Clinical Trials /

Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders

NCT04079179

Description:

This is a research study of a drug called cobimetinib in children and adults diagnosed with Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or does not respond to treatment. Cobimetinib blocks activation of a protein called Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in histiocytosis cells. Four different groups of patients will be enrolled.

Related Conditions:
  • Erdheim-Chester Disease
  • Histiocytic Sarcoma
  • Juvenile Xanthogranuloma
  • Langerhans Cell Histiocytosis
  • Sinus Histiocytosis with Massive Lymphadenopathy
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders
  • Official Title: A Phase 2 Study to Assess the Safety and Efficacy of Cobimetinib in Refractory Langerhans Cell Histiocytosis, LCH-Associated Neurodegenerative Disease, and Other Histiocytic Disorders.

Clinical Trial IDs

  • ORG STUDY ID: H-43475 NACHO COBI
  • NCT ID: NCT04079179

Conditions

  • Langerhan's Cell Histiocytosis
  • Juvenile Xanthogranuloma
  • Erdheim-Chester Disease
  • Rosai Dorfman Disease
  • Neuro-Degenerative Disease
  • Histiocytic Sarcoma
  • Histiocytic Disorders, Malignant

Interventions

DrugSynonymsArms
CobimetinibCOTELLIC, RO5514041Patients < 30 years with recurrent LCH (Grp1)

Purpose

This is a research study of a drug called cobimetinib in children and adults diagnosed with Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or does not respond to treatment. Cobimetinib blocks activation of a protein called Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in histiocytosis cells. Four different groups of patients will be enrolled.

Detailed Description

      Histiocytic disorders are diseases caused by misfunctioning or buildup of particular immune
      cells called histiocytes. Many histiocytic disorders (LCH, juvenile xanthogranuloma (JXG),
      Erdheim-Chester disease (ECD), and Rosai-Dorfman Disease (RDD)) arises from blood cells that
      receive incorrect growth signals. These incorrect signals are caused by changes in genes
      (mutations) that lead to tissue damage (lesions) which causes disease. Some patients with LCH
      can develop neurodegeneration (LCH-ND) which is damage to neurons that results in reduced
      brain function, from LCH cells that go to the brain and activate inflammation. LCH arises
      from blood cells that receive incorrect growth signals. These incorrect signals are caused by
      mutations (changes in genes). The LCH blood cells can create changes in the structure of
      almost any organ, and can cause damage to normal organ function.

      The purpose of this research study is to learn whether cobimetinib is safe and effective in
      subjects diagnosed with LCH, LCH-ND, RDD, JXG and ECD which may have a specfic mutation
      called BRAF-V600E. In healthy cells, certain proteins (called BRAF and MEK) are thought to
      help control normal cell growth. BRAF-V600E is a specific change in a gene that may cause
      cancer cells to grow and spread by sending constant signals to the MEK protein. Cobimetinib
      is designed to attach to and block the activity of MEK.
    

Trial Arms

NameTypeDescriptionInterventions
Patients < 30 years with recurrent LCH (Grp1)ExperimentalChildren and young adults (<30 years) with recurrent active LCH lesions (may also have LCH-ND).
  • Cobimetinib
Patients of any age with LCH-ND (Grp2)ExperimentalPatients of any age with progressive LCH Neurodegenerative Disease (LCH-ND) without other sites of active LCH.
  • Cobimetinib
Patients <30 years with other histiocytic disorders (Grp3)ExperimentalNewly diagnosed or relapsed/refractory children and young adults (<30 years) with other histiocytic disorders including juvenile xanthogranuloma, Erdheim-Chester disease, histiocytic sarcoma and Rosai-Dorfman disease.
  • Cobimetinib
Patients ≥ 30 years with LCH/histiocytic disorders (Grp4)ExperimentalAdults (≥30 years) with LCH or other histiocytic disorder with recurrent active lesions (may also have LCH-ND).
  • Cobimetinib

Eligibility Criteria

        INCLUSION CRITERIA:

          -  For Group 1: Participant must be less than 30 years of age at the time of enrollment

          -  For Group 2: Participant may be any age at the time of enrollment

          -  For Group 3: Participant must be less than 30 years of age at the time of enrollment

          -  For Group 4: Participant must be 30 years of age or older at the time of enrollment

          -  Participant must be able to take an enteral dose and formulation of medication. Study
             medication is only available as an oral suspension or tablet which may be taken by
             mouth or other enteral route such as nasogastric or gastric tube.

