Clinical Trials /

Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

NCT04322383

Description:

Background: Most people with hairy cell leukemia have a BRAF gene mutation. They can be treated with BRAF inhibitors, drugs that target this mutation. For people who do not have this mutation, BRAF inhibitors are not a treatment option. We found that in hairy cell leukemia, when BRAF is not mutated, the MEK gene frequently is. Binimetinib is a MEK inhibitor which targets MEK. It is important to determine if this drug can be a good treatment option in those who cannot benefit treatment with BRAF inhibitors. Objective: To see if binimetinib is an effective treatment for hairy cell leukemia that does not have a BRAF mutation. Eligibility: People ages 18 and older with hairy cell leukemia without a mutation in the BRAF gene and whose disease either did not respond to treatment or came back after treatment Design: Participants will be screened with: - Medical history - Physical exam - Blood and urine tests - Lung and heart tests - Eye exam - Bone marrow biopsy: A needle will be injected through the participant s skin into the bone to remove a sample of marrow. - CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They might receive a contrast agent by vein. Before they start treatment, participants will have an abdominal ultrasound, pulmonary function tests, and exercise stress tests. Participants will take binimetinib by mouth twice daily in 28-day cycles. They will keep a medication diary. Participants will have at least one visit before every cycle. Visits will include repeats of some screening tests. Participants may continue treatment as long as their disease does not get worse and they do not have bad side effects. About a month after their last dose of treatment, participants will have a follow-up visit. They will then have visits once a year. ...

Related Conditions:
  • Hairy Cell Leukemia
  • Hairy Cell Leukemia Variant
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant
  • Official Title: Phase 2 Trial for Binimetinib for Patients With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

Clinical Trial IDs

  • ORG STUDY ID: 200075
  • SECONDARY ID: 20-C-0075
  • NCT ID: NCT04322383

Conditions

  • Hairy Cell Leukemia

Interventions

DrugSynonymsArms
binimetinibArm 1/Experimental therapy

Purpose

Background: Most people with hairy cell leukemia have a BRAF gene mutation. They can be treated with BRAF inhibitors, drugs that target this mutation. For people who do not have this mutation, BRAF inhibitors are not a treatment option. We found that in hairy cell leukemia, when BRAF is not mutated, the MEK gene frequently is. Binimetinib is a MEK inhibitor which targets MEK. It is important to determine if this drug can be a good treatment option in those who cannot benefit treatment with BRAF inhibitors. Objective: To see if binimetinib is an effective treatment for hairy cell leukemia that does not have a BRAF mutation. Eligibility: People ages 18 and older with hairy cell leukemia without a mutation in the BRAF gene and whose disease either did not respond to treatment or came back after treatment Design: Participants will be screened with: - Medical history - Physical exam - Blood and urine tests - Lung and heart tests - Eye exam - Bone marrow biopsy: A needle will be injected through the participant s skin into the bone to remove a sample of marrow. - CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They might receive a contrast agent by vein. Before they start treatment, participants will have an abdominal ultrasound, pulmonary function tests, and exercise stress tests. Participants will take binimetinib by mouth twice daily in 28-day cycles. They will keep a medication diary. Participants will have at least one visit before every cycle. Visits will include repeats of some screening tests. Participants may continue treatment as long as their disease does not get worse and they do not have bad side effects. About a month after their last dose of treatment, participants will have a follow-up visit. They will then have visits once a year. ...

Detailed Description

      Background:

        -  Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias,
           or approximately 1900 new cases per year in the US.

        -  BRAF V600E mutation is very common in classic HCL.

        -  HCL variant (HCLv) is wild type for BRAF and is more aggressive compared to classic HCL
           due to its lower response and shorter duration of response to standard purine analog
           chemotherapy. The median survival is only ~6 years compared to >25 years for classic
           HCL.

        -  CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34+ immunoglobulin
           rearrangement, are wild-type for BRAF, and confer a poor prognosis when treated with
           standard purine analog chemotherapy.

        -  While BRAF and MEK combination inhibition is making an impact in the treatment of BRAF
           V600E mutated HCL, this treatment is not applicable for patients with BRAF-WT HCL/HCLv.
           Furthermore, with poor survival outcomes in this patient population, lack of targeted
           therapy constitutes a clear unmet need.

        -  Recently, several BRAF WT HCL/HCLv patients have received MEK inhibitors by
           compassionate use and have had lifesaving partial to complete remission, however the
           response has not been assessed systematically in clinical trials.

        -  Binimetinib (also known as MEK162) is an orally bioavailable, selective and potent
           mitogenactivated protein (MAP) kinase kinase (MEK1 and MEK2) inhibitor, which is
           approved for use in combination with encorafenib for the treatment of patients with
           BRAF-mutant melanoma

        -  We have described MAP2K1 (MEK) mutations which may drive the aggressive clinical
           behavior of BRAF WT HCL/HCLv patients, but MEK inhibition may be clinically useful even
           in these patients without known MAP2K1 (MEK) mutations.

