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
Purpose
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. Ipilimumab and nivolumab may block tumor growth by targeting certain cells. 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.
Conditions
- BRAF NP_004324.2:p.V600X
- Metastatic Melanoma
- Recurrent Melanoma
- Stage III Cutaneous Melanoma AJCC v7
- Stage IIIA Cutaneous Melanoma AJCC v7
- Stage IIIB Cutaneous Melanoma AJCC v7
- Stage IIIC Cutaneous Melanoma AJCC v7
- Stage IV Cutaneous Melanoma AJCC v6 and v7
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- STEP 1
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
- Women must not be pregnant or breast-feeding
- 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 any woman, regardless of sexual orientation
or 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)
- 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
and sexually active males must use at least two other accepted and effective methods
of contraception and/or abstain from sexual intercourse for at least 7 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)
- 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 >= 2 weeks prior to entering the study and
recovered from any adverse events associated with treatment; prior surgery must be >=
4 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 active 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; patients with only whole brain irradiation for treatment of CNS metastases
will be ineligible
- 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 > 3 years prior to the time of registration; patients
with history of RAS mutation-positive tumors are not eligible regardless of interval
from the current study; Note: prospective RAS testing is not required; however, if the
results of previous RAS testing are known, they must be used in assessing eligibility
- 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 > 9 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)
- Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement
and =< 7 x ULN for patients with known bone involvement)
- 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
- Serum lactate dehydrogenase (LDH) < 10 X ULN (patients with LDH > 10 X ULN are felt to
have aggressive disease and should be considered for BRAF inhibitor therapy off
protocol), 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, history of bleeding
diathesis or need for concurrent anticoagulation (international normalized ratio [INR]
=< 1.5 and partial thromboplastin time [PTT] within 1.1 x ULN), 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)/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) =< lower limit of normal on cardiac
echocardiogram (echo) or multi gated acquisition scan (MUGA)
- Intra-cardiac defibrillator
- History of abnormal cardiac valve morphology (>= grade 2) documented by ECHO
(subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be
entered on study); subjects with moderate valvular thickening should not be
entered on study
- History or evidence of current clinically significant uncontrolled cardiac
arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30
days prior to dosing are eligible
- Treatment refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
therapy
- Individuals who are known to be human immunodeficiency virus (HIV) infected are
eligible (note: HIV testing is not required for entry into the study)
- Patients with evidence of active hepatitis B virus (HBV) or hepatitis C Virus (HCV)
infection are not eligible; patients with cleared HBV and HCV infection will be
allowed
- 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; 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 ARM FOR PATIENTS WITH PROGRESSIVE DISEASE)
- 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 ipilimumab +
nivolumab treatment
- History of autoimmune disease, excluding interstitial lung disease or
pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib
therapy
