickman Cancer Center
Adrian, Michigan, 49221
Riverwood Healthcare Center
Aitkin, Minnesota, 56431
New York Oncology Hematology PC - Albany Medical Center
Albany, New York, 12208
Lovelace Medical Center-Saint Joseph Square
Albuquerque, New Mexico, 87102
University of New Mexico Cancer Center
Albuquerque, New Mexico, 87106
New Mexico Oncology Hematology Consultants
Albuquerque, New Mexico, 87109
Presbyterian Kaseman Hospital
Albuquerque, New Mexico, 87110
Lehigh Valley Hospital-Cedar Crest
Allentown, Pennsylvania, 18103
American Fork Hospital / Huntsman Intermountain Cancer Center
American Fork, Utah, 84003
Mary Greeley Medical Center
Ames, Iowa, 50010
McFarland Clinic - Ames
Ames, Iowa, 50010
Community Hospital of Anaconda
Anaconda, Montana, 59711
Cancer Care Center at Island Hospital
Anacortes, Washington, 98221
Kaiser Permanente-Anaheim
Anaheim, California, 92806
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, 98508
Anchorage Radiation Therapy Center
Anchorage, Alaska, 99504
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, 99508
Alaska Oncology and Hematology LLC
Anchorage, Alaska, 99508
Alaska Women's Cancer Care
Anchorage, Alaska, 99508
Anchorage Oncology Centre
Anchorage, Alaska, 99508
Katmai Oncology Group
Anchorage, Alaska, 99508
Providence Alaska Medical Center
Anchorage, Alaska, 99508
AnMed Health Cancer Center
Anderson, South Carolina, 29621
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Ann Arbor, Michigan, 48106
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, 48109
Aspirus Cancer Care-Antigo-Volm Cancer Center
Antigo, Wisconsin, 54409
Mission Hope Medical Oncology - Arroyo Grande
Arroyo Grande, California, 93420
PCR Oncology
Arroyo Grande, California, 93420
AdventHealth Infusion Center Asheville
Asheville, North Carolina, 28803
Duluth Clinic Ashland
Ashland, Wisconsin, 54806
Northwest Wisconsin Cancer Center
Ashland, Wisconsin, 54806
University Cancer and Blood Center LLC
Athens, Georgia, 30607
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
Northside Hospital
Atlanta, Georgia, 30342
Sutter Auburn Faith Hospital
Auburn, California, 95602
Sutter Cancer Centers Radiation Oncology Services-Auburn
Auburn, California, 95603
MultiCare Auburn Medical Center
Auburn, Washington, 98001
Augusta University Medical Center
Augusta, Georgia, 30912
The Medical Center of Aurora
Aurora, Colorado, 80012
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045
Rush-Copley Medical Center
Aurora, Illinois, 60504
Mount Sinai Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180
Virginia Mason Bainbridge Island Medical Center
Bainbridge Island, Washington, 98110
Saint Alphonsus Cancer Care Center-Baker City
Baker City, Oregon, 97814
Kaiser Permanente-Baldwin Park
Baldwin Park, California, 91706
Greater Baltimore Medical Center
Baltimore, Maryland, 21204
Saint Agnes Hospital
Baltimore, Maryland, 21229
MedStar Franklin Square Medical Center/Weinberg Cancer Institute
Baltimore, Maryland, 21237
CommonSpirit Saint Joseph Hospital - Bardstown
Bardstown, Kentucky, 40004
LSU Health Baton Rouge-North Clinic
Baton Rouge, Louisiana, 70805
Our Lady of the Lake Physician Group
Baton Rouge, Louisiana, 70808
Louisiana Hematology Oncology Associates LLC
Baton Rouge, Louisiana, 70809
Mary Bird Perkins Cancer Center
Baton Rouge, Louisiana, 70809
Ochsner Health Center-Summa
Baton Rouge, Louisiana, 70809
Medical Center of Baton Rouge
Baton Rouge, Louisiana, 70816
Ochsner High Grove
Baton Rouge, Louisiana, 70836
Bronson Battle Creek
Battle Creek, Michigan, 49017
UHHS-Chagrin Highlands Medical Center
Beachwood, Ohio, 44122
UPMC-Heritage Valley Health System Beaver
Beaver, Pennsylvania, 15009
Indu and Raj Soin Medical Center
Beavercreek, Ohio, 45431
Nebraska Medicine-Bellevue
Bellevue, Nebraska, 68123
