Vanderbilt Clinical Trials

Conditions

• Clinical Stage III Cutaneous Melanoma AJCC v8
• Clinical Stage IV Cutaneous Melanoma AJCC v8
• Metastatic Melanoma
• Recurrent Melanoma
• Unresectable Melanoma

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- 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)

- 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

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To determine whether initial treatment with either combination ipilimumab + nivolumab (with subsequent dabrafenib mesylate [dabrafenib] in combination with trametinib dimethyl sulfoxide [trametinib]) or dabrafenib in combination with trametinib (with subsequent ipilimumab + nivolumab) significantly improves 2 year overall survival (OS) in patients with unresectable stage III or stage IV BRAFV600 mutant melanoma. SECONDARY CLINICAL OBJECTIVES: I. To evaluate the impact of initial treatment on median OS and hazard ratio for death. II. To determine whether initial treatment choice significantly improves 3 year OS. III. To evaluate the anti-tumor activities (Response Evaluation Criteria in Solid Tumors [RECIST]-defined response rate, median progression-free survival [PFS]) and safety profiles of ipilimumab + nivolumab and dabrafenib-trametinib in a Cooperative Group trial of patients with V600 mutant melanoma. IV. To evaluate the activity (RECIST-defined response rate, median PFS) and safety of dabrafenib + trametinib in patients who have had disease progression on ipilimumab + nivolumab and in comparison to its activity and safety in ipilimumab + nivolumab naive patients. V. To evaluate the activity of ipilimumab + nivolumab (RECIST-defined response rate, median PFS) and safety in patients who have had disease progression on dabrafenib + trametinib and in comparison to its activity and safety in dabrafenib + trametinib naive patients. VI. To assess the feasibility of crossover to the alternative treatment strategy (percentage of patients who are able to crossover from one arm to the other and complete at least an initial course [12 weeks] of treatment after cross-over without intervening symptomatic disease progression or treatment limiting toxicity). SECONDARY LABORATORY OBJECTIVES: I. Association of inherited variation with immune mediated adverse events and response to ipilimumab + nivolumab. Ia. To determine the association of inherited genetic variation and immune-associated adverse events in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines, cytokine receptors and within the major histocompatibility complex (MHC) region and an agnostic genome-wide single nucleotide polymorphism (SNP)-based approach; Ib. To investigate the association between inherited genetics and survival in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines profile, cytokine receptors and within the MHC region and an agnostic genome-wide SNP-based approach; Ic. To replicate genomic markers identified in the above aims in an independent sample set of patients treated with ipilimumab containing regimens and preliminarily characterize their potential functional role by completing replication of variation as associated with immune-related adverse events (irAEs) and survival and bio-informatic assessment of genomic markers. II. To determine the utility of circulating BRAF levels in determining the response and resistance to either BRAF/MEK directed and/or combination immunotherapy in patients with BRAF mutant melanoma. IIa. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600 mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and resistance to combination BRAF/MEK directed therapy; IIb. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600 mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and resistance to combination immunotherapy; IIc. To compare the kinetics of peripheral blood BRAFV600 levels during response and resistance in groups of patients receiving BRAF targeted therapy or combination immunotherapy as initial therapy; IId. To compare the kinetics of peripheral blood BRAFV600 levels during response and resistance to combination BRAF targeted therapy or combination immunotherapy in individual patients (initial treatment 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 (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.