- Patients crossing over from nivolumab/ipilimumab to 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 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
- Patients must have melanoma that is metastatic and clearly progressive on prior
therapy
- Patients must be at least 2 weeks and within 12 weeks from documented progressive
disease (PD) on Step 1 of current study; all sites of disease must be evaluated within
4 weeks prior to registration
- 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
- 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
- Patients are ineligible if they have any currently active 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
dabrafenib/trametinib to nivolumab (nivo)/ipilimumab (ipi) must not have taken any
steroids =< 10 days prior to registration for the purpose of managing their brain
metastases; patients with only whole brain irradiation for treatment of CNS metastases
are ineligible
- 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
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Arm A (immunotherapy) |
IMMUNOTHERAPY INDUCTION (COURSES 1-2): Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C. |
|
|
Experimental Arm B (BRAF inhibitor therapy) |
Patients receive dabrafenib PO BID and trametinib PO daily on days 1-42. Courses 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. |
|
|
Experimental Arm C (BRAF inhibitor therapy) |
Patients receive dabrafenib PO BID and trametinib PO daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. |
|
|
Experimental Arm D (immunotherapy) |
IMMUNOTHERAPY INDUCTION (COURSES 1-2): Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. |
|
Recruiting Locations
Birmingham, Alabama 35233
Robert M. Conry
800-828-8816
Anchorage, Alaska 98508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Fairbanks, Alaska 99701
John A. Keech
907-458-5380
Hot Springs, Arkansas 71913
Little Rock, Arkansas 72205
Issam Makhoul
501-686-8274
Anaheim, California 92807
Gary L. Buchschacher
626-564-3455
Baldwin Park, California 91706
Gary L. Buchschacher
626-564-3455
Bellflower, California 90706
Gary L. Buchschacher
626-564-3455
Berkeley, California 94704
Burbank, California 91505
Duarte, California 91010
Fontana, California 92335
Gary L. Buchschacher
626-564-3455
Fresno, California 93720
Tatjana Kolevska
510-891-3400
Harbor City, California 90710
Gary L. Buchschacher
626-564-3455
Irvine, California 92618
Gary L. Buchschacher
626-564-3455
Los Angeles, California 90027
Gary L. Buchschacher
626-564-3455
Los Angeles, California 90034
Gary L. Buchschacher
626-564-3455
Los Angeles, California 90095
Bartosz Chmielowski
888-798-0719
Mountain View, California 94040
Mountain View, California 94040
Novato, California 94945
Oakland, California 94611
Tatjana Kolevska
510-891-3400
Ontario, California 91761
Gary L. Buchschacher
626-564-3455
Palo Alto, California 94301
Panorama City, California 91402
Gary L. Buchschacher
626-564-3455
Rancho Cucamonga, California 91730
Rancho Mirage, California 92270
Varun Gupta
760-834-3798
Richmond, California 94801
Tatjana Kolevska
510-891-3400
Riverside, California 92505
Gary L. Buchschacher
626-564-3455
Roseville, California 95661
Tatjana Kolevska
510-891-3400
Sacramento, California 95816
Sacramento, California 95825
Tatjana Kolevska
510-891-3400
San Diego, California 92108
Gary L. Buchschacher
626-564-3455
San Diego, California 92120
Gary L. Buchschacher
626-564-3455
San Francisco, California 94115
San Marcos, California 92078
Gary L. Buchschacher
626-564-3455
Santa Clara, California 95051
Tatjana Kolevska
510-891-3400
Stockton, California 95210
Tatjana Kolevska
510-891-3400
Sunnyvale, California 94086
Vallejo, California 94589
Tatjana Kolevska
510-891-3400
Walnut Creek, California 94596
Tatjana Kolevska
510-891-3400
Woodland Hills, California 91367
Gary L. Buchschacher
626-564-3455
Aurora, Colorado 80045
Karl D. Lewis
720-848-0650
Colorado Springs, Colorado 80907
Mehmet S. Copur
501-622-2100
Colorado Springs, Colorado 80907
Mehmet S. Copur
501-622-2100
Colorado Springs, Colorado 80909
Karl D. Lewis
720-848-0650
Denver, Colorado 80210