Overlake Medical Center
Bellevue, Washington, 98004
Swedish Cancer Institute-Eastside Oncology Hematology
Bellevue, Washington, 98005
Kaiser Permanente-Bellflower
Bellflower, California, 90706
PeaceHealth Saint Joseph Medical Center
Bellingham, Washington, 98225
Strecker Cancer Center-Belpre
Belpre, Ohio, 45714
Sanford Joe Lueken Cancer Center
Bemidji, Minnesota, 56601
Saint Charles Health System
Bend, Oregon, 97701
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, 94704
Saint Luke's University Hospital-Bethlehem Campus
Bethlehem, Pennsylvania, 18015
Lehigh Valley Hospital - Muhlenberg
Bethlehem, Pennsylvania, 18017
Saint Vincent Frontier Cancer Center
Billings, Montana, 59102
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Sanford Bismarck Medical Center
Bismarck, North Dakota, 58501
OSF Saint Joseph Medical Center
Bloomington, Illinois, 61701
Illinois CancerCare-Bloomington
Bloomington, Illinois, 61704
Saint Joseph's/Candler - Bluffton Campus
Bluffton, South Carolina, 29910
Saint Elizabeth Boardman Hospital
Boardman, Ohio, 44512
Prisma Health Cancer Institute - Spartanburg
Boiling Springs, South Carolina, 29316
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, 83706
Saint Luke's Cancer Institute - Boise
Boise, Idaho, 83712
Central Care Cancer Center - Bolivar
Bolivar, Missouri, 65613
Parkland Health Center-Bonne Terre
Bonne Terre, Missouri, 63628
McFarland Clinic - Boone
Boone, Iowa, 50036
Boulder Community Foothills Hospital
Boulder, Colorado, 80303
Bozeman Health Deaconess Hospital
Bozeman, Montana, 59715
Essentia Health Saint Joseph's Medical Center
Brainerd, Minnesota, 56401
United Hospital Center
Bridgeport, West Virginia, 26330
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114
Trinity Health Medical Center - Brighton
Brighton, Michigan, 48114
Bristol Regional Medical Center
Bristol, Tennessee, 37620
Wellmont Medical Associates Oncology and Hematology-Bristol
Bristol, Tennessee, 37620
Ballad Health Cancer Care - Bristol
Bristol, Virginia, 24201
Saint Joseph Regional Cancer Center
Bryan, Texas, 77802
Roswell Park Cancer Institute
Buffalo, New York, 14263
Providence Saint Joseph Medical Center/Disney Family Cancer Center
Burbank, California, 91505
Saint Anne Hospital
Burien, Washington, 98166
Mills-Peninsula Medical Center
Burlingame, California, 94010
Saint James Community Hospital and Cancer Treatment Center
Butte, Montana, 59701
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, 83605
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
Cameron Park, California, 95682
Illinois CancerCare-Canton
Canton, Illinois, 61520
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, 48188
Trinity Health Medical Center - Canton
Canton, Michigan, 48188
Mercy Cancer Center - Cape Girardeau
Cape Girardeau, Missouri, 63703
Saint Francis Medical Center
Cape Girardeau, Missouri, 63703
Memorial Hospital of Carbondale
Carbondale, Illinois, 62902
Caro Cancer Center
Caro, Michigan, 48723
Carson Tahoe Regional Medical Center
Carson City, Nevada, 89703
SIH Cancer Institute
Carterville, Illinois, 62918
Illinois CancerCare-Carthage
Carthage, Illinois, 62321
Eden Hospital Medical Center
Castro Valley, California, 94546
Sandra L Maxwell Cancer Center
Cedar City, Utah, 84720
Dayton Physicians LLC-Miami Valley South
Centerville, Ohio, 45459
Miami Valley Hospital South
Centerville, Ohio, 45459
Centralia Oncology Clinic
Centralia, Illinois, 62801
Providence Regional Cancer System-Centralia
Centralia, Washington, 98531
Christiana Care Health System-Concord Health Center
Chadds Ford, Pennsylvania, 19317
Chambersburg Hospital
Chambersburg, Pennsylvania, 17201
Cancer Center of Kansas - Chanute
Chanute, Kansas, 66720
Roper Hospital
Charleston, South Carolina, 29401
Charleston Oncology - Roper
