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

Last updated: August 26, 2024
Sponsor: Carl Allen
Overall Status: Active - Recruiting

Phase

2

Condition

Histiocytoma

Multiple Sclerosis

Neurologic Disorders

Treatment

Cobimetinib

Clinical Study ID

NCT04079179
H-43475 NACHO COBI
  • All Genders

Study Summary

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.

Eligibility Criteria

Inclusion

INCLUSION CRITERIA:

Age at study entry

  • For Group 1: Participant must be at least 6 months of age and less than 21 years ofage at the time of enrollment

  • For Group 2: Participant may be at least 6 months of age at the time of enrollment

  • For Group 3: Participant must be at least 6 months of age and less than 21 years ofage at the time of enrollment

  • For Group 4: Participant must be 21 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 betaken by mouth or other enteral route such as nasogastric or gastric tube.

  • Biopsy proven LCH -AND

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

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

  • Biopsy proven JXG, ECD, RDD, histiocytic sarcoma, or other histiocytic lesion (newlydiagnosed 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 7days).

  • 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 supportallowed).

Adequate Renal Function Defined as:

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

Maximum Serum Creatinine (mg/dL) Age 2 to < 6 years: Male 0.8 mg/dL, 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) forage

  • AST and ALT ≤ 3x ULN (≤ 5 x ULN for participants with liver involvement)

  • 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 echocardiogramat baseline, as determined by echocardiography or multigated acquisition scan (MUGA)within 28 days prior to enrollment. Depending on institutional standard, either FSor LVEF is adequate for enrollment if only one value is measured; if both values aremeasured, then both values must meet criteria above

Pregnancy/Birth Control

  • Female patients of childbearing potential require a negative urine or serumpregnancy test for eligibility and again at database registration, if more than 2weeks has elapsed.

  • Female patients of childbearing potential must agree to follow the contraceptiverequirements using two forms of effective contraceptive methods for the duration ofthe study treatment. Male patients with sexual partners who are pregnant or whocould become pregnant (i.e., women of child-bearing potential) must agree to use twoforms of effective methods of contraception (one of which must be a barrier method)during the treatment period and for at least 3 months after the last dose of thestudy drug to avoid pregnancy and/or potential adverse effects on a developingembryo. Agreement to true abstinence (not periodic abstinence or withdrawal method)is an acceptable method of birth control.

Exclusion

EXCLUSION CRITERIA:

  • Prior and Concomitant Use of Drugs with CYP3A4 inducing/inhibiting activity: Patienttaking strong inducers or inhibitors of CYP3A4 within 14 days prior to studyenrollment, 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 ofall associated toxicity to ≤ Grade 1 prior to study enrollment (exception foralopecia and ototoxicity which do not need to be resolved ≤ Grade 1). Patients musthave fully recovered from the acute toxic effects of all prior anti-cancer therapyand must meet the following minimum duration from prior anti-cancer directed therapyprior to enrollment. If after the required timeframe, the laboratory eligibilitycriteria are met, the patient is considered to have recovered adequately.

  • Radiation therapy within the 28 days prior to enrollment.

  • Any prior treatment with Cobimetinib.

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

  • Treatment with hormonal therapy (except hormone replacement therapy or oralcontraceptives), immunotherapy, biologic therapy, investigational therapy, orherbal 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 stemcell transplant) or allogeneic stem cell transplant within 90 days prior toenrollment. Anti-GVHD agents post-transplant: Patients who are receivingcyclosporine, tacrolimus or other agents to prevent graft-versus-host diseasepost bone marrow transplant are not eligible for this trial.

  • For patients with brain tumors (intracranial masses), use of anticoagulantswithin 7 days prior to enrollment.

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

  • Patient has received treatment with investigational therapy within 4 weeksprior to initiation of study drug.

  • Patients taking anticoagulants or have a pre-existing bleeding disorderunrelated to histiocytic disease.

  • 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 documentedfungal infection of the nail beds) within 28 days prior to enrollment that hasnot completely resolved.

  • Major surgical procedure or significant traumatic injury within 28 days priorto enrollment, or anticipation of need for major surgical procedure during thecourse of the study. Placement of a vascular access device or minor surgery ispermitted within fourteen (14) days prior to study enrollment (provided thatthe wound has healed).

  • History of significant bowel resection that would preclude adequate absorptionor other significant malabsorptive disease.

  • History of pneumonitis.

  • Ophthalmologic considerations: Patients with known significant ophthalmologicconditions or known risk factors for retinal vein occlusion are not eligible.Specifically, patients with a history of retinal vein occlusion (RVO), retinaldetachment, retinal pathology on ophthalmologic exam, retinopathy ofprematurity, central serous chorioretinopathy (CSSCR), neovascular retinopathy,intraocular pressure > 21 mmHg, and predisposing factors to RVO (e.g.,uncontrolled hypertension, diabetes, or hyperlipidemia, coagulopathy) will beexcluded. Patients with longstanding and stable ophthalmologic findingssecondary to existing conditions are eligible with appropriate writtendocumentation and approval from Study Chair.

  • History of solid organ transplantation: Patients who have received a priorsolid organ transplantation are not eligible.

  • Any other disease, metabolic or psychological dysfunction, physical examinationfinding, or clinical laboratory finding giving reasonable suspicion of adisease or condition that in the opinion of the investigator contraindicatesuse of an investigational drug or places the patient at unacceptable risk fromtreatment complications.

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

  • Clinically significant cardiac arrhythmias including brady-arrhythmias and/orpatients who require anti-arrhythmic therapy (with the exception of betablockers or digoxin). Patients with controlled atrial fibrillation are notexcluded.

  • Unstable arrhythmia

  • Unstable angina, or new-onset angina within 3 months prior to initiation ofstudy treatment

  • Symptomatic congestive heart failure, defined as New York Heart AssociationClass 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 daysof enrollment.

  • Female patients who are pregnant or lactating. Pregnant or lactating women will notbe entered on this study because there is no available information regarding humanfetal or teratogenic toxicities.

Study Design

Total Participants: 90
Treatment Group(s): 1
Primary Treatment: Cobimetinib
Phase: 2
Study Start date:
April 19, 2021
Estimated Completion Date:
December 31, 2029

Study 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 specific 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.

Connect with a study center

  • Phoenix Children's Hospital

    Phoenix, Arizona 85016
    United States

    Active - Recruiting

  • Arkansas Children's Hospital

    Little Rock, Arkansas 72202
    United States

    Active - Recruiting

  • Children's Hospital of Orange County

    Orange, California 92868
    United States

    Active - Recruiting

  • Children's National Hospital

    Washington, District of Columbia 20010
    United States

    Active - Recruiting

  • John Hopkins University School of Medicine

    Baltimore, Maryland 21287
    United States

    Active - Recruiting

  • Dana Farber Cancer Institute, Boston Children's

    Boston, Massachusetts 02215
    United States

    Active - Recruiting

  • Memorial Sloan Kettering Cancer Center

    New York, New York 10065
    United States

    Active - Recruiting

  • NACHO Consortium

    Memphis, Tennessee 38105
    United States

    Site Not Available

  • Children's Medical Center

    Dallas, Texas 75235
    United States

    Active - Recruiting

  • Children's Medical Center- UTSW

    Dallas, Texas 75235
    United States

    Active - Recruiting

  • Texas Children's Hospital

    Houston, Texas 77030
    United States

    Active - Recruiting

  • University of Wisconsin-American Family Children's Hospital

    Madison, Wisconsin 53792
    United States

    Active - Recruiting

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