          -  Biopsy proven LCH -AND

          -  Failure of at least front-line therapy for high-risk LCH with evaluable disease. -OR

          -  Failure of at least second-line therapy for low-risk LCH with evaluable disease. -OR

          -  Diagnosis of LCH-associated neurodegenerative disease with radiologic or clinical
             progression within the past 3 months. -OR

          -  Biopsy proven JXG, ECD, RDD, histiocytic sarcoma, or other histiocytic lesion (newly
             diagnosed or relapsed/refractory disease) with evaluable active disease.

        Performance Level:

        -Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of
        age.

        Adequate Hematologic Function Defined as:

          -  ANC ≥ 0.75 x 10^9/L (unsupported/without growth factor stimulant)

          -  Platelet count ≥ 75 x 10^9/L (unsupported/without transfusion within the past 7 days).

          -  Patients with marrow disease must have platelet count of >/= 75 x 10^9/L (transfusion
             support allowed) and must not be refractory to platelet transfusions.

          -  Hemoglobin ≥ 8 g/dL (unsupported/without transfusion within the past 7 days)

          -  Patients with marrow disease must have hemoglobin ≥ 8 g/dL (transfusion support
             allowed).

        Adequate Renal Function Defined as:

        - Calculated creatinine clearance (or radioisotope GFR) ≥ 70 mL/min/1.73m^2 or serum
        creatinine based on age/gender as follows:

        Maximum Serum Creatinine (mg/dL) Age 2 to < 6 years: Male 0.8 mg/d, Female 0.8; 6 to < 10
        years: Male 1 mg/dL,Female 1; 10 to < 13 years: Male 1.2 mg/dL; Female 1.2; 13 to < 16
        years: Male 1.5 mg/dL ; Female 1.4;

        ≥ 16 years: Male 1.7 mg/dL; Female 1.4;

        Adequate Liver Function Defined as:

          -  Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for
             age

          -  AST and ALT ≤ 2.5x ULN for age.

          -  Serum albumin ≤ 2 g/dL.

        For patients with liver disease caused by histiocytic disorder:

        • Patients may be enrolled with abnormal bilirubin, AST, ALT and albumin with documentation
        of histiocytic liver disease.

        Adequate Cardiac Function Defined as:

          -  Fractional shortening (FS) of ≥ 30% or ejection fraction of ≥ 50% by echocardiogram at
             baseline, as determined by echocardiography or multigated acquisition scan (MUGA)
             within 21 days prior to study enrollment. Depending on institutional standard, either
             FS or LVEF is adequate for enrollment if only one value is measured; if both values
             are measured, then both values must meet criteria above

          -  Female patients of childbearing potential require a negative urine or serum pregnancy
             test for eligibility and again at enrollment, if more than 2 weeks has elapsed.

          -  Female patients of childbearing potential must agree to follow the contraceptive
             requirements using two forms of effective contraceptive methods for the duration of
             the study treatment.

        EXCLUSION CRITERIA:

        - Prior and Concomitant Use of Drugs with CYP3A4 inducing/inhibiting activity: Patient
        taking strong inducers or inhibitors of CYP3A4 within 14 days prior to study enrollment,
        including but not limited to the following: erythromycin, clarithromycin, ketoconazole,
        azithromycin, itraconazole, grapefruit juice or St. John's wort.

          -  Prior Therapy Restrictions Completion of previous chemotherapy, immunotherapy,
             radiotherapy, or targeted therapy for LCH (or other histiocytic disorder) at least 28
             days (except where specified below) prior to study enrollment, with resolution of all
             associated toxicity to ≤ Grade 1 prior to study enrollment (exception for alopecia and
             ototoxicity which do not need to be resolved ≤ Grade 1). Patients must have fully
             recovered from the acute toxic effects of all prior anti-cancer therapy and must meet
             the following minimum duration from prior anti-cancer directed therapy prior to
             enrollment. If after the required timeframe, the laboratory eligibility criteria are
             met, the patient is considered to have recovered adequately.

               -  Radiation therapy within the last 28 days.

               -  Any prior treatment with Cobimetinib.

               -  Treatment with a long-acting hematopoietic growth factor within 14 days prior to
                  initiation of study drug or a short-acting hematopoietic growth factor within 7
                  days prior to study enrollment.

               -  Treatment with hormonal therapy (except hormone replacement therapy or oral
                  contraceptives), immunotherapy, biologic therapy, investigational therapy, or
                  herbal cancer therapy within 28 days or < 5 half-lives, whichever is longer,
                  prior to study enrollment.