Charleston, South Carolina, 29403
Charleston Oncology - Saint Francis
Charleston, South Carolina, 29414
Medical University of South Carolina
Charleston, South Carolina, 29425
Vandalia Health/CAMC Institute for Academic Medicine
Charleston, West Virginia, 25304
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
Erlanger Medical Center
Chattanooga, Tennessee, 37403
Memorial Hospital
Chattanooga, Tennessee, 37404
Chelsea Hospital
Chelsea, Michigan, 48118
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118
Northwestern University
Chicago, Illinois, 60611
Rush MD Anderson Cancer Center
Chicago, Illinois, 60612
Adventist Health Cancer Care Center Chico
Chico, California, 95973
Adena Regional Medical Center
Chillicothe, Ohio, 45601
Marshfield Clinic-Chippewa Center
Chippewa Falls, Wisconsin, 54729
Oncology Hematology Care Inc-Eden Park
Cincinnati, Ohio, 45202
Oncology Hematology Care Inc-Mercy West
Cincinnati, Ohio, 45211
University of Cincinnati Cancer Center-UC Medical Center
Cincinnati, Ohio, 45219
Good Samaritan Hospital - Cincinnati
Cincinnati, Ohio, 45220
Oncology Hematology Care Inc-Anderson
Cincinnati, Ohio, 45230
Oncology Hematology Care Inc-Kenwood
Cincinnati, Ohio, 45236
Bethesda North Hospital
Cincinnati, Ohio, 45242
Oncology Hematology Care Inc-Blue Ash
Cincinnati, Ohio, 45242
TriHealth Cancer Institute-Westside
Cincinnati, Ohio, 45247
TriHealth Cancer Institute-Anderson
Cincinnati, Ohio, 45255
Clackamas Radiation Oncology Center
Clackamas, Oregon, 97015
Providence Cancer Institute Clackamas Clinic
Clackamas, Oregon, 97015
Hematology Oncology Consultants-Clarkston
Clarkston, Michigan, 48346
Newland Medical Associates-Clarkston
Clarkston, Michigan, 48346
Wake Forest University at Clemmons
Clemmons, North Carolina, 27012
Case Western Reserve University
Cleveland, Ohio, 44106
MetroHealth Medical Center
Cleveland, Ohio, 44109
Cleveland Clinic Cancer Center/Fairview Hospital
Cleveland, Ohio, 44111
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Southeastern Medical Oncology Center-Clinton
Clinton, North Carolina, 28328
Mercy Cancer Center-West Lakes
Clive, Iowa, 50325
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
Clive, Iowa, 50325
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814
Coffeyville Regional Medical Center
Coffeyville, Kansas, 67337
Penrose-Saint Francis Healthcare
Colorado Springs, Colorado, 80907
Rocky Mountain Cancer Centers-Penrose
Colorado Springs, Colorado, 80907
UCHealth Memorial Hospital Central
Colorado Springs, Colorado, 80909
Memorial Hospital North
Colorado Springs, Colorado, 80920
Saint Francis Cancer Center
Colorado Springs, Colorado, 80923
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Mount Carmel East Hospital
Columbus, Ohio, 43213
Columbus Oncology and Hematology Associates Inc
Columbus, Ohio, 43214
Riverside Methodist Hospital
Columbus, Ohio, 43214
Grant Medical Center
Columbus, Ohio, 43215
The Mark H Zangmeister Center
Columbus, Ohio, 43219
Mount Carmel Health Center West
Columbus, Ohio, 43222
Doctors Hospital
Columbus, Ohio, 43228
Mercy Hospital
Coon Rapids, Minnesota, 55433
Mary Imogene Bassett Hospital
Cooperstown, New York, 13326
Bay Area Hospital
Coos Bay, Oregon, 97420
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
Commonwealth Cancer Center-Corbin
Corbin, Kentucky, 40701
Alegent Health Mercy Hospital
Council Bluffs, Iowa, 51503
Mary Bird Perkins Cancer Center - Covington
Covington, Louisiana, 70433
Northshore Oncology Associates-Covington
Covington, Louisiana, 70433
Greater Regional Medical Center
Creston, Iowa, 50801
Oncology Hematology Care Inc-Crestview
Crestview Hills, Kentucky, 41017
Northside Hospital-Forsyth
Cumming, Georgia, 30041
Parkland Memorial Hospital
Dallas, Texas, 75235