Mehmet S. Copur
501-622-2100
Denver, Colorado 80218
Durango, Colorado 81301
Mehmet S. Copur
501-622-2100
Durango, Colorado 81301
Mehmet S. Copur
501-622-2100
Englewood, Colorado 80113
Englewood, Colorado 80113
Fort Collins, Colorado 80524
Karl D. Lewis
720-848-0650
Golden, Colorado 80401
Mehmet S. Copur
501-622-2100
Greeley, Colorado 80631
Lakewood, Colorado 80228
Mehmet S. Copur
501-622-2100
Lakewood, Colorado 80228
Mehmet S. Copur
501-622-2100
Littleton, Colorado 80122
Mehmet S. Copur
501-622-2100
Longmont, Colorado 80501
Mehmet S. Copur
501-622-2100
Longmont, Colorado 80501
Mehmet S. Copur
501-622-2100
Loveland, Colorado 80539
Parker, Colorado 80138
Mehmet S. Copur
501-622-2100
Parker, Colorado 80138
Mehmet S. Copur
501-622-2100
Pueblo, Colorado 81004
Mehmet S. Copur
501-622-2100
Pueblo, Colorado 81008
Mehmet S. Copur
501-622-2100
Thornton, Colorado 80260
Mehmet S. Copur
501-622-2100
Norwich, Connecticut 06360
Dennis E. Slater
860-886-8362
Stamford, Connecticut 06904
Salvatore A. Del Prete
203-323-8944
Washington, District of Columbia 20007
Michael B. Atkins
202-444-2223
Washington, District of Columbia 20010
Michael B. Atkins
202-444-2223
Aventura, Florida 33180
Daytona Beach, Florida 32114
Miami Beach, Florida 33140
Miami, Florida 33136
Lynn G. Feun
305-243-2647
Athens, Georgia 30607
Atlanta, Georgia 30322
David H. Lawson
404-778-1868
Atlanta, Georgia 30342
Atlanta, Georgia 30342
Ronald G. Steis
404-303-3355
Augusta, Georgia 30912
Cumming, Georgia 30041
Ronald G. Steis
404-303-3355
Decatur, Georgia 30033
Savannah, Georgia 31405
Howard A. Zaren
912-819-5704
'Aiea, Hawaii 96701
Jeffrey L. Berenberg
808-586-2979
'Aiea, Hawaii 96701
Jeffrey L. Berenberg
808-486-6000
Honolulu, Hawaii 96813
Jeffrey L. Berenberg
808-586-2979
Honolulu, Hawaii 96813
Jeffrey L. Berenberg
808-586-2979
Honolulu, Hawaii 96813
Jeffrey L. Berenberg
808-586-2979
Honolulu, Hawaii 96813
Jeffrey L. Berenberg
808-522-4333
Honolulu, Hawaii 96813
Jeffrey L. Berenberg
808-586-2979
Honolulu, Hawaii 96817
Jeffrey L. Berenberg
808-586-2979
Honolulu, Hawaii 96817
Jeffrey L. Berenberg
808-586-2979
Honolulu, Hawaii 96826
Jeffrey L. Berenberg
808-983-6090
Lihue, Hawaii 96766
Jeffrey L. Berenberg
808-535-7960
Boise, Idaho 83706
Christopher M. Reynolds
208-367-7954
Boise, Idaho 83712
Caldwell, Idaho 83605
Christopher M. Reynolds
208-367-7954
Coeur d'Alene, Idaho 83814
Emmett, Idaho 83617
Christopher M. Reynolds
208-367-7954
Fruitland, Idaho 83619
Meridian, Idaho 83642
Christopher M. Reynolds
208-367-7954
Meridian, Idaho 83642
Nampa, Idaho 83686
Christopher M. Reynolds
208-367-7954
Nampa, Idaho 83686
Post Falls, Idaho 83854
Sandpoint, Idaho 83864
Twin Falls, Idaho 83301
Aurora, Illinois 60504
Bloomington, Illinois 61704
Canton, Illinois 61520
Centralia, Illinois 62801
Chicago, Illinois 60611
Chicago, Illinois 60612
Danville, Illinois 61832
Decatur, Illinois 62526
Decatur, Illinois 62526
Effingham, Illinois 62401
Effingham, Illinois 62401
Eureka, Illinois 61530
Evanston, Illinois 60201
Bruce E. Brockstein
847-570-2109
Galesburg, Illinois 61401
Galesburg, Illinois 61401
Bryan A. Faller
309-344-2831
Geneva, Illinois 60134
John D. Ayers
847-827-9060
Glenview, Illinois 60026
Bruce E. Brockstein
847-570-2109
Highland Park, Illinois 60035
Bruce E. Brockstein
847-570-2109
Macomb, Illinois 61455
Mattoon, Illinois 61938
Maywood, Illinois 60153
Joseph I. Clark
708-202-8387
Ottawa, Illinois 61350
Pekin, Illinois 61554
Pekin, Illinois 61554
Peoria, Illinois 61615
Peoria, Illinois 61615
Peoria, Illinois 61636
Peoria, Illinois 61637
Peru, Illinois 61354
Peru, Illinois 61354
Bryan A. Faller
815-664-4141
Springfield, Illinois 62702
Bryan A. Faller
217-545-7929
Springfield, Illinois 62702
Bryan A. Faller
800-444-7541
Springfield, Illinois 62781
Bryan A. Faller
217-788-3528
Swansea, Illinois 62226
Urbana, Illinois 61801
Urbana, Illinois 61801
Warrenville, Illinois 60555
John D. Ayers
847-827-9060
Yorkville, Illinois 60560
Indianapolis, Indiana 46202
Theodore F. Logan
888-342-7602
Indianapolis, Indiana 46202
Theodore F. Logan
317-630-7808
