Clinical Trials /

Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation

NCT02231775

Description:

This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation
  • Official Title: Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)

Clinical Trial IDs

  • ORG STUDY ID: 2014-0409
  • SECONDARY ID: NCI-2014-01969
  • SECONDARY ID: 2014-0409
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02231775

Conditions

  • BRAF V600E Mutation Present
  • BRAF V600K Mutation Present
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436Treatment (dabrafenib, trametinib, surgery)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (dabrafenib, trametinib, surgery)

Purpose

This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Study enrollment was stopped in April 2016 due to a substantial improvement in RFS in Arm
      B vs Arm A treated patients. The study was redesigned in August 2016 as a single-arm study
      with a new primary objective:

      To compare relapse-free survival (RFS) between patients who develop a pathologic Complete
      Response (pCR) or do not achieve a pCR following dabrafenib and trametinib neoadjuvant
      combination therapy in patients with locally advanced BRAF V600 mutated melanoma.

      SECONDARY OBJECTIVES:

      I. To compare overall survival of patients with pathologic complete response (pCR) and
      patients without pCR who are receiving dabrafenib and trametinib neoadjuvant therapy followed
      by adjuvant combination therapy.

      II. To identify biomarkers predictive of response through collection of serial blood draws
      and biopsies in patients receiving neoadjuvant dabrafenib and trametinib combination therapy.

      III. To evaluate the safety of dabrafenib and trametinib in combination in this patient
      population.

      EXPLORATORY OBJECTIVES:

      I. To evaluate and perform further advanced imaging analysis on magnetic resonance imaging
      (MRI), computed tomography (CT), and positron emission tomography (PET) scanned (if
      available) images collected on patients enrolled onto this study.

      OUTLINE:

      Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD)
      for 8 weeks. After completion of 8 weeks of dabrafenib and trametinib, patients undergo
      surgery. Approximately 1 week after surgery, patients receive dabrafenib PO BID and
      trametinib PO QD for 44 additional weeks in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (dabrafenib, trametinib, surgery)ExperimentalPatients receive dabrafenib PO BID and trametinib PO QD for 8 weeks. After completion of 8 weeks of dabrafenib and trametinib, patients undergo surgery. Approximately 1 week after surgery, patients receive dabrafenib PO BID and trametinib PO QD for 44 additional weeks in the absence of disease progression or unacceptable toxicity.
  • Dabrafenib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form

          -  Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by
             American Joint Committee on Cancer (AJCC) version 7; the definition of resectability
             can be determined by the patient's surgical oncologist and verified via discussion at
             Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology
             staff; resectable tumors are defined as having no significant vascular, neural or bony
             involvement; only cases where a complete surgical resection with tumor-free margins
             can safely be achieved are defined as resectable; multicenter sites: confirmation of
             diagnosis via histology or cytology will be made by the local site pathologist;
             likewise, resectability determination will be made by the site's multidisciplinary
             team

          -  Patients must be medically fit enough to undergo surgery as determined by the surgical
             oncology team

          -  BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical
             Laboratory Improvement Amendments (CLIA) certified laboratory

          -  Patients must have measurable disease, defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Hemoglobin >= 9.5 g/dL

          -  Platelets >= 100 x 10^9/L

          -  Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin
             time (PTT) =< 1.5 x upper limit of normal (ULN)

          -  Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if
             bilirubin is fractionated and direct bilirubin < 35%)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1

          -  Albumin >= 2.5 g/dL

          -  Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour
             urine creatinine clearance >= 50 mL/min

          -  Male subjects must agree to use one of the contraception methods listed below; this
             criterion must be followed from the time of the first dose of study medication until 4
             weeks after the last dose of study medication; however, it is advised that
             contraception be used for a total of 16 weeks following the last dose (based on the
             lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent
             with the preferred and usual lifestyle of the subject; periodic abstinence (e.g.
             calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
             acceptable methods of contraception; b) condom (during non-vaginal intercourse with
             any partner - male or female) OR c) condom and occlusive cap (diaphragm or
             cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during
             sexual intercourse with a female)

          -  A female subject is eligible to participate if she is of: a) non-childbearing
             potential defined as pre-menopausal females with a documented tubal ligation or
             hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in
             questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH]
             > 40 MlU/mL and estradiol < 40 pg/mL [< 140 pmol/L] is confirmatory); females on
             hormone replacement therapy (HRT) and whose menopausal status is in doubt will be
             required to use one of the contraception methods listed below if they wish to continue
             their HRT during the study; otherwise, they must discontinue HRT to allow confirmation
             of post-menopausal status prior to study enrollment; for most forms of HRT, at least
             2-4 weeks will elapse between the cessation of therapy and the blood draw; this
             interval depends on the type and dosage of HRT; following confirmation of their
             post-menopausal status, they can resume use of HRT during the study without use of a
             contraceptive method; b) child-bearing potential and agrees to use one of the
             contraception methods listed below for an appropriate period of time (as determined by
             the product label or investigator) prior to the start of dosing to sufficiently
             minimize the risk of pregnancy at that point; female subjects must agree to use
             contraception until 4 weeks after the last dose of study medication, and must have a
             negative serum or urine pregnancy test within 14 days prior to the start of dosing

          -  Female subjects contraception methods: a) abstinence; b) intrauterine device (IUD) or
             intrauterine system (IUS) that meets the < 1% failure rate as stated in the product
             label; c) male partner sterilization prior to the female subject's entry into the
             study, and this male is the sole partner for that subject; d) double barrier method:
             condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent
             (foam/gel/film/cream/suppository)

        Exclusion Criteria:

          -  Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or
             biologic therapy) or investigational anti-cancer drug within 28 days

          -  Current use of a prohibited medication or requires any of these medications during
             treatment with study drug

          -  Prior BRAF or mitogen-activated protein kinase kinase (MEK) directed therapy

          -  Prior malignancy except for the following: adequately treated basal cell or squamous
             cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any
             cancer from which the patient has been disease-free for 2 years

          -  Any major surgery within the last 3 weeks

          -  History of central serous retinopathy (CSR) or retinal vein occlusion (RVO), or
             predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension,
             uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of
             hyperviscosity or hypercoagulability syndromes)

          -  Presence of active gastrointestinal disease or other condition that will interfere
             significantly with the absorption, distribution, metabolism, or excretion of drugs

          -  Brain metastases or bone metastases; patients with brain metastases must have received
             treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic
             foci must be stable for 8 weeks prior to starting study drug

          -  Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch
             block)

          -  Uncontrolled arrhythmias

          -  Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system

          -  Pregnant or lactating female

          -  Unwillingness or inability to follow the procedures required in the protocol

          -  Uncontrolled diabetes, hypertension or other medical conditions that may interfere
             with assessment of toxicity

          -  Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse-free survival (RFS)
Time Frame:Up to 12 months
Safety Issue:
Description:RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Up to 1 year
Safety Issue:
Description:The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.
Measure:Complete pathologic response
Time Frame:Up to 1 year
Safety Issue:
Description:Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.
Measure:Incidence of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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