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Carle at The Riverfront
Danville, Illinois, 61832
Geisinger Medical Center
Danville, Pennsylvania, 17822
Sutter Davis Hospital
Davis, California, 95616
Good Samaritan Hospital - Dayton
Dayton, Ohio, 45406
Miami Valley Hospital
Dayton, Ohio, 45409
Dayton Physician LLC - Englewood
Dayton, Ohio, 45415
Miami Valley Hospital North
Dayton, Ohio, 45415
Halifax Health Cancer Center for Hope - Daytona Beach
Daytona Beach, Florida, 32114
Corewell Health Dearborn Hospital
Dearborn, Michigan, 48124
Emory Decatur Hospital
Decatur, Georgia, 30033
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526
Decatur Memorial Hospital
Decatur, Illinois, 62526
Essentia Health - Deer River Clinic
Deer River, Minnesota, 56636
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
Northwestern Medicine Cancer Center Kishwaukee
DeKalb, Illinois, 60115
Delaware Health Center-Grady Cancer Center
Delaware, Ohio, 43015
Grady Memorial Hospital
Delaware, Ohio, 43015
AdventHealth Porter
Denver, Colorado, 80210
Presbyterian - Saint Lukes Medical Center - Health One
Denver, Colorado, 80218
Saint Joseph Hospital - Cancer Centers of Colorado
Denver, Colorado, 80218
Rose Medical Center
Denver, Colorado, 80220
Mercy Medical Center - Des Moines
Des Moines, Iowa, 50314
UI Health Care Mission Cancer and Blood - Laurel Clinic
Des Moines, Iowa, 50314
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Henry Ford Health Saint John Hospital
Detroit, Michigan, 48236
Essentia Health Saint Mary's - Detroit Lakes Clinic
Detroit Lakes, Minnesota, 56501
Illinois CancerCare-Dixon
Dixon, Illinois, 61021
Cancer Center of Kansas - Dodge City
Dodge City, Kansas, 67801
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Kaiser Permanente Dublin
Dublin, California, 94568
Dublin Methodist Hospital
Dublin, Ohio, 43016
Northside Hospital - Duluth
Duluth, Georgia, 30096
Essentia Health Cancer Center
Duluth, Minnesota, 55805
Essentia Health Saint Mary's Medical Center
Duluth, Minnesota, 55805
Miller-Dwan Hospital
Duluth, Minnesota, 55805
CommonSpirit Cancer Center Mercy
Durango, Colorado, 81301
Mercy Medical Center
Durango, Colorado, 81301
Prisma Health Cancer Institute - Easley
Easley, South Carolina, 29640
Henry Ford River District Hospital
East China Township, Michigan, 48054
Pocono Medical Center
East Stroudsburg, Pennsylvania, 18301
Marshfield Clinic Cancer Center at Sacred Heart
Eau Claire, Wisconsin, 54701
Marshfield Medical Center-EC Cancer Center
Eau Claire, Wisconsin, 54701
Fairview Southdale Hospital
Edina, Minnesota, 55435
Swedish Cancer Institute-Edmonds
Edmonds, Washington, 98026
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Crossroads Cancer Center
Effingham, Illinois, 62401
Cancer Center of Kansas - El Dorado
El Dorado, Kansas, 67042
Walter Knox Memorial Hospital
Emmett, Idaho, 83617
Mountain Blue Cancer Care Center - Swedish
Englewood, Colorado, 80113
Swedish Medical Center
Englewood, Colorado, 80113
Saint Elizabeth Hospital
Enumclaw, Washington, 98022
Ephrata Cancer Center
Ephrata, Pennsylvania, 17522
Ephrata Community Hospital
Ephrata, Pennsylvania, 17522
OSF Saint Francis Hospital and Medical Group
Escanaba, Michigan, 49829
Illinois CancerCare-Eureka
Eureka, Illinois, 61530
NorthShore University HealthSystem-Evanston Hospital
Evanston, Illinois, 60201
Deaconess Clinic Downtown
Evansville, Indiana, 47713
Providence Regional Cancer Partnership
Everett, Washington, 98201
Fairbanks Memorial Hospital
Fairbanks, Alaska, 99701
Oncology Hematology Care Inc-Healthplex
Fairfield, Ohio, 45014
Essentia Health Cancer Center-South University Clinic
Fargo, North Dakota, 58103
Sanford South University Medical Center
Fargo, North Dakota, 58103
Sanford Broadway Medical Center
Fargo, North Dakota, 58122
Sanford Roger Maris Cancer Center