Indianapolis, Indiana 46237
Stephen E. Rubenstein
317-528-7060
Indianapolis, Indiana 46237
Stephen E. Rubenstein
317-528-7060
Mooresville, Indiana 46158
Stephen E. Rubenstein
317-528-7060
Ames, Iowa 50010
Joseph J. Merchant
515-239-2621
Ames, Iowa 50010
Joseph J. Merchant
515-239-2621
Boone, Iowa 50036
Joseph J. Merchant
515-239-2621
Clive, Iowa 50325
Mehmet S. Copur
501-622-2100
Clive, Iowa 50325
Mehmet S. Copur
501-622-2100
Council Bluffs, Iowa 51503
Mehmet S. Copur
501-622-2100
Creston, Iowa 50801
Mehmet S. Copur
501-622-2100
Des Moines, Iowa 50314
Mehmet S. Copur
501-622-2100
Des Moines, Iowa 50314
Mehmet S. Copur
501-622-2100
Fort Dodge, Iowa 50501
Joseph J. Merchant
515-239-2621
Jefferson, Iowa 50129
Joseph J. Merchant
515-239-2621
Marshalltown, Iowa 50158
Joseph J. Merchant
515-239-2621
Sioux City, Iowa 51101
Donald B. Wender
712-252-0088
West Des Moines, Iowa 50266
Mehmet S. Copur
501-622-2100
Chanute, Kansas 66720
Shaker R. Dakhil
316-268-5374
Dodge City, Kansas 67801
Shaker R. Dakhil
316-268-5374
El Dorado, Kansas 67042
Shaker R. Dakhil
316-268-5374
Fort Scott, Kansas 66701
Shaker R. Dakhil
316-268-5374
Garden City, Kansas 67846
Great Bend, Kansas 67530
Independence, Kansas 67301
Shaker R. Dakhil
316-268-5374
Kansas City, Kansas 66112
Kansas City, Kansas 66160
Kingman, Kansas 67068
Shaker R. Dakhil
316-268-5374
Lawrence, Kansas 66044
Shaker R. Dakhil
316-268-5374
Liberal, Kansas 67905
Shaker R. Dakhil
316-268-5374
Manhattan, Kansas 66502
Shaker R. Dakhil
316-268-5784
McPherson, Kansas 67460
Shaker R. Dakhil
316-268-5374
Newton, Kansas 67114
Shaker R. Dakhil
316-268-5374
Olathe, Kansas 66061
Overland Park, Kansas 66210
Parsons, Kansas 67357
Shaker R. Dakhil
316-268-5374
Pratt, Kansas 67124
Shaker R. Dakhil
316-268-5374
Salina, Kansas 67401
Shaker R. Dakhil
316-268-5374
Salina, Kansas 67401
Topeka, Kansas 66606
Wellington, Kansas 67152
Shaker R. Dakhil
316-268-5374
Westwood, Kansas 66205
Wichita, Kansas 67208
Shaker R. Dakhil
316-268-5374
Wichita, Kansas 67208
Shaker R. Dakhil
316-268-5374
Wichita, Kansas 67214
Shaker R. Dakhil
316-268-5374
Wichita, Kansas 67214
Shaker R. Dakhil
316-268-5374
Winfield, Kansas 67156
Shaker R. Dakhil
316-268-5374
Bardstown, Kentucky 40004
Mehmet S. Copur
501-622-2100
Corbin, Kentucky 40701
Mehmet S. Copur
501-622-2100
Lexington, Kentucky 40504
Mehmet S. Copur
501-622-2100
Lexington, Kentucky 40509
Mehmet S. Copur
501-622-2100
Louisville, Kentucky 40202
Mehmet S. Copur
501-622-2100
Louisville, Kentucky 40202
Jason A. Chesney
502-562-3429
Louisville, Kentucky 40215
Mehmet S. Copur
501-622-2100
Louisville, Kentucky 40245
Mehmet S. Copur
501-622-2100
Shepherdsville, Kentucky 40165
Mehmet S. Copur
501-622-2100
Baton Rouge, Louisiana 70805
Baton Rouge, Louisiana 70809
Baton Rouge, Louisiana 70809
Baton Rouge, Louisiana 70809
Covington, Louisiana 70433
Houma, Louisiana 70360
New Orleans, Louisiana 70112
New Orleans, Louisiana 70112
Augusto C. Ochoa
504-903-3000
New Orleans, Louisiana 70121
Marc R. Matrana
504-842-3708
Baltimore, Maryland 21204
Mei Tang
443-849-3706
Baltimore, Maryland 21229
Carole B. Miller
410-368-2910
Baltimore, Maryland 21237
Michael B. Atkins
202-444-2223
Frederick, Maryland 21701
Adrian, Michigan 49221
Rex B. Mowat
517-265-0116
Ann Arbor, Michigan 48106
Christopher M. Reynolds
208-367-7954
Ann Arbor, Michigan 48109
Leslie A. Fecher
800-865-1125
Battle Creek, Michigan 49017
Brighton, Michigan 48114
Christopher M. Reynolds
208-367-7954
Brighton, Michigan 48114
Christopher M. Reynolds
208-367-7954
Canton, Michigan 48188
Christopher M. Reynolds
208-367-7954
Canton, Michigan 48188
Christopher M. Reynolds
208-367-7954
Caro, Michigan 48723
Christopher M. Reynolds
208-367-7954
Chelsea, Michigan 48118
Christopher M. Reynolds
208-367-7954
Chelsea, Michigan 48118
Christopher M. Reynolds
208-367-7954
Clarkston, Michigan 48346
Christopher M. Reynolds
208-367-7954
Clarkston, Michigan 48346
Christopher M. Reynolds
208-367-7954
Detroit, Michigan 48201
Lawrence E. Flaherty
313-576-9363
Detroit, Michigan 48236
Christopher M. Reynolds
