Encorafenib Plus Binimetinib for People With BRAF V600E Mutated Relapsed/Refractory HCL

Brief Title

Encorafenib Plus Binimetinib for People With BRAF V600E Mutated Relapsed/Refractory HCL

Official Title

Phase 2 Trial of Encorafenib Plus Binimetinib for Patients With BRAF V600E Mutated Relapsed/Refractory HCL

Brief Summary


      Hairy cell leukemia (HCL) does not usually respond to chemotherapy. Most people with HCL have
      a BRAF gene mutation. This can increase the growth of cancer cells. Vemurafenib has been
      tested to treat these people. However, researchers think a combination of drugs might work


      To test if treatment with a combination of encorafenib and binimetinib in BRAF mutant

      HCL is more effective than treatment with vemurafenib.


      People ages 18 and older with BRAF mutant HCL that did not respond to or came back after


      Participants will be screened with:

      Medical history

      Physical exam

      Bone marrow biopsy: A needle will be injected through the participant s skin and into a bone
      to remove liquid.

      Blood and urine tests

      Heart and lung function tests

      CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They may
      have a contrast agent injected into a vein.

      Eye exam

      Participants will take the study drugs by mouth in 28-day cycles. They will take encorafenib
      daily. They will take binimetinib twice daily. They will keep a pill diary.

      Participants will take their temperature daily.

      Participants will have at least 1 visit before each cycle. Visits will include repeats of
      some screening tests. They will also include abdominal ultrasounds, exercise stress tests,
      and skin evaluations.

      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.
      Then they will have annual follow-ups....

Detailed Description


        -  Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias,
           or approximately 1900 new cases/year in the US. The nucleoside analogs cladribine and
           pentostatin are highly active as monotherapy with complete remission (CR) rates of 80 to
           90%. However, there is no cure from chemotherapy and patients eventually relapse with
           worse efficacy and cumulative toxicity (stem cell damage and neuropathy) with each
           repeated chemotherapy course.

        -  About 90% of classic HCL patients have the BRAF V600E mutation, which leads to
           Rasindependent activation of the MAPK pathway, causing increased phosphorylation
           (hyperactivation) of MEK, followed by ERK, therefore promoting the proliferation and
           survival of

      HCL cells.

        -  The BRAF inhibitor, vemurafenib, when used as a single agent for the treatment of HCL
           achieved high response rate with CR rate of 38% in 50 patients reported from 2 trials,
           however, treatment was limited to several months and responses lacked durability, with
           median CR duration of 19 months in 1 trial. In this trial, 100% of the CRs were positive
           for minimal residual disease (MRD) by immunohistochemistry (IHC), and failure to
           eradicate MRD after several months of vemurafenib likely lead to the lack of CR

        -  In a recent trial of combined inhibition of BRAF and MEK using dabrafenib and trametinib
           treatment, 49% of 41 evaluable patients achieved CR, and MRD was eradicated in 15% of
           patients on this trial. At NIH, we enrolled a total of 28 HCL patients on this trial and
           achieved a CR rate of 68% amongst our patients by managing toxicity and allowing
           patients to remain on treatment.

        -  A major challenge in the long-term treatment of HCL patients with dabrafenib and
           trametinib is managing fever, which has necessitated long-term or intermittent steroids
           use for most patients.

        -  In the COLOMBUS trial, the combination of the BRAF inhibitor, encorafenib and the MEK
           inhibitor, binimetinib was found to be superior to vemurafenib for BRAF V600E+ melanoma
           with respect to PFS and OS and was well tolerated with low rates of toxicities including

        -  To our knowledge, neither encorafenib nor binimetinib has been tested in HCL, but the
           low rate of pyrexia with encorafenib plus binimetinib in melanoma suggests that this
           combination may be well tolerated in HCL.


      -To determine if treatment with combination encorafenib and binimetinib in BRAF V600E+HCL is
      associated with a CR rate which exceeds that of vemurafenib.


        -  BRAF V600E mutant HCL 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 or equal to 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.


        -  Phase 2 trial, single arm, non-randomized trial to determine if the combination of
           encorafenib and binimetinib achieves a CR rate in HCL which is historically higher than
           that of vemurafenib.

        -  Simon optimal 2-phase design will be used to rule out an unacceptable CR rate of 35% in
           favor of an improved 55% CR rate.