Fargo, North Dakota, 58122
Parkland Health Center - Farmington
Farmington, Missouri, 63640
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, 48334
Virginia Mason Federal Way Medical Center
Federal Way, Washington, 98002
Saint Francis Hospital
Federal Way, Washington, 98003
Lake Region Healthcare Corporation-Cancer Care
Fergus Falls, Minnesota, 56537
Armes Family Cancer Center
Findlay, Ohio, 45840
Blanchard Valley Hospital
Findlay, Ohio, 45840
Orion Cancer Care
Findlay, Ohio, 45840
Cancer Hematology Centers - Flint
Flint, Michigan, 48503
Genesee Hematology Oncology PC
Flint, Michigan, 48503
Genesys Hurley Cancer Institute
Flint, Michigan, 48503
Hurley Medical Center
Flint, Michigan, 48503
Kaiser Permanente-Fontana
Fontana, California, 92335
Poudre Valley Hospital
Fort Collins, Colorado, 80524
McFarland Clinic - Trinity Cancer Center
Fort Dodge, Iowa, 50501
Holy Cross Hospital
Fort Lauderdale, Florida, 33308
Cancer Center of Kansas - Fort Scott
Fort Scott, Kansas, 66701
Essentia Health - Fosston
Fosston, Minnesota, 56542
Atrium Medical Center-Middletown Regional Hospital
Franklin, Ohio, 45005-1066
Dayton Physicians LLC-Atrium
Franklin, Ohio, 45005
Vanderbilt-Ingram Cancer Center Cool Springs
Franklin, Tennessee, 37067
Frederick Memorial Hospital
Frederick, Maryland, 21701
FMH James M Stockman Cancer Institute
Frederick, Maryland, 21702
Palo Alto Medical Foundation-Fremont
Fremont, California, 94538
Kaiser Permanente-Fresno
Fresno, California, 93720
Unity Hospital
Fridley, Minnesota, 55432
Saint Luke's Cancer Institute - Fruitland
Fruitland, Idaho, 83619
Illinois CancerCare-Galesburg
Galesburg, Illinois, 61401
Western Illinois Cancer Treatment Center
Galesburg, Illinois, 61401
Central Care Cancer Center - Garden City
Garden City, Kansas, 67846
Saint Catherine Hospital
Garden City, Kansas, 67846
Northwestern Medicine Cancer Center Delnor
Geneva, Illinois, 60134
Adams Cancer Center
Gettysburg, Pennsylvania, 17325
Tacoma/Valley Radiation Oncology Centers-Gig Harbor
Gig Harbor, Washington, 98332
MultiCare Gig Harbor Medical Park
Gig Harbor, Washington, 98335
NorthShore University HealthSystem-Glenbrook Hospital
Glenview, Illinois, 60026
Mountain Blue Cancer Care Center
Golden, Colorado, 80401
Southeastern Medical Oncology Center-Goldsboro
Goldsboro, North Carolina, 27534
Wayne Memorial Hospital
Goldsboro, North Carolina, 27534
CTCA at Western Regional Medical Center
Goodyear, Arizona, 85338
Nebraska Cancer Specialists/Oncology Hematology West PC
Grand Island, Nebraska, 68803
Grand Valley Oncology
Grand Junction, Colorado, 81505
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
Grand Rapids, Michigan, 49503
About this study
Official title: DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a Phase III Trial
This 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.
Read the detailed description
PRIMARY OBJECTIVE:
- 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:
- 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.
- 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:
- 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 versus [vs] crossover treatment).
SECONDARY PATIENT REPORTED OUTCOMES OBJECTIVES:
- 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:
- 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.
EXPLORATORY CORRELATIVE OBJECTIVES:
- To assess serum based biomarkers of efficacy and adverse events due to treatment with immune checkpoint inhibitors.
II. To monitor tumor response by comparing changes in circulating cell-free mutant tumor deoxyribonucleic acid (DNA) (ctDNA) as a readout of tumor burden (a) at week 12 relative to baseline before treatment in responders and non-responders; (b) before and during immunosuppressive treatment to control irAEs.