208-367-7954
East China Township, Michigan 48054
Christopher M. Reynolds
208-367-7954
Escanaba, Michigan 49829
Farmington Hills, Michigan 48334
Flint, Michigan 48503
Christopher M. Reynolds
208-367-7954
Flint, Michigan 48503
Christopher M. Reynolds
208-367-7954
Flint, Michigan 48503
Christopher M. Reynolds
208-367-7954
Flint, Michigan 48503
Christopher M. Reynolds
208-367-7954
Grand Rapids, Michigan 49503
Grand Rapids, Michigan 49503
Grosse Pointe Woods, Michigan 48236
Christopher M. Reynolds
208-367-7954
Grosse Pointe Woods, Michigan 48236
Christopher M. Reynolds
208-367-7954
Grosse Pointe Woods, Michigan 48236
Christopher M. Reynolds
208-367-7954
Kalamazoo, Michigan 49001
Kalamazoo, Michigan 49007
Lansing, Michigan 48912
Christopher M. Reynolds
208-367-7954
Livonia, Michigan 48154
Christopher M. Reynolds
208-367-7954
Livonia, Michigan 48154
Christopher M. Reynolds
208-367-7954
Macomb, Michigan 48044
Christopher M. Reynolds
208-367-7954
Macomb, Michigan 48044
Christopher M. Reynolds
208-367-7954
Marlette, Michigan 48453
Christopher M. Reynolds
208-367-7954
Monroe, Michigan 48162
Rex B. Mowat
517-265-0116
Muskegon, Michigan 49444
Pontiac, Michigan 48341
Christopher M. Reynolds
208-367-7954
Pontiac, Michigan 48341
Christopher M. Reynolds
208-367-7954
Pontiac, Michigan 48341
Christopher M. Reynolds
208-367-7954
Pontiac, Michigan 48341
Christopher M. Reynolds
208-367-7954
Reed City, Michigan 49677
Rochester Hills, Michigan 48309
Christopher M. Reynolds
208-367-7954
Saginaw, Michigan 48601
Christopher M. Reynolds
208-367-7954
Saginaw, Michigan 48604
Christopher M. Reynolds
208-367-7954
Sterling Heights, Michigan 48312
Christopher M. Reynolds
208-367-7954
Tawas City, Michigan 48764
Warren, Michigan 48088
Christopher M. Reynolds
208-367-7954
Warren, Michigan 48093
Christopher M. Reynolds
208-367-7954
Warren, Michigan 48093
Christopher M. Reynolds
208-367-7954
Warren, Michigan 48093
Christopher M. Reynolds
208-367-7954
Warren, Michigan 48093
Christopher M. Reynolds
208-367-7954
Warren, Michigan 48093
Christopher M. Reynolds
208-367-7954
West Branch, Michigan 48661
Christopher M. Reynolds
208-367-7954
Wyoming, Michigan 49519
Ypsilanti, Michigan 48106
Christopher M. Reynolds
208-367-7954
Ypsilanti, Michigan 48197
Christopher M. Reynolds
208-367-7954
Bemidji, Minnesota 56601
Preston D. Steen
712-252-0088
Brainerd, Minnesota 56401
Bret E. Friday
888-203-7267
Coon Rapids, Minnesota 55433
Duluth, Minnesota 55805
Bret E. Friday
888-203-7267
Duluth, Minnesota 55805
Bret E. Friday
888-203-7267
Duluth, Minnesota 55805
Bret E. Friday
888-203-7267
Edina, Minnesota 55435
Fergus Falls, Minnesota 56537
Bret E. Friday
888-203-7267
Fridley, Minnesota 55432
Maplewood, Minnesota 55109
Minneapolis, Minnesota 55407
Minneapolis, Minnesota 55415
Minneapolis, Minnesota 55454
Robbinsdale, Minnesota 55422
Saint Paul, Minnesota 55101
Saint Paul, Minnesota 55102
Shakopee, Minnesota 55379
Stillwater, Minnesota 55082
Virginia, Minnesota 55792
Bret E. Friday
844-681-7944
Woodbury, Minnesota 55125
Bonne Terre, Missouri 63628
Bryan A. Faller
314-996-5569
Cape Girardeau, Missouri 63703
Cape Girardeau, Missouri 63703
Bryan A. Faller
573-651-5550
Jefferson City, Missouri 65109
Kansas City, Missouri 64108
Saint Louis, Missouri 63131
Bryan A. Faller
314-996-5569
Sainte Genevieve, Missouri 63670
Bryan A. Faller
314-996-5569
Springfield, Missouri 65804
Jay W. Carlson
888-221-4849
Springfield, Missouri 65807
Jay W. Carlson
888-221-4849
Sullivan, Missouri 63080
Bryan A. Faller
314-996-5569
Sunset Hills, Missouri 63127
Bryan A. Faller
314-996-5569
Anaconda, Montana 59711
Bozeman, Montana 59715
Great Falls, Montana 59405
Helena, Montana 59601
Kalispell, Montana 59901
Missoula, Montana 59802
Bellevue, Nebraska 68123
Grand Island, Nebraska 68803
Mehmet S. Copur
501-622-2100
Kearney, Nebraska 68845
Mehmet S. Copur
501-622-2100
Kearney, Nebraska 68847
Mehmet S. Copur
501-622-2100
Lincoln, Nebraska 68510
Mehmet S. Copur
402-483-2827
Omaha, Nebraska 68114
Ralph J. Hauke
402-354-5144
Omaha, Nebraska 68118
Omaha, Nebraska 68122
Mehmet S. Copur
