Clinical Trials /

Single-agent Cobimetinib for Adults With Histiocytic Disorders

NCT02649972

Description:

The purpose of this study is to find out what effects, good or bad, Cobimetinib has in patients with histiocytosis. Cobimetinib is an investigational oral medication that blocks MEK1.

Related Conditions:
  • Histiocytosis
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Single-agent Cobimetinib for Adults With Histiocytic Disorders
  • Official Title: Phase II Trial of Single-agent Cobimetinib for Adults With Histiocytic Disorders

Clinical Trial IDs

  • ORG STUDY ID: 15-216
  • NCT ID: NCT02649972

Conditions

  • Histiocytic Disorders

Interventions

DrugSynonymsArms
CobimetinibCobimetinib

Purpose

The purpose of this study is to find out what effects, good or bad, Cobimetinib has in patients with histiocytosis. Cobimetinib is an investigational oral medication that blocks MEK1.

Trial Arms

NameTypeDescriptionInterventions
CobimetinibExperimentalThis is an open-label, multicenter, phase II study exploring the efficacy and safety of single-agent Cobimetinib in patients with histiocytic disorders whose tumors are 1) BRAFV600 wildtype or 2) BRAFV600E mutant and are intolerant to, or unable to access, BRAF inhibitors.
  • Cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed histiocytic disorder or histologic findings compatible with a
             histiocytic disorder in the context of confirmatory radiologic findings confirmed by
             the enrolling institution.

          -  One of the following:

               -  Documentation of BRAF V600E mutation and inability to access of BRAF inhibitor or
                  prior treatment with a BRAF inhibitor discontinued due intolerable side effects
                  or toxicity prior to progression, -OR-

               -  Documentation of wild-type BRAF V600 mutational status

               -  Patients with BRAF-mutated ECD/LCH who have had disease progression on BRAF
                  inhibitor therapy would be eligible but would require tissue biopsy (or available
                  tissue) for genotyping before participating.

          -  Measurable disease according to PET Response Criteria, confirmed by the MSK
             investigator radiologist, with the exception of patients with cutaneous disease that
             can be measured and followed by RECIST criteria

          -  Histiocytic disorder must be (a) multi-system disease or (b) disease that is recurrent
             or refractory to standard therapies, or (c) single-system disease with that is
             unlikely to benefit from conventional and less toxic therapies, based on the best
             available evidence (for example, CNS or cardiac infiltration, retroperitoneal
             fibrosis, prior chemotherapy, or other medical history or co-morbidities, etc)

          -  Life expectancy > 12 weeks

          -  Age ≥ 16 years

          -  ECOG performance status ≤ 3 (May be converted from Karnofsky Performance Status)

          -  Adequate bone marrow function as indicated by the following:

               -  ANC > 1000/uL

               -  Platelets ≥ 50,000/uL

               -  Hemoglobin ≥ 8.5 g/dL.

          -  Patients with cytopenias below these thresholds deemed to be the result of disease
             will be considered eligible.

          -  Adequate renal function, as indicated by:

               -  creatinine ≤ 1.5 the upper limit of normal (ULN) -OR-

               -  Estimated creatinine clearance of > 50 ml/min

          -  As for #7, patients with renal dysfunction deemed to be the result of disease will be
             considered eligible.

          -  Adequate liver function, as defined by bilirubin ≤ 1.5 ULN

          -  AND AST/ALT < 3 ULN

          -  Ability to swallow pills

          -  Negative serum pregnancy test within 7 days prior to commencement of dosing in
             premenopausal women. Women of non-childbearing potential may be included without serum
             pregnancy test if they are either surgically sterile or have been postmenopausal for ≥
             1 year.

          -  Fertile men and women must use an effective method of contraception during treatment
             and for at least 6 months after completion of treatment as directed by their
             physician. Effective methods of contraception are defined as those which result in a
             low failure rate (i.e., less than 1% per year) when used consistently and correctly
             (for example implants, injectables, combined oral contraception or intra-uterine
             devices). At the discretion of the Investigator, acceptable methods of contraception
             may include total abstinence in cases where the lifestyle of the patient ensures
             compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal,
             post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

          -  Patients must be willing to consent for protocol #12-245 for IMPACT testing (for MSK
             patients ONLY).

        Exclusion Criteria:

          -  Prior treatment with a MEK inhibitor

          -  Active infection requiring intravenous antibiotics

          -  Pregnant, lactating or breast feeding women

          -  Prior radiation therapy within the last 14 days

          -  Unwillingness or inability to comply with study and follow-up procedures.

          -  Any foods/supplements that are strong inhibitors or inducers of CYP3A are prohibited
             at least 7 days prior to initiation of and during study treatment

          -  History of or evidence of retinal pathology on ophthalmologic examination that is
             considered a risk factor for neurosensory retinal detachment, RVO, or neovascular
             macular degeneration

          -  The risk factors for RVO are listed below. Exclusion should be considered by clinical
             discretion if they have the following conditions:

               -  Uncontrolled glaucoma with intra-ocular pressures > 21mmHg

               -  Serum cholesterol ≥ Grade 2

               -  Hypertriglyceridemia ≥ Grade 2

               -  Hyperglycemia ≥ Grade 2

          -  History of clinically significant cardiac dysfunction, unless deemed to be the direct
             result of disease, including the following:

               -  Current unstable angina

               -  Symptomatic congestive heart failure of NYHA class 2 or higher

               -  Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension
                  controlled with anti-hypertensives to ≤ Grade 2 are eligible).

               -  Left ventricular ejection fraction (LVEF) below institutional lower limit of
                  normal or below 50%

               -  Uncontrolled Arrhythmias

               -  Myocardial infarction, severe/unstable angina, symptomatic congestive heart
                  failure, cerebrovascular accident or transient ischemic attack within the
                  previous 6 months
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:best overall response
Time Frame:1 year
Safety Issue:
Description:by PET Response Criterial (PRC), with a dichotomous BOR of CR or PR versus neither of those. Assuming we use this binary endpoint of response, defined as best overall response of CR or PR versus not using the PET Response Criteria (PRC), a sample size of 18 patients provides 90% power to test the hypothesis that the response rate is promising (defined as 35% or higher) against a non-promising rate of 10% or lower.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Cobimetinib
  • 15-216

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