III. To monitor organ-specific adverse events (irAEs) using circulating cell-free, tissue-specific methylated DNA (cmeDNA) as a readout of tissue-specific toxicity (a) at the time of grade 3-4 irAE relative to baseline and control patients without irAEs; (b) during immunosuppressive treatment for irAEs.
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 (or before), 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 (or before), 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.
All patients also undergo computed tomography (CT), echocardiography (ECHO) or multigated acquisition scan (MUGA), and collection of blood samples throughout the trial.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
- Conditions
- Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma, Recurrent Melanoma, Unresectable Melanoma
- Being tested
- Biospecimen Collection, Computed Tomography, Dabrafenib Mesylate, Echocardiography Test, Ipilimumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo collection of blood samples
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
Dabrafenib MesylateDrug
Also called Dabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, Tafinlar
Given PO
Echocardiography TestProcedure or surgery
Also called EC, Echocardiography
Undergo ECHO
IpilimumabBiological
Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016
Given IV
Multigated Acquisition ScanProcedure or surgery
Also called Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, MUGA
Undergo MUGA scan
NivolumabBiological
Also called ABP 206, BCD-263, BMS 936558, BMS-936558
Given IV
Quality-of-Life AssessmentOther
Also called Quality of Life Assessment
Ancillary studies
Trametinib Dimethyl SulfoxideDrug
Also called Mekinist, Meqsel, Spexotras
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Arm A (immunotherapy) | Experimental | 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. Upon disease progression (or before), patients re-register and cross over to Arm C.
Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial. Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Biological: Ipilimumab; Procedure: Multigated Acquisition Scan; Biological: Nivolumab; Other: Quality-of-Life Assessment |
| Arm B (BRAF inhibitor therapy) | Experimental | 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 (or before), patients re-register and cross over to Arm D.
Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial. Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Dabrafenib Mesylate; Procedure: Echocardiography Test; Procedure: Multigated Acquisition Scan; Other: Quality-of-Life Assessment; Drug: Trametinib Dimethyl Sulfoxide |
| Arm C (BRAF inhibitor therapy) | Experimental | 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.
Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial. Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Dabrafenib Mesylate; Procedure: Echocardiography Test; Procedure: Multigated Acquisition Scan; Other: Quality-of-Life Assessment; Drug: Trametinib Dimethyl Sulfoxide |
| Arm D (immunotherapy) | Experimental | 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.
Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial. Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Biological: Ipilimumab; Procedure: Multigated Acquisition Scan; Biological: Nivolumab; Other: Quality-of-Life Assessment |
What is being measured
The primary outcome is the main question the study is designed to answer.
2-year Overall Survival (OS)
Overall Survival (OS) was defined as the time from randomization to death from any cause. Patients who have not died would be censored at the date of last known alive. 2-year OS rate was defined as a proportion of patients who are alive after two years of follow-up time among all cases who have died within 2 years or alive after 2-year follow-up time. Kaplan-Meier method was used to estimate 2-year OS.
Measured: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry
Secondary outcomes (10)
Median Overall Survival
Overall Survival (OS) was defined as the time from randomization to death from any cause. Patients who have not died would be censored at the date of last known alive. Median overall survival was estimated using Kaplan-Meier method.
Measured: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry
3-year OS
Overall Survival (OS) was defined as the time from randomization to death from any cause. Patients who have not died would be censored at the date of last known alive. 3-year OS rate was defined as a proportion of patients who are alive after three years of follow-up time among all cases who have died within 3 years or alive after 3-year follow-up time. Kaplan-Meier method was used to estimate 3-year OS.
Measured: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry
Median Progression-free Survival (Arm A vs Arm B)
Progression-Free Survival (PFS) was defined as the time from randomization to disease progression or death (whichever occurs first). Cases without an event to date was censored at the date of last disease assessment documenting the patient was free of progression. Progression was evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Median PFS was estimated using Kaplan-Meier method.
Measured: assessed at baseline and then every 12 weeks from start of treatment if patient is < 2 years from study entry (or < 2 years from crossover), then every 6 months until 5 years from study entry
Median Progression-free Survival (Arm A vs Arm D)
Progression-Free Survival (PFS) was defined as the time from randomization (arm A) or crossover (arm D) to disease progression or death (whichever occurs first). Cases without an event to date was censored at the date of last disease assessment documenting the patient was free of progression. Progression was evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Median PFS was estimated using Kaplan-Meier method.