      Objective:

      -To determine the overall response rate (ORR) to binimetinib, in patients with BRAF WT HCL
      and HCLv.

      Eligibility:

        -  BRAF WT HCL or HCLv with at least 1 prior purine analog treatment

        -  Need for treatment as evidenced by any one of the following: ANC <1 x10^3/mcL, Hgb
           <10g/dL, Platelet count <100 x10^3/mcL, leukemia cell count >5 x10^3/mcL, symptomatic
           splenomegaly, enlarging HCL mass > 2cm in short axis.

        -  Greater than 18 years of age

        -  No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy
           requiring treatment.

        -  No chemotherapy, immunotherapy, investigational agent or radiotherapy within 4 weeks
           prior to the start of study treatment.

      Design:

        -  Single arm phase 2 trial to determine ORR in patients with relapsed/refractory BRAF WT
           HCL and HCLv.

        -  2-phase minimax design will be used to rule out an unacceptable 10% in favor of an
           improved 25% ORR.

        -  Initially 16 evaluable patients will be enrolled. If 2 or more achieve a major response,
           then accrual will continue to a total of 31 evaluable patients.

        -  Binimetinib will be given at a dose of 45mg BID for as long as patients can continue
           dosing chronically without significant toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1/Experimental therapyExperimentalTreatment with binimetinib
  • binimetinib

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Histologically confirmed diagnosis of HCL or HCLv according to morphological and
             immunophenotypic criteria of WHO classification of lymphoid neoplasm. Patients should
             have at least one of the following indications for therapy:

               1. Absolute neutrophil count (ANC) <1 x10^3/mcL

               2. Hemoglobin <10g/dL

               3. Platelets<100 x10^3/mcL

               4. Symptomatic splenomegaly

               5. Enlarging HCL mass or bone lesion > 2cm in short axis

               6. Leukemia cell count >5x10^3/mcL

        Patients who have eligible blood counts within 4 weeks prior to initiation of study therapy
        will not be considered ineligible if subsequent blood counts prior to initiation of study
        therapy fluctuate and become ineligible up until the time of the initiation of study
        therapy.

          -  Refractory or relapsed disease - defined as either:

               -  Refractory- no response or disease progression in less than or equal to 1 year
                  following first-line treatment with a purine analog, or

               -  Relapsed- having relapsed following treatment with at least 1 prior purine-analog
                  treatments

          -  Patients must be BRAF WT as confirmed from fresh bone marrow aspirate and/or
             peripheral blood sample, or lymph node/mass by the Laboratory of Pathology, NCI

          -  Patients who are ineligible for, unable to obtain in a timely manner, cannot access,
             unwilling to undergo or have failed Moxetumomab Pasudotox trial at NCI

          -  Age greater than or equal to 18 years

          -  ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
             60%).

          -  Patients must have adequate organ and marrow function as defined below:

          -  Total bilirubin less than or equal to 3x upper limit of normal (ULN), unless
             consistent with Gilbert s (ratio between total and direct bilirubin > 5)

          -  AST and ALT less than or equal to 3x ULN

          -  Alkaline phosphatase < 2.5x ULN

          -  Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than
             or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional
             normal calculated using eGFR

          -  Serum albumin greater than or equal to 2 g/dL

          -  Prothrombin time (PT)/International Normalized Ratio < 2.5x ULN (If on warfarin,
             PT/INR < 3.5x ULN; If on any other anticoagulation, Prothrombin time (PT) < 2.5x ULN

          -  Fibrinogen greater than or equal to 0.5x lower limit of normal

          -  The effects of binimetinib on the developing human fetus are unknown therefore
             participants must use effective methods of contraception as directed below.

               -  Females of childbearing potential (FOCBP) who are sexually active with a
                  nonsterilized male partner must use a highly effective method of contraception
                  and not donate ova prior to study entry and or the duration of study treatment
                  and until 30 days after the last dose of binimetinib. Periodic abstinence, the
                  rhythm method, and the withdrawal method are not acceptable methods of
                  contraception. Females of childbearing potential are defined as those who are not
                  surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or
                  complete hysterectomy) or those who are premenarchal or postmenopausal (defined
                  as 12 months with no menses without an alternative medical cause). A highly
                  effective method of contraception is defined as one that results in a low failure
                  rate (i.e., less than 1% per year) when used consistently and correctly. Not all
                  methods of contraception are highly effective. Female subjects must use a
                  hormonal method in addition to a barrier method alone, to minimize the chance of
                  pregnancy. Should a woman become pregnant or suspect she is pregnant while she or
                  her partner is participating in this study, she should inform her treating
                  physician immediately.

