Clinical Trials /

Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations

NCT02296112

Description:

This phase II trial studies trametinib in treating patients with melanoma with v-Raf murine sarcoma viral oncogene homolog B (BRAF) non-V600 mutations that has spread to other places in the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations
  • Official Title: A Phase II Open-Label, Two-Arm Study of the MEK Inhibitor, Trametinib, to Investigate the Safety and Anti-Cancer Activity in Subjects With Melanoma With BRAF Non-V600 Mutations

Clinical Trial IDs

  • ORG STUDY ID: VICC MEL 1457
  • SECONDARY ID: NCI-2014-02185
  • SECONDARY ID: MEL1457
  • SECONDARY ID: GSK1120212
  • SECONDARY ID: VICC MEL 1457
  • SECONDARY ID: P30CA068485
  • NCT ID: NCT02296112

Conditions

  • Recurrent Melanoma
  • Stage IIIB Melanoma
  • Stage IIIC Melanoma
  • Stage IV Melanoma

Interventions

DrugSynonymsArms
trametinibGSK1120212, JTP-74057, MekinistTreatment (trametinib)

Purpose

This phase II trial studies trametinib in treating patients with melanoma with v-Raf murine sarcoma viral oncogene homolog B (BRAF) non-V600 mutations that has spread to other places in the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the clinical efficacy of trametinib in advanced BRAF nonV600mutation (MUT)
      melanoma ("high activity" group).

      SECONDARY OBJECTIVES:

      I. To characterize the safety of trametinib. II. To evaluate the progression-free survival
      (PFS) and overall survival (OS) of trametinib in advanced BRAF nonV600MUT melanoma.

      TERTIARY OBJECTIVES:

      I. To determine the clinical efficacy of trametinib in advanced BRAF nonV600MUT melanoma
      ("low activity/unknown" group).

      II. Identify mechanisms of resistance to trametinib in this patient population.

      OUTLINE:

      Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib)ExperimentalPatients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Signed written informed consent

          -  Histologically or cytologically confirmed diagnosis of melanoma

          -  BRAF mutation in loci other than V600 (BRAF nonV600 MUT) or BRAF fusion detected by
             genetic testing of the primary tumor or regional/distant metastasis

          -  Subjects must provide either a fresh or archived tumor sample for correlative study
             analyses

          -  For subjects with melanoma, archived or freshly biopsied tumor tissue (preferred) must
             be obtained prior to enrollment; to ensure prompt delivery of tumor samples, tissue
             shipment tracking information must be provided before administration of study
             treatment can be initiated

          -  Measurable disease (i.e., present with at least one measurable lesion per Response
             Evaluation Criteria In Solid Tumors [RECIST], version 1.1)

          -  All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
             values) must be =< grade 1 according to the Common Terminology Criteria for Adverse
             Events version 4 (CTCAE version 4.0) at the time of randomization

          -  Able to swallow and retain oral medication and must not have any clinically
             significant gastrointestinal abnormalities that may alter absorption such as
             malabsorption syndrome or major resection of the stomach or bowels

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to randomization and agree to use effective contraception

          -  Men with a female partner of childbearing potential must have either had a prior
             vasectomy or agree to use effective contraception

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

          -  Absolute neutrophil count (ANC) >= 1.0 × 10^9/L

          -  Hemoglobin >= 9 g/dL

          -  Platelet count >= 75 x 10^9/L

          -  Prothrombin time (PT)/international normalized ratio (INR)* =< 1.3 x upper limit of
             normal (ULN)

               -  Subjects receiving anticoagulation treatment may be allowed to participate with
                  INR established within the therapeutic range prior to randomization; PT and
                  partial thromboplastin time (PTT) > 1.5 x ULN are permitted in these subjects

          -  PTT =< 1.3 x ULN

          -  Albumin >= 2.5 g/dL

          -  Total bilirubin =< 1.5 x ULN

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN

          -  Creatinine =< 1.5 ULN or calculated creatinine clearance* >= 50 mL/min

               -  Calculate creatinine clearance using standard Cockcroft-Gault formula; creatinine
                  clearance must be >= 50 mL/min to be eligible

          -  Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by
             echocardiogram (ECHO)

        Exclusion Criteria:

          -  No prior therapy with inhibitors affecting the mitogen-activated protein kinase (MAPK)
             pathways at any level (BRAF, mitogen-activated protein [MAP]/extracellular
             signal-related kinase [ERK] kinase [MEK], neuroblastoma RAS viral [v-ras] oncogene
             homolog [NRAS], ERK inhibitors) for unresectable stage IIIC or stage IV (metastatic)
             melanoma; no limit to other therapies (immunotherapy or chemotherapy); prior systemic
             treatment in the adjuvant setting is allowed; (note: ipilimumab treatment must end at
             least 8 weeks prior to study day 1)