               -  Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell
                  transplant) or allogeneic stem cell transplant within 90 days prior to study
                  enrollment. Anti-GVHD agents post-transplant: Patients who are receiving
                  cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease
                  post bone marrow transplant are not eligible for this trial.

               -  For patients with brain tumors (intracranial masses), use of anticoagulants
                  within 7 days prior to study enrollment.

               -  Corticosteroid therapy <0.5 mg/kg/day averaged during the month prior to study
                  enrollment is permissible but must be discontinued fourteen (14) days prior to
                  prior to study enrollment. Patients with documented brain lesions receiving
                  corticosteroids for management of cerebral edema must be on a stable dose for
                  fourteen (14) days prior to study enrollment.

               -  Patient has received treatment with investigational therapy within 4 weeks prior
                  to initiation of study drug.

          -  Exclusions for other illness

               -  Other active malignancy or history of secondary malignancy.

               -  Refractory nausea and vomiting, malabsorption, external biliary shunt

               -  Infection: Patients who have a known active infection (excluding documented
                  fungal infection of the nail beds) within 28 days prior to study enrollment that
                  has not completely resolved.

               -  Major surgical procedure or significant traumatic injury within 28 days prior to
                  study enrollment, or anticipation of need for major surgical procedure during the
                  course of the study. Placement of a vascular access device or minor surgery is
                  permitted within fourteen (14) days of study enrollment (provided that the wound
                  has healed).

               -  History of significant bowel resection that would preclude adequate absorption or
                  other significant malabsorptive disease.

               -  History of pneumonitis.

               -  Ophthalmologic considerations: Patients with known significant ophthalmologic
                  conditions or known risk factors for retinal vein occlusion are not eligible.
                  Specifically, patients with a history of retinal vein occlusion (RVO), retinal
                  detachment, retinal pathology on ophthalmologic exam, retinopathy of prematurity,
                  central serous chorioretinopathy (CSSCR), neovascular retinopathy, intraocular
                  pressure > 21 mmHg, and predisposing factors to RVO (e.g., uncontrolled
                  hypertension, diabetes, or hyperlipidemia, coagulopathy) will be excluded.
                  Patients with longstanding and stable ophthalmologic findings secondary to
                  existing conditions are eligible with appropriate documentation and approval from
                  Study (Co)Chair and Coordinating Center.

               -  History of solid organ transplantation: Patients who have received a prior solid
                  organ transplantation are not eligible.

               -  Any other disease, metabolic or psychological dysfunction, physical examination
                  finding, or clinical laboratory finding giving reasonable suspicion of a disease
                  or condition that in the opinion of the investigator contraindicates use of an
                  investigational drug or places the patient at unacceptable risk from treatment
                  complications.

          -  History of clinically significant cardiac dysfunction, including the following:

               -  Clinically significant cardiac arrhythmias including brady-arrhythmias and/or
                  patients who require anti-arrhythmic therapy (with the exception of beta blockers
                  or digoxin). Patients with controlled atrial fibrillation are not excluded.

               -  Unstable arrhythmia

               -  Unstable angina, or new-onset angina within 3 months prior to initiation of study
                  treatment

               -  Symptomatic congestive heart failure, defined as New York Heart Association Class
                  II or higher

               -  Myocardial infarction within 3 months prior to initiation of study treatment

          -  Known chronic human immunodeficiency virus (HIV).

          -  History of Grade ≥ 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of
             study entry.

          -  Female patients who are pregnant or lactating. Pregnant or lactating women will not be
             entered on this study because there is no available information regarding human fetal
             or teratogenic toxicities.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rates using modified RECiST criteria
Time Frame:12 months
Safety Issue:
Description:Proportion of participants with (complete response, partial response, stable disease, progressive disease) by 1 year of therapy with Cobimetinib. It is assumed that at each protocol-specified timepoint, a response assessment occurs. Status calculation will occur at each timepoint for patients who have measurable disease at baseline per the criteria defined in the protocol.

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:12 months
Safety Issue:
Description:Progression Free Survival defined as the length of time during and after the treatment of a disease, that a patient lives with the disease but it does not get worse.
Measure:Nature and Severity of Adverse Events
Time Frame:12 months
Safety Issue:
Description:Assessment of the nature and severity of adverse events in patients treated with Cobimetinib for histiocytic disorders.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Carl Allen

Trial Keywords

  • Cobimetinib
  • Langerhans Cell Histiocytosis (LCH)

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