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Nivolumab and Trametinib With or Without Dabrafenib in Treating Patients With BRAF Mutated or Wild Type Metastatic Stage III-IV Melanoma That Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02910700
Recruitment Status : Recruiting
First Posted : September 22, 2016
Last Update Posted : December 18, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE September 20, 2016
First Posted Date  ICMJE September 22, 2016
Last Update Posted Date December 18, 2019
Actual Study Start Date  ICMJE December 9, 2016
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 29, 2018)
Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors version 1.1 on both arms [ Time Frame: From the time of initial response until documented tumor progression, assessed up to 3 years ]
The ORR for each treatment group will be computed along using 95% Clopper Pearson confidence interval.
Original Primary Outcome Measures  ICMJE
 (submitted: September 20, 2016)
Objective Response Rate (ORR) in Participants with BRAF- Mutated or BRAF-Wild Type Metastatic Melanoma [ Time Frame: 12 weeks ]
ORR measured by imaging with RECIST 1.1.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 29, 2018)
  • Incidence of adverse events assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ]
    The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. Will describe all dose limiting toxicities and other serious (>= grade 3) on a patient-by-patient basis; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will be tabulated.
  • Complete response [ Time Frame: Up to 3 years ]
    Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
  • Partial response [ Time Frame: Up to 3 years ]
    Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
  • Incidence of stable disease [ Time Frame: From the start of the treatment until the criteria for progression are met, assessed up to 3 years ]
    Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
  • Overall survival (OS) [ Time Frame: From treatment start date to last known vital sign, assessed up to 3 years ]
    The Kaplan-Meier method will be used to estimate OS. Associations between OS and clinical measures of interest will be determined using Cox proportional hazards regression models.
  • Progression-free survival (PFS) [ Time Frame: From treatment start date to date of disease progression or death or the last evaluation date, assessed up to 3 years ]
    The Kaplan-Meier method will be used to estimate PFS. Associations between PFS and clinical measures of interest will be determined using Cox proportional hazards regression models.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2016)
Overall survival (OS) [ Time Frame: 3 years post treatment completion ]
OS computed from treatment start date to last known vital sign.
Current Other Pre-specified Outcome Measures
 (submitted: October 29, 2018)
Circulating and tumor markers [ Time Frame: Baseline up to 3 years ]
Will be compare by the Wilcoxon signed-rank test. The false discovery rate will be controlled at 20% by the procedure of Bejamini and Hochberg's method.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nivolumab and Trametinib With or Without Dabrafenib in Treating Patients With BRAF Mutated or Wild Type Metastatic Stage III-IV Melanoma That Cannot Be Removed by Surgery
Official Title  ICMJE A Phase II Study of the TRIplet Combination of Dabrafenib, Nivolumab, and Trametinib in Patients With Metastatic Melanoma (TRIDeNT)
Brief Summary This phase II trial studies the side effects and how well nivolumab and trametinib with or without dabrafenib work in treating patients with BRAF-mutated or wild type stage III-IV melanoma that has spread to other places in the body or cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Trametinib and dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if nivolumab and trametinib with or without dabrafenib may work better in treating patients with BRAF-mutated or wild type metastatic melanoma.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability, and efficacy (objective response rates by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of nivolumab in combination with dabrafenib and/or trametinib in patients with BRAF-mutated metastatic melanoma.

SECONDARY OBJECTIVES:

I. Safety and tolerability of the triplet combination (nivolumab-dabrafenib-trametinib [NDT]).

II. Efficacy of the combinations as measured by the depth and duration of response by RECIST 1.1 on Cohort A, and modified RECIST 1.1 (to include intracranial response) in Cohort B III. Pharmacodynamic evaluation of combination on circulating markers (immune monitoring).

IV. Pharmacodynamic evaluation of combination on tumor tissues. V. Progression- free survival and overall survival.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A (NDT): Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, dabrafenib orally (PO) twice daily (BID) on days 1-28, and trametinib PO once daily (QD) on days 1-28.

ARM B (NT, CLOSED TO ACCRUAL ): Patients receive nivolumab IV over 30 minutes on day 1 and 15 and trametinib PO QD on days 1-28.