          -  BRAFV600 mutation positive

          -  NRAS codon 12, 13, or 61 mutation

          -  Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
             biologic therapy, or immunotherapy within 21 days prior to study day 1, or daily or
             weekly chemotherapy without the potential for delayed toxicity within 14 days prior to
             study day 1

          -  Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
             whichever is shorter, prior to study day 1

          -  Current use of a prohibited medication as described

          -  History of another malignancy

               -  Exception: subjects who have been disease-free for 3 years, or subjects with a
                  history of completely resected, non-melanoma skin cancer, or subjects with
                  indolent second malignancies are eligible; T1a melanoma and melanoma in situ are
                  permitted; consult GlaxoSmithKline (GSK) Medical Monitor if unsure whether second
                  malignancies meet requirements specified above

          -  Any serious or unstable pre-existing medical conditions (aside from malignancy
             exceptions specified above), psychiatric disorders, or other conditions that could
             interfere with the subject's safety, obtaining informed consent, or compliance with
             study procedures

          -  Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
             virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
             infection will be permitted)

          -  History of leptomeningeal disease or spinal cord compression secondary to metastasis

          -  Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery
             and the disease has been confirmed stable (i.e., no increase in lesion size) for at
             least 6 weeks with two consecutive magnetic resonance imaging (MRI) scans using
             contrast prior to study day 1; enzyme inducing anticonvulsants are not allowed while
             patients are on study treatment

          -  A history or evidence of cardiovascular risk including any of the following:

               -  A QT interval corrected for heart rate using the Bazett's formula (QTc) >= 480
                  msec

               -  A history or evidence of current clinically significant uncontrolled arrhythmias

                    -  Exception: subjects with atrial fibrillation controlled for > 30 days prior
                       to study day 1

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to study day 1

               -  A history or evidence of current >= class I congestive heart failure as defined
                  by the New York Heart Association (NYHA) guidelines

               -  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

               -  Patients with intra-cardiac defibrillators or permanent pacemakers

               -  Known cardiac metastases

          -  A history or current evidence of retinal vein occlusion (RVO) including:

               -  History of RVO or

               -  Visible retinal pathology as assessed by ophthalmic examination that is
                  considered a risk factor for RVO such as:

                    -  Evidence of new optic disc cupping

                    -  Evidence of new visual field defects

                    -  Intraocular pressure > 21 mmHg as measured by tonography

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study treatments, their excipients, and/or dimethyl
             sulfoxide (DMSO)

          -  History of interstitial lung disease or pneumonitis

          -  Females who are pregnant or nursing
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate in "high affinity" group
Time Frame:Up to 12 months
Safety Issue:
Description:Per RECIST criteria version (v.) 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.

Secondary Outcome Measures

Measure:Progression-Free Survival
Time Frame:On‐study date to lesser of date of progression or date of death from any cause (assessed up to 3 years)
Safety Issue:
Description:Progression of disease as defined by RECIST 1.1 criteria will be reported. Will also perform subset analysis for PFS stratified by baseline characteristics including lactate dehydrogenase level, metastatic stage, and previous therapy (particularly whether a subject has received immune-based therapy).
Measure:Duration of response in "high affinity" group
Time Frame:Date of first partial or complete response as defined by RECIST 1.1 criteria to date of progression up to 3 years
Safety Issue:
Description:Estimated probable duration from date of objective response to date of disease progression, using the Kaplan‐Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >= 20% increase in sum of longest diameters of target lesions, unequivocal progression of non‐target lesions, or appearance of new lesions.
Measure:Clinical benefit (complete response [CR] + partial response [PR] + stable disease [SD]) per RECIST v. 1.1 in "high affinity" group
Time Frame:Up to 12 months
Safety Issue:
Description:Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.
Measure:Overall Survival
Time Frame:On‐study date to date of death from any cause (assessed up to 3 years)
Safety Issue:
Description:Estimated probable duration of life from on‐study date to date of death from any cause, using the Kaplan‐Meier method with censoring.
Measure:Number of patients with each worst‐grade toxicity
Time Frame:On‐study date to 30 days following final dose of study drug, up to 3 years
Safety Issue:
Description:Safety profile shown by count of patients according to the worst‐grade toxicity experienced by each, where worst‐grade toxicity is per National Cancer Institute (NCI) common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life‐threatening; grade 5, death.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Last Updated

November 20, 2017