PRIMARY OBJECTIVE:
I. To determine whether initial treatment with either combination ipilimumab + nivolumab
(with subsequent dabrafenib mesylate [dabrafenib] in combination with trametinib dimethyl
sulfoxide [trametinib]) or dabrafenib in combination with trametinib (with subsequent
ipilimumab + nivolumab) significantly improves 2 year overall survival (OS) in patients with
unresectable stage III or stage IV BRAFV600 mutant melanoma.
SECONDARY CLINICAL OBJECTIVES:
I. To evaluate the impact of initial treatment on median OS and hazard ratio for death.
II. To determine whether initial treatment choice significantly improves 3 year OS.
III. To evaluate the anti-tumor activities (Response Evaluation Criteria in Solid Tumors
[RECIST]-defined response rate, median progression-free survival [PFS]) and safety profiles
of ipilimumab + nivolumab and dabrafenib-trametinib in a Cooperative Group trial of patients
with V600 mutant melanoma.
IV. To evaluate the activity (RECIST-defined response rate, median PFS) and safety of
dabrafenib + trametinib in patients who have had disease progression on ipilimumab +
nivolumab and in comparison to its activity and safety in ipilimumab + nivolumab naive
patients.
V. To evaluate the activity of ipilimumab + nivolumab (RECIST-defined response rate, median
PFS) and safety in patients who have had disease progression on dabrafenib + trametinib and
in comparison to its activity and safety in dabrafenib + trametinib naive patients.
VI. To assess the feasibility of crossover to the alternative treatment strategy (percentage
of patients who are able to crossover from one arm to the other and complete at least an
initial course [12 weeks] of treatment after cross-over without intervening symptomatic
disease progression or treatment limiting toxicity).
SECONDARY LABORATORY OBJECTIVES:
I. Association of inherited variation with immune mediated adverse events and response to
ipilimumab + nivolumab.
Ia. To determine the association of inherited genetic variation and immune-associated adverse
events in patients with metastatic melanoma treated with ipilimumab containing regimens by
completing candidate-based gene and pathway analyses of genes involved in lymphocyte
activation, cytokines, cytokine receptors and within the major histocompatibility complex
(MHC) region and an agnostic genome-wide single nucleotide polymorphism (SNP)-based approach.
Ib. To investigate the association between inherited genetics and survival in patients with
metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based
gene and pathway analyses of genes involved in lymphocyte activation, cytokines profile,
cytokine receptors and within the MHC region and an agnostic genome-wide SNP-based approach.
Ic. To replicate genomic markers identified in the above aims in an independent sample set of
patients treated with ipilimumab containing regimens and preliminarily characterize their
potential functional role by completing replication of variation as associated with
immune-related adverse events (irAEs) and survival and bio-informatic assessment of genomic
markers.
II. To determine the utility of circulating BRAF levels in determining the response and
resistance to either BRAF/MEK directed and/or combination immunotherapy in patients with BRAF
mutant melanoma.
IIa. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600
mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and
resistance to combination BRAF/MEK directed therapy.
IIb. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600
mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and
resistance to combination immunotherapy.
IIc. To compare the kinetics of peripheral blood BRAFV600 levels during response and
resistance in groups of patients receiving BRAF targeted therapy or combination immunotherapy
as initial therapy.
IId. To compare the kinetics of peripheral blood BRAFV600 levels during response and
resistance to combination BRAF targeted therapy or combination immunotherapy in individual
patients (initial treatment versus [vs] crossover treatment).
SECONDARY PATIENT REPORTED OUTCOMES OBJECTIVES:
I. To evaluate differences in overall health between initial treatment arms (dabrafenib +
trametinib vs. ipilimumab + nivolumab immunotherapy) at 2 years, accounting for toxicities
and overall survival. (Primary) II. To assess differences in overall function over 2 years
between initial treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab.
(Secondary) III. To document the effects of treatment crossover and treatment administration
sequence on symptom burden and overall function. (Secondary) IIIa. To compare differences in
function and symptoms by treatment sequence for ipilimumab + nivolumab (arm A vs. D), and
dabrafenib + trametinib, (arm B vs. C) at baseline, 6 weeks, 12 weeks, and 6 months after the
initiation of each treatment.
IIIb. To describe the frequency and severity of treatment toxicities at baseline, 6 weeks, 12
weeks, and 6 months after initiation of each treatment.
EXPLORATORY TOBACCO USE OBJECTIVES:
I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other
forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported
cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose
modifications).
II. To determine the effects of tobacco on patient-reported physical symptoms and
psychological symptoms.
III. To examine quitting behaviors and behavioral counseling/support and cessation medication
utilization.
IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose
intensity, and therapeutic benefit.
EXPLORATORY CORRELATIVE OBJECTIVES:
I. 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, patients re-register
and cross over to Arm C.
ARM C: Patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib
dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of
disease progression or unacceptable toxicity.
ARM B: Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO daily
on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or
unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm
D.
ARM D:
IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and
ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2
cycles in the absence of disease progression or unacceptable toxicity.
IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on
days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
Inclusion Criteria:
- STEP 1
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
- 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 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, 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
- 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)
- 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)
- 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 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 ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients must have
melanoma that is metastatic and clearly progressive on prior therapy
- STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients must be at
least 1 week from documented progressive disease (PD) on Step 1 of current study; all
sites of disease must be evaluated within 4 weeks prior to registration
- STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): 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 ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): 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 ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): 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 and sexually
active males must use at least two other accepted and effective methods of
contraception and/or to 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
Exclusion Criteria:
- 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 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)
- 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; 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
- 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 ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): 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 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 pote