               -  Non-sterilized male participants who are sexually active with a female partner of
                  childbearing potential must agree to use methods of contraception that are highly
                  effective or acceptable, and not donate sperm from study entry until 90 days
                  after the last dose of binimetinib.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

          -  Must co-enroll in study 10-C-0066: Collection of Human Samples to Study Hairy Cell and
             other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment

        EXCLUSION CRITERIA:

          -  Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks prior
             to the start of study treatment.

          -  Prior therapy with binimetinib.

          -  Patients who are receiving any other investigational agents or have received an
             investigational agent within 14 days prior to the start of study treatment.

          -  Patients who have undergone major surgery less than or equal to 6 weeks prior to start
             of study treatment or who have not recovered from side effects of such procedure.

          -  Known hypersensitivity or contraindication to any component of binimetinib or its
             excipients.

          -  Inability to swallow and retain study drug.

          -  Is pregnant or breastfeeding or expecting to conceive within the projected duration of
             the study treatment, starting with the screening visit . Pregnant women are excluded
             from this study because binimetinib has the potential for teratogenic or abortifacient
             effects. Because there is an unknown but potential risk for adverse events in nursing
             infants secondary to treatment of the mother with binimetinib, breastfeeding should be
             discontinued if the mother is treated.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, cardiac disfunction (details as below), uncontrolled pulmonary infection,
             pulmonary edema or psychiatric illness/social situations that would limit compliance
             with study requirements.

          -  Evidence of active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection.

        Note: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled. If
        positive for Hepatitis B core antibody or surface antigen the patient must be on Tenofovir
        or Entecavir and Hepatitis B Viral deoxyribonucleic acid (DNA) load must be <2000 IU/mL

          -  Active second malignancy requiring treatment other than minor resection of indolent
             cancers like basal cell and squamous skin cancers.

          -  Human immunodeficiency virus (HIV)-positive patients unless taking appropriate anti-
             HIV medications with a CD4 count of > 200. Otherwise, there may be an increased risk
             of infections.

          -  History of an allogeneic bone marrow or stem cell transplant.

          -  Known history of acute or chronic pancreatitis

          -  Impaired cardiovascular function or clinically significant cardiovascular disease
             including, but not limited to, any of the following:

               1. History of acute coronary syndromes (including myocardial infarction, unstable
                  angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 3
                  months prior to initiation of study therapy

               2. Congestive heart failure requiring treatment (New York Heart Association Grade
                  greater than or equal to 2);

               3. Left ventricular ejection fraction (LVEF) < 50% as determined by Multigated
                  Acquisition Scan (MUGA) or Transthoracic echocardiogram (TTE);

               4. Uncontrolled hypertension defined as persistent systolic blood pressure greater
                  than or equal to 160 mmHg or diastolic blood pressure greater than or equal to
                  100 mmHg despite current therapy;

               5. History or presence of clinically significant cardiac arrhythmias (including
                  resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal
                  supraventricular tachycardia);

               6. Triplicate average baseline QTcF interval greater than or equal to 480 ms.

          -  Impairment of gastrointestinal function or disease which may significantly alter the
             absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or
             diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal
             absorption), or recent (less than or equal to 3 months) history of a partial or
             complete bowel obstruction, or other conditions that will interfere significantly with
             the absorption of oral drugs.

          -  Concurrent neuromuscular disorder that is associated with elevated CK (e.g.,
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
             muscular atrophy).

          -  History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled
             glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability
             syndromes); history of retinal degenerative disease.

          -  History of thromboembolic or cerebrovascular events less than or equal to 12 weeks
             prior to the first dose of study treatment. Examples include transient ischemic
             attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or
             sub-massive) deep vein thrombosis or pulmonary emboli.

        Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in
        hemodynamic instability are allowed to enroll as long as they are on a stable dose of
        anticoagulants for at least 4 weeks.

        Note: Patients with thromboembolic events related to indwelling catheters or other
        procedures may be enrolled.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:overall response rate
Time Frame:every year
Safety Issue:
Description:Percentage of patients with the best overall response of CR or PR to therapy

Secondary Outcome Measures

Measure:CR rate
Time Frame:every year
Safety Issue:
Description:the time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR
Measure:Progression free survival
Time Frame:every year
Safety Issue:
Description:duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first
Measure:Overall survival
Time Frame:every year
Safety Issue:
Description:the time from the start of the treatment until time of death from any cause
Measure:time to next treatment
Time Frame:every year
Safety Issue:
Description:duration of time from the start of the binimetinib to next line of treatment
Measure:safety
Time Frame:every 4 weeks
Safety Issue:
Description:The fraction of patients with toxicity noted will be reported by grade and type of toxicity identified.
Measure:different response relative to MAP2K1 mutations
Time Frame:every year
Safety Issue:
Description:determine whether the response to binimetinib is different in patients with and without MAP2K1 (MEK mutations), in patients for which MEK status is known

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • MEK1
  • Inhibitor
  • MEK2
  • MEK162

Last Updated

April 2, 2020