Measured: assessed at baseline and then every 12 weeks from start of treatment if patient is < 2 years from study entry (or < 2 years from crossover), then every 6 months until 5 years from study entry
Median Progression-free Survival (Arm B vs Arm C)
Progression-Free Survival (PFS) was defined as the time from randomization (arm B) or crossover (arm C) to disease progression or death (whichever occurs first). Cases without an event to date was censored at the date of last disease assessment documenting the patient was free of progression. Progression was evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Median PFS was estimated using Kaplan-Meier method.
Measured: assessed at baseline and then every 12 weeks from start of treatment if patient is < 2 years from study entry (or < 2 years from crossover), then every 6 months until 5 years from study entry
Percentage of Crossover
Percentage of crossover was defined as percentage of patients who are able to cross-over from one arm to the other and complete at least an initial course (12 weeks) of treatment after crossover without intervening symptomatic disease progression or treatment limiting toxicity.
Measured: assessed at crossover and 12 weeks after treatment post-crossover
Overall Health
The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) score was used to measure overall health. Differences between treatment groups in the mean Q-TWiST score were calculated. For each score, a 95% confidence interval (CI) and two-sided P-value for testing the null hypothesis of no difference between treatment groups were conducted using a Z-test (with normal approximation), with standard errors calculated by the bootstrap method.
Measured: assessed at baseline and 2 years after initiation of treatment
Response Rate (Arm A vs Arm B)
Response was assessed based on the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Response rate was defined as proportion of patients with complete response or partial response. Response rates were compared using the Mantel-Haenszel test (stratified by ECOG PS and LDH) test in arms A vs. B
Measured: assessed at baseline and then every 12 weeks from start of treatment if patient is < 2 years from study entry (or < 2 years from crossover), then every 6 months until 5 years from study entry
Response Rate (Arm A vs Arm D)
Response was assessed based on the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Response rate was defined as proportion of patients with complete response or partial response. Response rates were compared using Fisher exact test in arms A vs D.
Measured: assessed at baseline and then every 12 weeks from start of treatment if patient is < 2 years from study entry (or < 2 years from crossover), then every 6 months until 5 years from study entry
Response Rate (Arm B vs Arm C)
Response was assessed based on the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Response rate was defined as proportion of patients with complete response or partial response. Response rates were compared using Fisher exact test in arms B vs C.
Measured: assessed at baseline and then every 12 weeks from start of treatment if patient is < 2 years from study entry (or < 2 years from crossover), then every 6 months until 5 years from study entry
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2014 (estimated)
- Study start8 Sep 2015
- Primary completion30 Sep 2023
- Study completion19 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Clinical Stage III Cutaneous Melanoma AJCC v8Studies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 267 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Michael B Atkins, Principal investigator, ECOG-ACRIN Cancer Research Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02224781
- Sponsor's protocol ID
- NCI-2014-01747
- Other IDs
- NCI-2014-01747, EA6134, EA6134, U10CA180820
- Status last verified
- Jul 2026
- First submitted
- 22 Aug 2014
- Last updated
- 22 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Atkins MB, Lee SJ, Chmielowski B, Tarhini AA, Cohen GI, Truong TG, Moon HH, Davar D, O'Rourke M, Stephenson JJ, Curti BD, Urba WJ, Brell JM, Funchain P, Kendra KL, Ikeguchi AP, Jaslowski A, Bane CL, Taylor MA, Bajaj M, Conry RM, Ellis RJ, Logan TF, Laudi N, Sosman JA, Crockett DG, Pecora AL, Okazaki IJ, Reganti S, Chandra S, Guild S, Chen HX, Streicher HZ, Wolchok JD, Ribas A, Kirkwood JM. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023 Jan 10;41(2):186-197. doi: 10.1200/JCO.22.01763. Epub 2022 Sep 27.
PubMed 36166727Barker CA, Salama AK. New NCCN Guidelines for Uveal Melanoma and Treatment of Recurrent or Progressive Distant Metastatic Melanoma. J Natl Compr Canc Netw. 2018 May;16(5S):646-650. doi: 10.6004/jnccn.2018.0042.
PubMed 29784747