In both arms, courses repeat every 28 days for 3 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days then every 3 months for up to 3 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • BRAF Gene Mutation
  • BRAF wt Allele
  • 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
Intervention  ICMJE
  • Drug: Dabrafenib
    Given PO
    Other Names:
    • BRAF Inhibitor GSK2118436
    • GSK-2118436A
    • GSK2118436
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Other: Pharmacological Study
    Correlative studies
  • Drug: Trametinib
    Given PO
    Other Names:
    • GSK1120212
    • JTP-74057
    • MEK Inhibitor GSK1120212
    • Mekinist
Study Arms  ICMJE
  • Experimental: Arm A (NDT): Nivolumab + Dabrafenib + Trametinib
    Patients receive nivolumab IV over 30 minutes on day 1, dabrafenib PO BID on days 1-28, and trametinib PO QD on days 1-28.
    Interventions:
    • Drug: Dabrafenib
    • Other: Laboratory Biomarker Analysis
    • Biological: Nivolumab
    • Other: Pharmacological Study
    • Drug: Trametinib
  • Experimental: Arm B (NT, closed to accrual): Nivolumab + Trametinib
    Patients receive nivolumab IV over 30 minutes on day 1 and trametinib PO QD on days 1-28.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Biological: Nivolumab
    • Other: Pharmacological Study
    • Drug: Trametinib
Publications * Not Provided

*   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: July 17, 2018)
51
Original Estimated Enrollment  ICMJE
 (submitted: September 20, 2016)
60
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed metastatic melanoma (stage IV) or unresectable stage III that have progressed on prior PD-1 directed therapy; patients with BRAF or BRAF-wild-type are eligible
  • Prior therapies for metastatic melanoma are allowed, including chemo-, cytokine-, immuno, biological and vaccine-therapy as long as they did not include BRAFi, MEKi; patients who have progressed on anti-PD-1 therapy in the adjuvant setting are also allowed; prior ipilimumab or PD-1 directed therapy will be allowed with a washout period of 2 weeks and if all autoimmune adverse events have resolved to grade 1 (except endocrine abnormalities that require continuous replacement)
  • Evidence of evaluable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Patients with melanoma brain metastases are allowed; brain metastases status will determine cohort allocation. Subjects with brain metastases are eligible if: [Cohort A] (a) metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks after treatment is complete and within 14 days of the first dose of nivolumab administration; or [Cohort B] (b) if they are untreated but asymptomatic and have had previous PD-1 treatment; or (c) if they are untreated and symptomatic but symptoms are controlled on stable or decreasing doses of steroids for 14 days prior to drug administration; or (d) they have untreated leptomeningeal disease (LMD) as long as they fulfill all other eligibility requirements. Note: Patients are excluded if they require high doses of systemic corticosteroids (> 8 mg equivalent of dexamethasone) to control central nervous system (CNS) symptoms
  • White blood cells (WBC) >= 2000 /uL (within one week prior to registration)
  • Neutrophils >= 1500 /uL (within one week prior to registration)
  • Platelets >= 100 x 10^3 /uL (within one week prior to registration)
  • Hemoglobin > 9.0 g/dL (within one week prior to registration)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula) (within one week prior to registration)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (within one week prior to registration)
  • Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) (within one week prior to registration)
  • Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug; WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of nivolumab
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients that had grade 3/4 immune-related adverse events (AEs) on ipilimumab that required more than 12 weeks of immune suppression with corticosteroids
  • History of interstitial lung disease or pneumonitis
  • History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Active, known or suspected autoimmune disease; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism and/or hypophysitis due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • Require systemic treatment with either corticosteroids (> 8 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease
  • Known history of a positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS); HIV-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • History of allergy or adverse drug reaction to the study drug components (nivolumab, dabrafenib, or trametinib) or drugs of similar chemical or biologic composition; patients with a history of severe hypersensitivity reaction to any monoclonal antibody should also be excluded
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Uncontrolled intercurrent illness (requiring IV antibiotic treatment) including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant and/or breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with nivolumab, dabrafenib, and trametinib
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: Hussein Tawbi 713-792-2921 htawbi@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02910700
Other Study ID Numbers  ICMJE 2015-0605
NCI-2016-01940 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2015-0605 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
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: Hussein Tawbi M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date December 2019

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