Clinical Trials /

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

NCT02910700

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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: A Phase II Study of the TRIplet Combination of Dabrafenib, Nivolumab, and Trametinib in Patients With Metastatic Melanoma (TRIDeNT)

Clinical Trial IDs

  • ORG STUDY ID: 2015-0605
  • SECONDARY ID: NCI-2016-01940
  • SECONDARY ID: 2015-0605
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02910700

Conditions

  • 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

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436Arm A (NDT): Nivolumab + Dabrafenib + Trametinib
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (NDT): Nivolumab + Dabrafenib + Trametinib
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistArm A (NDT): Nivolumab + Dabrafenib + Trametinib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (NDT): Nivolumab + Dabrafenib + TrametinibExperimentalPatients receive nivolumab IV over 30 minutes on day 1, dabrafenib PO BID on days 1-28, and trametinib PO QD on days 1-28.
  • Dabrafenib
  • Nivolumab
  • Trametinib
Arm B (NT, closed to accrual): Nivolumab + TrametinibExperimentalPatients receive nivolumab IV over 30 minutes on day 1 and trametinib PO QD on days 1-28.
  • Nivolumab
  • Trametinib

Eligibility Criteria

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

Primary Outcome Measures

Measure: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
Safety Issue:
Description:The ORR for each treatment group will be computed along using 95% Clopper Pearson confidence interval.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure:Complete response
Time Frame:Up to 3 years
Safety Issue:
Description:Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Measure:Partial response
Time Frame:Up to 3 years
Safety Issue:
Description:Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Measure:Incidence of stable disease
Time Frame:From the start of the treatment until the criteria for progression are met, assessed up to 3 years
Safety Issue:
Description:Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Measure:Overall survival (OS)
Time Frame:From treatment start date to last known vital sign, assessed up to 3 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

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

Last Updated