501-622-2100
Omaha, Nebraska 68122
Mehmet S. Copur
501-622-2100
Omaha, Nebraska 68124
Mehmet S. Copur
501-622-2100
Omaha, Nebraska 68124
Omaha, Nebraska 68130
Mehmet S. Copur
501-622-2100
Omaha, Nebraska 68131
Mehmet S. Copur
501-622-2100
Omaha, Nebraska 68198
Papillion, Nebraska 68046
Mehmet S. Copur
501-622-2100
Henderson, Nevada 89052
John A. Ellerton
702-384-0013
Henderson, Nevada 89052
John A. Ellerton
702-384-0013
Henderson, Nevada 89052
John A. Ellerton
702-822-2000
Henderson, Nevada 89074
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89102
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89106
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89128
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89128
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89128
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89144
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89148
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89148
John A. Ellerton
702-384-0013
Las Vegas, Nevada 89169
John A. Ellerton
702-384-0013
Reno, Nevada 89502
John A. Ellerton
702-384-0013
Reno, Nevada 89503
John A. Ellerton
805-474-9143
Reno, Nevada 89509
John A. Ellerton
702-384-0013
Hackensack, New Jersey 07601
Donna T. McNamara
201-996-2879
Albuquerque, New Mexico 87102
Albuquerque, New Mexico 87109
Las Cruces, New Mexico 88011
Rio Rancho, New Mexico 87124
Buffalo, New York 14263
Marc S. Ernstoff
877-275-7724
Cooperstown, New York 13326
Rochester, New York 14642
Paul M. Barr
585-275-5830
Syracuse, New York 13210
Rahul Seth
315-464-5476
Asheville, North Carolina 28803
Raymond Thertulien
828-213-4150
Clinton, North Carolina 28328
James N. Atkins
252-399-7491
Goldsboro, North Carolina 27534
James N. Atkins
252-399-7491
Goldsboro, North Carolina 27534
James N. Atkins
252-399-7491
Hendersonville, North Carolina 28791
James E. Radford
828-696-1341
Jacksonville, North Carolina 28546
James N. Atkins
252-399-7491
Jacksonville, North Carolina 28546
James N. Atkins
252-399-7491
Kinston, North Carolina 28501
Peter R. Watson
252-559-2200
Winston-Salem, North Carolina 27104
Asheesh Shipstone
423-578-8538
Bismarck, North Dakota 58501
Preston D. Steen
712-252-0088
Fargo, North Dakota 58103
Bret E. Friday
888-203-7267
Fargo, North Dakota 58122
Preston D. Steen
712-252-0088
Fargo, North Dakota 58122
Preston D. Steen
712-252-0088
Fargo, North Dakota 58122
Preston D. Steen
712-252-0088
Beachwood, Ohio 44122
Henry B. Koon
800-641-2422
Centerville, Ohio 45459
Centerville, Ohio 45459
Cincinnati, Ohio 45219
Cincinnati, Ohio 45220
Mehmet S. Copur
501-622-2100
Cincinnati, Ohio 45242
Mehmet S. Copur
501-622-2100
Cincinnati, Ohio 45247
Mehmet S. Copur
501-622-2100
Cincinnati, Ohio 45255
Mehmet S. Copur
501-622-2100
Cleveland, Ohio 44106
Henry B. Koon
800-641-2422
Cleveland, Ohio 44109
Cleveland, Ohio 44111
Ahmad Tarhini
866-223-8100
Cleveland, Ohio 44195
Ahmad Tarhini
866-223-8100
Columbus, Ohio 43210
Columbus, Ohio 43214
Columbus, Ohio 43214
Columbus, Ohio 43215
Timothy D. Moore
614-566-4475
Dayton, Ohio 45406
Dayton, Ohio 45415
Dayton, Ohio 45415
Franklin, Ohio 45005
Greenville, Ohio 45331
Kettering, Ohio 45409
Kettering, Ohio 45429
Maumee, Ohio 43537
Rex B. Mowat
517-265-0116
Maumee, Ohio 43537
Rex B. Mowat
517-265-0116
Mayfield Heights, Ohio 44124
Ahmad Tarhini
866-223-8100
Newark, Ohio 43055
Newark, Ohio 43055
Perrysburg, Ohio 43551
Rex B. Mowat
517-265-0116
Portsmouth, Ohio 45662
Sandusky, Ohio 44870
Ahmad Tarhini
866-223-8100
Toledo, Ohio 43623
Rex B. Mowat
517-265-0116
Toledo, Ohio 43623
Rex B. Mowat
517-265-0116
Troy, Ohio 45373
Troy, Ohio 45373
West Chester, Ohio 45069
Oklahoma City, Oklahoma 73104
Baker City, Oregon 97814
Christopher M. Reynolds
208-367-7954
Bend, Oregon 97701
Clackamas, Oregon 97015
Clackamas, Oregon 97015
Coos Bay, Oregon 97420
Newberg, Oregon 97132
Ontario, Oregon 97914
Christopher M. Reynolds
208-367-7954
Portland, Oregon 97213
Portland, Oregon 97225
Allentown, Pennsylvania 18103
Christopher M. Reynolds
208-367-7954
Beaver, Pennsylvania 15009
Diwakar Davar
