Clinical Trials /

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 phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as BRAFV600 and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

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: DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a Phase III Trial

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

  • 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
  • Unresectable Cutaneous Melanoma

Interventions

DrugSynonymsArms
Dabrafenib MesylateDabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, TafinlarArm B (BRAF inhibitor therapy)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, Ipilimumab Biosimilar CS1002, MDX-010, MDX-CTLA4, YervoyArm A (immunotherapy)
NivolumabBMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, OpdivoArm A (immunotherapy)
Trametinib Dimethyl SulfoxideMekinistArm B (BRAF inhibitor therapy)

Purpose

This phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as BRAFV600 and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

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, 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (immunotherapy)ExperimentalIMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C.
  • Ipilimumab
  • Nivolumab
Arm B (BRAF inhibitor therapy)ExperimentalPatients 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.
  • Dabrafenib Mesylate
  • Trametinib Dimethyl Sulfoxide
Arm C (BRAF inhibitor therapy)ExperimentalPatients 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.
  • Dabrafenib Mesylate
  • Trametinib Dimethyl Sulfoxide
Arm D (immunotherapy)ExperimentalIMMUNOTHERAPY 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.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

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

Primary Outcome Measures

Measure:Overall survival (OS) rate
Time Frame:The time from randomization to death from any cause, assessed for up to 2 years
Safety Issue:
Description:Defined as the proportion of patients alive after 2 years of follow-up time. 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 lactate dehydrogenase [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 B) and presented graphically.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:The time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years
Safety Issue:
Description:Evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Distribution will be estimated using the Kaplan-Meier method. PFS will be compared using the log-rank test.
Measure:Response rate
Time Frame:Up to 5 years
Safety Issue:
Description:According to RECIST 1.1. 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:Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. 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 AEs
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed using CTCAE v 4.0. 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 AEs
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed using CTCAE v 4.0. 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

August 26, 2021