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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

NCT02224781

Description:

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. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Randomized Phase III Trial of Dabrafenib + Trametinib Followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab Followed by Dabrafenib + Trametinib at Progression in Patients With Advanced BRAFV600 Mutant Melanoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01747
  • SECONDARY ID: NCI-2014-01747
  • SECONDARY ID: EA6134
  • SECONDARY ID: EA6134
  • SECONDARY ID: EA6134
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT02224781

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

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436Arm C (BRAF inhibitor therapy)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm A (immunotherapy)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (immunotherapy)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistArm C (BRAF inhibitor therapy)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (immunotherapy)ExperimentalIMMUNOTHERAPY 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.
    Arm B (BRAF inhibitor therapy)ExperimentalPatients 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.
    • Dabrafenib
    • Trametinib
    Arm C (BRAF inhibitor therapy)ExperimentalPatients 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.
    • Dabrafenib
    • Trametinib
    Arm D (immunotherapy)ExperimentalIMMUNOTHERAPY 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.

      Eligibility 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
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Overall survival (OS) rate, defined as the proportion of patients alive after 2 years of follow-up time
      Time Frame:The time from randomization to death from any cause, assessed for up to 2 years
      Safety Issue:
      Description:Will be estimated and compared between the two arms using the Mantel-Haenszel test based (stratified by Eastern Cooperative Oncology Group (ECOG) performance status [PS] and LDH) based on two-sided overall type I error rate of 0.05 adjusting for two-interim analysis. Mantel-Haenszel test will compare the 2-year OS rates while controlling for the stratification factors. The difference in 2-year OS rates in arms A and B will be estimated and presented with 95% repeated confidence interval of Jennison-Turnbull. In addition, OS distribution will be estimated using the Kaplan-Meier method. The distribution of OS will be compared using the stratified log rank test. Hazard of OS will be estimated as a function of time in arm A and in arm B (as randomized in step 1 to arm A versus [vs.] B) and presented graphically.

      Secondary Outcome Measures

      Measure:Progression-free survival (PFS), evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
      Time Frame:The time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years
      Safety Issue:
      Description:Distribution will be estimated using the Kaplan-Meier method. PFS will be compared using the log-rank test.
      Measure:Response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Response rates will be compared using the Mantel-Haenszel test (stratified by ECOG PS and LDH) test in arms A vs. B. Response rate for patients who are treated with ipilimumab/nivolumab before crossover (arm A) vs. for patients who were initially treated with dabrafenib/trametinib and crossed over to ipilimumab/nivolumab will be compared (arm D). Response rates will be compared using the Fisher's exact test.
      Measure:Toxicity rate for individual adverse events (AEs)
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
      Measure:Toxicity rate for categorized adverse events (AEs)
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
      Measure:Toxicity rate for worst degree adverse events (AEs)
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.

      Details

      Phase:Phase 3
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:National Cancer Institute (NCI)

      Last Updated