412-692-2001
Bethlehem, Pennsylvania 18015
Bethlehem, Pennsylvania 18017
Christopher M. Reynolds
208-367-7954
Danville, Pennsylvania 17822
Joseph J. Vadakara
570-271-5251
Greensburg, Pennsylvania 15601
Diwakar Davar
412-692-2001
Johnstown, Pennsylvania 15901
Diwakar Davar
412-692-2001
Lewisburg, Pennsylvania 17837
Joseph J. Vadakara
570-271-5251
McKeesport, Pennsylvania 15132
Diwakar Davar
412-692-2001
Moon, Pennsylvania 15108
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15212
Larisa Greenberg
877-284-2000
Pittsburgh, Pennsylvania 15213
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15213
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15215
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15224
Larisa Greenberg
877-284-2000
Pittsburgh, Pennsylvania 15232
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15232
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15237
Diwakar Davar
412-692-2001
Pittsburgh, Pennsylvania 15243
Diwakar Davar
412-692-2001
Sayre, Pennsylvania 18840
Philip A. Lowry
800-836-0388
Seneca, Pennsylvania 16346
Diwakar Davar
412-692-2001
Uniontown, Pennsylvania 15401
Diwakar Davar
412-692-2001
Washington, Pennsylvania 15301
Diwakar Davar
412-692-2001
West Reading, Pennsylvania 19611
Terrence P. Cescon
610-988-9323
Wexford, Pennsylvania 15090
Larisa Greenberg
877-284-2000
Charleston, South Carolina 29425
Daniel Y. Reuben
843-792-9321
Easley, South Carolina 29640
Jeffrey K. Giguere
864-679-3966
Greenville, South Carolina 29601
Robert D. Siegel
864-255-1713
Greenville, South Carolina 29605
Jeffrey K. Giguere
864-679-3966
Greenville, South Carolina 29605
Jeffrey K. Giguere
864-679-3966
Greenville, South Carolina 29605
Jeffrey K. Giguere
864-679-3966
Greenville, South Carolina 29607
Robert D. Siegel
864-255-1713
Greenville, South Carolina 29615
Jeffrey K. Giguere
864-679-3966
Greer, South Carolina 29650
Jeffrey K. Giguere
864-679-3966
Hilton Head Island, South Carolina 29926
Howard A. Zaren
912-819-5704
Seneca, South Carolina 29672
Jeffrey K. Giguere
864-679-3966
Spartanburg, South Carolina 29307
Jeffrey K. Giguere
864-679-3966
Sioux Falls, South Dakota 57104
Preston D. Steen
712-252-0088
Sioux Falls, South Dakota 57105
Sioux Falls, South Dakota 57117-5134
Preston D. Steen
712-252-0088
Chattanooga, Tennessee 37403
Larry L. Schlabach
423-778-6947
Chattanooga, Tennessee 37404
Mehmet S. Copur
501-622-2100
Franklin, Tennessee 37067
Kristin K. Ancell
800-811-8480
Hixson, Tennessee 37343
Mehmet S. Copur
501-622-2100
Kingsport, Tennessee 37660
Asheesh Shipstone
423-224-5593
Kingsport, Tennessee 37660
Asheesh Shipstone
423-224-5593
Knoxville, Tennessee 37916
Knoxville, Tennessee 37932
Nashville, Tennessee 37204
Kristin K. Ancell
800-811-8480
Nashville, Tennessee 37232
Kristin K. Ancell
800-811-8480
Oak Ridge, Tennessee 37830
Ooltewah, Tennessee 37363
Mehmet S. Copur
501-622-2100
Bryan, Texas 77802
Mehmet S. Copur
501-622-2100
Norton, Virginia 24273
Asheesh Shipstone
423-224-5593
Aberdeen, Washington 98520
Auburn, Washington 98001
John A. Keech
907-458-5380
Bainbridge Island, Washington 98110
John A. Keech
907-458-5380
Bellevue, Washington 98004
John A. Keech
907-458-5380
Bellingham, Washington 98225
Bremerton, Washington 98310
Bremerton, Washington 98310
Burien, Washington 98166
Mehmet S. Copur
501-622-2100
Centralia, Washington 98531
Edmonds, Washington 98026
Enumclaw, Washington 98022
Mehmet S. Copur
501-622-2100
Everett, Washington 98201
Federal Way, Washington 98002
John A. Keech
907-458-5380
Federal Way, Washington 98003
Mehmet S. Copur
501-622-2100
Gig Harbor, Washington 98332
John A. Keech
907-458-5380
Gig Harbor, Washington 98335
John A. Keech
907-458-5380
Issaquah, Washington 98029
Kennewick, Washington 99336
Lacey, Washington 98503
Lakewood, Washington 98499
Mehmet S. Copur
501-622-2100
Longview, Washington 98632
Lynnwood, Washington 98036
John A. Keech
907-458-5380
Port Townsend, Washington 98368
John A. Keech
907-458-5380
Poulsbo, Washington 98370
Poulsbo, Washington 98370
John A. Keech
907-458-5380
Puyallup, Washington 98372
John A. Keech
