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

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ClinicalTrials.gov Identifier: NCT02231775
Recruitment Status : Recruiting
First Posted : September 4, 2014
Last Update Posted : May 29, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE September 2, 2014
First Posted Date  ICMJE September 4, 2014
Last Update Posted Date May 29, 2019
Actual Study Start Date  ICMJE October 22, 2014
Estimated Primary Completion Date October 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2018)
Relapse-free survival (RFS) [ Time Frame: Up to 12 months ]
RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.
Original Primary Outcome Measures  ICMJE
 (submitted: September 2, 2014)
One-year Relapse-Free Survival Rate [ Time Frame: 1 year ]
Disease response recorded as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to RECIST 1.1 criteria.
Change History Complete list of historical versions of study NCT02231775 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2018)
  • Overall survival (OS) [ Time Frame: Up to 1 year ]
    The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.
  • Complete pathologic response [ Time Frame: Up to 1 year ]
    Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.
  • Incidence of adverse events [ Time Frame: Up to 1 year ]
    Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation
Official Title  ICMJE Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • BRAF V600E Mutation Present
  • BRAF V600K Mutation Present
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7
Intervention  ICMJE
  • Drug: Dabrafenib
    Given PO
    Other Names:
    • BRAF Inhibitor GSK2118436
    • GSK-2118436A
    • GSK2118436
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Procedure: Therapeutic Conventional Surgery
    Undergo surgery
  • Drug: Trametinib
    Given PO
    Other Names:
    • GSK1120212
    • JTP-74057
    • MEK Inhibitor GSK1120212
    • Mekinist
Study Arms  ICMJE Experimental: Treatment (dabrafenib, trametinib, surgery)
Patients 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.
Interventions:
  • Drug: Dabrafenib
  • Other: Laboratory Biomarker Analysis
  • Procedure: Therapeutic Conventional Surgery
  • Drug: Trametinib
Publications * Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, Glitza IC, Cormier J, Hwu WJ, Tawbi HA, Patel SP, Lee JE, Gershenwald JE, Spencer CN, Gopalakrishnan V, Bassett R, Simpson L, Mouton R, Hudgens CW, Zhao L, Zhu H, Cooper ZA, Wani K, Lazar A, Hwu P, Diab A, Wong MK, McQuade JL, Royal R, Lucci A, Burton EM, Reddy S, Sharma P, Allison J, Futreal PA, Woodman SE, Davies MA, Wargo JA. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018 Feb;19(2):181-193. doi: 10.1016/S1470-2045(18)30015-9. Epub 2018 Jan 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 10, 2017)
78
Original Estimated Enrollment  ICMJE
 (submitted: September 2, 2014)
84
Estimated Study Completion Date  ICMJE October 31, 2019
Estimated Primary Completion Date October 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jennifer Wargo 713-745-1553 jwargo@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02231775
Other Study ID Numbers  ICMJE 2014-0409
NCI-2014-01969 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2014-0409 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Jennifer Wargo M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP