Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: 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

Summary: 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).
  TERTIARY OBJECTIVES:
  I. Association of inherited variation with immune mediated adverse events and response to ipilimumab/nivolumab.
  II. 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.
  III. 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.
  IV. 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.
  V. 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.
  VI. 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.
  VII. 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.
  VIII. 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.
  IX. 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.
  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.

Eligibility: 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 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 BRAFV600 E or K 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 BRAFV600E or BRAFV600K mutations, 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]) that have been stable on head magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4 weeks following treatment and within 4 weeks of randomization could be eligible; patients must not have taken any steroids =< 14 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
  -  Absolute neutrophil count (ANC) >= 1,500/uL
  -  Platelet count >= 100,000/uL
  -  Hemoglobin > 9 g/dL
  -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min
  -  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
  -  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)
  -  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, Sjögren'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 can be less than 4 weeks from surgery or SRS to CNS metastases
  -  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 >= 2 weeks 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 SRS) that have been stable on head MRI or contrast CT scan for at least 4 weeks following treatment and within 4 weeks prior to Step 2 registration are eligible; patients crossing over to ipilimumab + nivolumab must not have taken any steroids =< 14 days prior to registration for the purpose of managing their brain metastases; this exclusion does not apply for patients crossing over to dabrafenib + trametinib; 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

Relevance to patient case: not relevant