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Single-agent Cobimetinib for Adults With Histiocytic Disorders

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ClinicalTrials.gov Identifier: NCT02649972
Recruitment Status : Recruiting
First Posted : January 8, 2016
Last Update Posted : May 4, 2018
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Histiocytic Disorders Drug: Cobimetinib Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Single-agent Cobimetinib for Adults With Histiocytic Disorders
Actual Study Start Date : January 2016
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Cobimetinib

Arm Intervention/treatment
Experimental: Cobimetinib
This is an open-label, single-center, 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.
Drug: Cobimetinib
Patients in this study will receive single-agent Cobimetinib 60mg oral daily for days 1-21 of each 28 day cycle. The rationale for single agent therapy, is the evidence for robust and sustained response to BRAF inhibitor monotherapy in histiocytic disorders harboring the BRAFV600E mutation. Patients will have the option to discontinue treatment after 12 cycles and will be monitored for disease relapse for an additional 12 months. In the event that disease relapse occurs within the 12 month monitoring period, patients will restart treatment and continue on study. Upon restarting, the assessment schedule will restart at cycle 1 and all assessments will occur at the same frequency and intervals.




Primary Outcome Measures :
  1. best overall response [ Time Frame: 1 year ]
    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.



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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed histiocytic disorder or histologic findings compatible with a histiocytic disorder in the context of confirmatory radiologic findings
  • 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
  • Measurable disease according to PET Response Criteria, 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.
  • To date, no patients with BRAF-mutated ECD/LCH have had disease progression on BRAF inhibitor therapy. Such patient would be eligible but would require tissue biopsy for genotyping before participating.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02649972


Contacts
Contact: Eli Diamond, MD 212-639-7576
Contact: David Hyman, MD 646-888-4544

Locations
United States, New York
Memoral Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Eli Diamond, MD    212-639-7576      
Contact: David Hyman, MD    646-888-4544      
Principal Investigator: Eli Diamond, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Genentech, Inc.
Investigators
Principal Investigator: Eli Diamond, MD Memorial Sloan Kettering Cancer Center

Additional Information:
Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT02649972     History of Changes
Other Study ID Numbers: 15-216
First Posted: January 8, 2016    Key Record Dates
Last Update Posted: May 4, 2018
Last Verified: May 2018

Keywords provided by Memorial Sloan Kettering Cancer Center:
Cobimetinib
15-216

Additional relevant MeSH terms:
Disease
Pathologic Processes