        -  Initially 12 evaluable patients will be enrolled. If 5 or more achieve CR, then accrual
           will continue to a total of 32 evaluable patients

        -  Encorafenib will be given at a dose of 450mg QD and binimetinib at a dose of 45mg BID
           for as long as patients can continue dosing chronically without significant toxicity

Study Phase

Phase 2

Study Type


Primary Outcome

CR rate

Secondary Outcome

 MRD negative CR


Hairy Cell Leukemia



Study Arms / Comparison Groups

 Arm 1/Experimental therapy
Description:  Treatment with encorafenib and binimetinib


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

October 28, 2020

Completion Date

July 31, 2024

Primary Completion Date

April 30, 2024

Eligibility Criteria


               1. Histologically confirmed diagnosis of HCL according to morphological and
                  immunophenotypic criteria of WHO classification [WHO, 2008 revised 2016] of
                  lymphoid neo

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

                    -  Hemoglobin <10g/dL

                    -  Platelets<100 x10(3)/mcL

                    -  Symptomatic splenomegaly

                    -  Enlarging HCL mass > 2cm in short axis

                    -  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.

               2. Patients must have BRAF V600E mutation as confirmed from fresh bone marrow
                  aspirate, peripheral blood sample, or lymph node/mass by the Laboratory of
                  Pathology, NCI

               3. 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

               4. Refractory or relapsed disease- defined as either:

                    -  Refractory- no response or disease progression in <=1 year following
                       first-line treatment with a purine analog, or

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

               5. Age >=18 years

               6. ECOG performance status <=2 (Karnofsky >60%)

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

                    -  Total bilirubin <= 3x upper limit of normal (ULN), unless consistent with
                       Gilbert s (ratio between total and direct bilirubin > 5)

                    -  AST and ALT <= 3x ULN

                    -  Alkaline phosphatase < 2.5x ULN

                    -  Serum creatinine <= 1.5 mg/dL or creatinine clearance >= 60 mL/min/1.73 m^2
                       for patients with creatinine levels above institutional normal calculated
                       using eGFR

                    -  Serum albumin >= 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 >= 0.5x lower limit of normal

               8. The effects of the study drugs on the developing human fetus are unknown
                  therefore participants must use effective methods of contraception as directed

                  --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 study drug. Periodic abstinence, the
                  rhythm method, and the withdrawal method are not acceptable methods of
                  contraception. There is a potential for encorafenib to induce CYP3A4, which may
                  reduce the effectiveness of hormonal contraception methods. Therefore, the use of
                  at least 1 form of nonhormonal contraception is required for females of
                  childbearing potential during study

                  treatment in this study. 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. 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.

                    -  Male participants must use a condom during treatment and through 90 days
                       after the end of systemic exposure to study drug/treatment. If the male
                       participant has a partner that is of child-bearing potential, the partner
                       should also use contraception through

                       90 days after the end of systemic exposure to study drug/treatment. In
                       addition, male participants must refrain from donating sperm during the
                       study treatment and through 90 days after the end of systemic exposure to
                       study drug/treatment. Males who have had a vasectomy qualify as having met
                       the requirement for a highly effective birth control method.

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

              10. 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


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

          2. Prior therapy with encorafenib and/or binimetinib

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

          4. 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

          5. Known hypersensitivity or contraindication to any component of binimetinib or
             encorafenib or their excipients

          6. Inability to swallow and retain study drugs.

          7. 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 and encorafenib have 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 encorafenib and
             binimetinib, breastfeeding should be discontinued if the mother is treated.

          8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, cardiac dysfunction, uncontrolled pulmonary infection, pulmonary edema or
             psychiatric illness/social situations that would limit compliance with study

          9. 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

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

         11. 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.

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

         13. Known history of acute or chronic pancreatitis.

         14. 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)
                  <3months 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.

         15. 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.

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

         17. 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.

         18. 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.

         19. Note: Patients with thromboembolic events related to indwelling catheters or other
             procedures may be enrolled

         20. Patients taking strong CYP3A4 inhibitors and strong/moderate CYP3A4 inducers




18 Years - N/A

Accepts Healthy Volunteers



Robert J Kreitman, M.D., (301) 435-2375, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Robert J Kreitman, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

September 29, 2020