907-458-5380
Puyallup, Washington 98372
John A. Keech
907-458-5380
Renton, Washington 98055
John A. Keech
907-458-5380
Seattle, Washington 98101
John A. Keech
907-458-5380
Seattle, Washington 98104
Seattle, Washington 98107
Seattle, Washington 98112
Seattle, Washington 98122-4307
Seattle, Washington 98122-5711
Shelton, Washington 98584
Tacoma, Washington 97405
John A. Keech
907-458-5380
Tacoma, Washington 98405
Mehmet S. Copur
501-622-2100
Tacoma, Washington 98405
John A. Keech
907-458-5380
Tacoma, Washington 98405
Mehmet S. Copur
501-622-2100
Tacoma, Washington 98405
John A. Keech
253-403-2394
Tacoma, Washington 98405
John A. Keech
907-458-5380
Vancouver, Washington 98664
Walla Walla, Washington 99362
Yelm, Washington 98597
Charleston, West Virginia 25304
Steven J. Jubelirer
304-388-9944
Huntington, West Virginia 25701
Maria R. Tria Tirona
304-399-6617
Morgantown, West Virginia 26506
Antigo, Wisconsin 54409
Harish G. Ahuja
877-405-6866
Chippewa Falls, Wisconsin 54729
Seth O. Fagbemi
800-347-0673
Eau Claire, Wisconsin 54701
Seth O. Fagbemi
800-924-8515
Green Bay, Wisconsin 54301-3526
Brian L. Burnette
920-433-8889
Green Bay, Wisconsin 54301
Green Bay, Wisconsin 54303
Brian L. Burnette
920-433-8889
Green Bay, Wisconsin 54303
La Crosse, Wisconsin 54601
Madison, Wisconsin 53792
Mark R. Albertini
608-256-1901
Manitowoc, Wisconsin 54221
Marinette, Wisconsin 54143
Marshfield, Wisconsin 54449
Seth O. Fagbemi
800-347-0673
Milwaukee, Wisconsin 53226
Amy K. Harker-Murray
214-648-7097
Minocqua, Wisconsin 54548
Seth O. Fagbemi
800-347-0673
Oconto Falls, Wisconsin 54154
Rice Lake, Wisconsin 54868
Seth O. Fagbemi
715-236-8100
Rice Lake, Wisconsin 54868
Seth O. Fagbemi
800-347-0673
Sheboygan, Wisconsin 53081
Stevens Point, Wisconsin 54482
Seth O. Fagbemi
855-829-8555
Sturgeon Bay, Wisconsin 54235-1495
Sturgeon Bay, Wisconsin 54235
Brian L. Burnette
920-433-8889
Wausau, Wisconsin 54401
Harish G. Ahuja
877-405-6866
Wausau, Wisconsin 54401
Seth O. Fagbemi
800-847-0016
Weston, Wisconsin 54476
Seth O. Fagbemi
715-393-1400
Wisconsin Rapids, Wisconsin 54494
Harish G. Ahuja
877-405-6866
Wisconsin Rapids, Wisconsin 54494
Seth O. Fagbemi
800-656-0664
More Details
- NCT ID
- NCT02224781
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Detailed Description
PRIMARY OBJECTIVES:
I. To determine whether initial treatment with either combination ipilimumab + nivolumab (with subsequent dabrafenib in combination with 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 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 of treatment after cross-over without intervening symptomatic disease progression or treatment limiting toxicity).
VII. Association of inherited variation with immune mediated adverse events and response to ipilimumab + nivolumab.
VIII. 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.
IX. 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.
X. 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.
XI. 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.
XII. 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.
XIII. 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.
XIV. 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.
XV. 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).
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) IV. 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.
V. To describe the frequency and severity of treatment toxicities at baseline, 6 weeks, 12 weeks, and 6 months after initiation of each treatment.
TERTIARY 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 (COURSES 1-2): Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses 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 orally (PO) twice daily (BID) and trametinib PO daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive dabrafenib PO BID and trametinib PO daily on days 1-42. Courses 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 (COURSES 1-2): Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses 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.