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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04322383
Recruitment Status : Not yet recruiting
First Posted : March 26, 2020
Last Update Posted : May 29, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.

...


Condition or disease Intervention/treatment Phase
Hairy Cell Leukemia Drug: binimetinib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial for Binimetinib for Patients With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant
Estimated Study Start Date : June 3, 2020
Estimated Primary Completion Date : April 30, 2024
Estimated Study Completion Date : July 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia

Arm Intervention/treatment
Experimental: Arm 1/Experimental therapy
Treatment with binimetinib
Drug: binimetinib
Binimetinib will be given orally at a dose of 45mg BID continuously for 28- day cycles with no resting period between cycles.




Primary Outcome Measures :
  1. overall response rate [ Time Frame: every year ]
    Percentage of patients with the best overall response of CR or PR to therapy


Secondary Outcome Measures :
  1. CR rate [ Time Frame: every year ]
    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

  2. Progression free survival [ Time Frame: every year ]
    duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

  3. Overall survival [ Time Frame: every year ]
    the time from the start of the treatment until time of death from any cause

  4. time to next treatment [ Time Frame: every year ]
    duration of time from the start of the binimetinib to next line of treatment

  5. safety [ Time Frame: every 4 weeks ]
    The fraction of patients with toxicity noted will be reported by grade and type of toxicity identified.

  6. different response relative to MAP2K1 mutations [ Time Frame: every year ]
    determine whether the response to binimetinib is different in patients with and without MAP2K1 (MEK mutations), in patients for which MEK status is known



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


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): NCT04322383


Contacts
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Contact: Theresa Yu, R.N. (301) 480-6195 theresa.yu@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Robert J Kreitman, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04322383    
Other Study ID Numbers: 200075
20-C-0075
First Posted: March 26, 2020    Key Record Dates
Last Update Posted: May 29, 2020
Last Verified: March 23, 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
MEK1
Inhibitor
MEK2
MEK162
Additional relevant MeSH terms:
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Leukemia
Leukemia, Hairy Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases