Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas

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Brief Title

Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas

Official Title

A Phase II Study of Binimetinib in Children and Adults With NF1 Associated Plexiform Neurofibromas (PNOC010)

Brief Summary

      This is a phase II open label study that will evaluate children ≥ 1 year of age and adults
      with neurofibromatosis type 1 (NF1) and plexiform neurofibromas treated with the MEK
      inhibitor, binimetinib. The primary objective is to determine if there is an adequate level
      of disease responsiveness to binimetinib in children and adults with NF1 and inoperable
      plexiform neurofibromas. The objective response to binimetinib is defined as ≥ 20% decrease
      in tumor volume reduction by 12 courses.
    

Detailed Description

      Patients ≥ 1 year with progressive NF1 and PN(s) by serial imaging or causing significant
      morbidity and that can be analyzed by volumetric MRI are eligible for this study. Initially,
      the study will open to adult patients,18 years and older, (Stratum A). The pediatric patients
      (Statum B) will be receive the pediatric maximum tolerated dose (MTD) of binimetinib that is
      currently being established in an ongoing phase 1 study (NCT02285439). For adult subjects,
      binimetinib (established adult RP2D) is taken orally twice a day. Dosing will be continuous,
      with 28 days defined as a course and will continue for a total of 24 courses or until one of
      the Off Treatment or Off Study criteria are met. Subjects will undergo volumetric assays of
      their targeted PN using MRI after every 4 courses for the first year and then every 6
      courses. MRI review of the volumetric assays will occur centrally under the guidance of Dr.
      Dombi at NCI. Subjects may receive additional courses beyond course 8 only if there is at
      least a 15% reduction in volume of the target tumor, as measured from baseline. Treatment
      beyond course 12 will be only be given to those subjects who achieve a response of ≥ 20%
      tumor shrinkage by volumetric analysis and can continue on therapy up to an additional year
      for a maximum of 24 total courses. For those who respond to binimetinib after 12 courses, an
      MRI scan of the target lesion must be performed at 4 and 12 months after stopping drug in
      order to determine whether response is maintained post-therapy. Subjects will be carefully
      monitored for development of binimetinib associated toxicities. Subjects will be removed from
      the study for significant toxicity, treatment delay of ≥ 21 days, or objective progression of
      tumor growth by ≥ 20% by volumetric analysis at any time.

      The investigational nature and objectives of this trial, the procedures and treatment
      involved, the risks, discomforts, and benefits, and potential alternatives therapies will be
      carefully explained to the subject and/or subject's parent(s) or guardian by the site
      Principal Investigator or designated associate investigator. A signed informed consent
      document will be obtained prior to determining eligibility and entry criteria to this trial.
      Subjects entered on this trial will be treated with therapeutic intent and response to
      therapy will be closely monitored. This protocol involves greater than minimal risk but
      presents the potential for direct benefit to individual subjects.

      Schedule of study evaluations are summarized below:

      Pre-Study (Eligibility Screening):

        -  Physical assessment, vital signs and neurological exam

        -  Complete medical history including past and current medical conditions, treatments, and
           surgeries.

        -  Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks

        -  Review of current medications

        -  Blood draw (about two tablespoons) for routine safety tests

        -  Serum or urine pregnancy test for females of childbearing age

        -  Eye exam

        -  Electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan
           of your heart

        -  MRI of neurofibroma tumors

        -  Functional evaluation: Depending on the location of your plexiform neurofibroma,
           specific functional assessments will be performed. The functional assessments may
           include a 6-Minute Walk-Test if you have a plexiform neurofibroma affecting your legs or
           airway, evaluation of muscle strength and range of motion if you have plexiform
           neurofibroma affecting your arms or legs, and/or grooved pegboard test if you have
           plexiform neurofibroma affecting your hands. The study team will review all evaluations
           that apply to you in detail

        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel
           and bladder dysfunction, and PN symptom checklist (upon study entry)

        -  Photography of visible PN (optional)

      End of course 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24:

        -  Medical history update and hospitalization since last study visit

        -  Physical assessment, vital signs, and neurological exam

        -  Karnofsky/Lansky performance status to assess your ability to perform everyday tasks

        -  Review of your medication diary and any side effects you may be experiencing

        -  Review of current medications

        -  Blood draw (about two tablespoons) for routine safety tests

        -  Serum or urine pregnancy test for females of childbearing age

      End of course 4, 8, 12, 18, and 24:

        -  Eye exam

        -  MRI of neurofibromas

        -  ECHO and ECG

        -  Functional evaluation: (see description above)

        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel
           and bladder dysfunction, and PN symptom checklist

        -  Photography of visible PN (optional): If you agree to take part, photographs of visible
           PN will be taken. Photos will be taken before treatment and then after cycles 4, 8, 12,
           18, and 24.

      End of course 1 and 4:

      • Blood draw (about one tablespoon) for cytokine studies (optional)

      End of Treatment Visit (this is an additional visit if the visit is not within the specified
      times mentioned above):

        -  Physical assessment, vital signs and neurological exam

        -  Medical history update and hospitalization since last study visit

        -  Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks

        -  Review of your medication diary and any side effects you may be experiencing

        -  Review of current medications

        -  Blood draw (about two tablespoons) for routine safety tests

        -  Serum or urine pregnancy test for females of childbearing age

        -  Eye exam

        -  Electrocardiogram (ECG) and ECHO or multigated acquisition (MUGA) scan of your heart

        -  MRI of neurofibroma tumors (for those who respond to binimetinib after 12 courses, an
           MRI at 4 and 12 months after stopping drug)

        -  Functional evaluation: (see description above)

        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel
           and bladder dysfunction, and PN symptom checklist

        -  Photography of visible PN (optional)

      The sample size is 20 subjects for each adult and children cohorts with a minimum target of
      17 evaluable subjects per cohort. Evaluable is defined as: any subjects who received ≥ one
      dose of binimetinib and had a ≥ Grade 3 binimetinib associated toxicity, or in absence of a ≥
      Grade 3 toxicity, any subjects who completed one full course of therapy; subjects who have
      completed at least two courses of therapy and had their first follow-up MRI evaluation except
      for discovery of a target tumor other than a PN; and any subjects who has at least two
      samples drawn for plasma cytokines/growth factors, one at baseline and at least one other
      after starting therapy.

      Data Safety Monitoring Board (DSMB) and a Medical Monitor have been established for this
      study for the purpose of ensuring data compliance and regular monitoring. An early stopping
      rules have been defined within the protocol. The early stopping rule will invoked for both
      Strata separately to potentially prevent accrual subjects onto the study in the event that
      binimetinib is associated with a higher than acceptable rate of dose-limiting toxicity (DLT)
      requiring removal from study (10% or higher) during the first 2 courses. Toxicity will be
      continuously monitored. If at any time >2 of the first 10 subjects or 4 or more of the first
      15 total subjects are removed for toxicity, then accrual will be stopped until the DSMB
      reviews the safety and efficacy data for the study. Based on the review, the DSMB can either
      recommend termination of the study or reopen recruitment. The Medical Monitor is a qualified
      physician who is not associated with this protocol and is a member of the DSMB. The Medical
      Monitor may perform oversight functions duties: may discuss the research protocol with the
      investigators, interview human subjects, and consult with others outside of the study about
      the research; shall have the authority to stop the research protocol in progress, remove
      individual subjects from protocol, and take whatever steps are necessary to protect the
      safety and well being of human subjects until the Institutional Review Board (IRB) can assess
      the monitor's report; and shall have the responsibility to promptly report the observation
      and findings to the IRB or other designated official/organization. The Medical Monitor is
      specifically required to review and provide written report of all unanticipated problems
      involving risk to subjects or others and serious adverse events.

      In addition, as part of the Data Safety Monitoring Plan, the Study Chairs and the NF
      Consortium Clinical Research Nurse Manager will review subject eligibility, study progress,
      safety issues, protocol deviations and adverse events. Monthly reports will be generated by
      the NF Consortium Data Management Center to assess completeness of data. Monthly phone
      conferences will take place between NF Consortium Operations Center and the Protocol Team to
      address data issues.

      The sample size for this trial is based on safety and feasibility factors. The data needed
      for safety is based on risk versus benefit, and for feasibility, we expect at least efficacy
      of 25% response rate. For safety reasons, subjects who do not achieve at least 15% reduction
      in volume of target tumor after 8 courses will be discontinued from the trial, as the
      likelihood of achieving a 20% reduction in tumor volume by 12 months is minimal. Safety
      analysis set will be described and summarized based on information regarding study treatment
      administrations, drug dosing and course compliance, and safety variables (e.g. adverse
      events/serious adverse events). All analyses for outcome results will be based on evaluable
      subjects. Given the difference in the clinical behavior of PN in the adults and pediatric
      subjects, the adult and children stratum will be analyzed independently.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change from Baseline Target Tumor Volume at 12 months

Secondary Outcome

 Incidence of Treatment-Emergent Adverse Events

Condition

Neurofibromatosis Type 1

Intervention

Binimetinib

Study Arms / Comparison Groups

 Open label study of Binimetinib (MEK162)
Description:  Subjects (≥ 18 years) (Stratum A) will receive a course of binimetinib by mouth twice a day (12 hours apart) of 45 mg/dose. Duration of each course is 4 weeks. After 8 courses, subjects will receive additional courses if MRI results showed at least 15% reduction in volume of the target tumor. Subjects can continue on therapy and will be evaluated at the end of 12 courses. Subjects who have ≥ 20% reduction in volume of the target tumor according to the MRI results can continue therapy up to an additional year (maximum of 24 total courses). Subjects who have not met the tumor reduction at the specified times will be removed from the study therapy. Subjects will be carefully monitored for toxicities associated with binimetinib.
Recruitment of subjects 1 - 17 years of age (Stratum B) is currently available. The pediatric maximum tolerated dose (MTD) of binimetinib the pediatric patients (Statum B) was established by a phase 1 study (NCT022).

Publications

* 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

Drug

Estimated Enrollment

40

Start Date

November 28, 2017

Completion Date

December 31, 2023

Primary Completion Date

December 31, 2022

Eligibility Criteria

        Inclusion Criteria

          -  Clinical diagnosis of NF1 using the NIH Consensus Conference criteria OR a documented
             constitutional NF1 mutation

          -  Plexiform neurofibroma(s) that are progressive or causing significant morbidity

          -  Presence of new plexiform neurofibroma on MRI or CT (documented by comparison with
             prior MRI or CT)

          -  Measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. Tumors must
             be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria)

          -  Patients must be ≥ 18 years of age at the time of enrollment.

          -  Performance Level: Karnofsky or Lansky ≥ 50%. If unable to walk due to paralysis, but
             in a wheelchair, patients will be considered ambulatory for the purpose of assessing
             the performance level

          -  Ability to swallow capsules/tablets

          -  Ability to comply with follow up procedures

          -  The effects of binimetinib on the developing human fetus are unknown. For this reason,
             women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and 3 months after completion of binimetinib
             administration. 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.

          -  Negative urine or serum β-HCG test (females of childbearing potential only).

        Prior Therapy:

          -  Patients are eligible if complete resection of a plexiform neurofibroma with
             acceptable morbidity is not feasible, or if a subject with surgical option refuses
             surgery,

          -  Patients who underwent surgery for a progressive plexiform neurofibroma will be
             eligible to enter the study after the surgery, provided the plexiform neurofibroma was
             incompletely resected and is evaluable by volumetric analysis.

          -  Patients previously treated for a plexiform neurofibroma or other tumor/malignancy,
             but must have fully recovered from the acute toxic effects of all prior chemotherapy
             or radiotherapy prior to entering this study.

          -  Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this
             study.

          -  At least 7 days since the completion of therapy with a hematopoietic growth factor
             that supports platelet, red or white cell number or function.

          -  At least 4 weeks since the completion of therapy with a biologic anti-neoplastic
             agent. For agents that have known adverse events occurring beyond 14 days after
             administration, this period must be extended beyond the time during which adverse
             events are known to occur.

          -  Patients must not have received an investigational drug within 4 weeks.

          -  Patients with endocrine deficiencies are allowed to receive physiologic or stress
             doses of steroids, if necessary.

          -  Radiation ≥ 6 months from involved field radiation to index plexiform neurofibroma(s),
             ≥ 6 weeks must have elapsed if patient has received radiation to areas outside index
             plexiform neurofibroma(s). Patients who have received radiation to the orbit at any
             time are excluded.

          -  At least 3 weeks since undergoing any major surgery and must be recovered from effects
             of surgery.

        Organ Function Requirements:

          -  Adequate bone marrow function defined as:

               -  Peripheral absolute neutrophil count (ANC) ≥ 1500/µL

               -  Platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving
                  platelet transfusions for at least 7 days prior to enrollment)

               -  Hemoglobin ≥ 10.0 gm/dL without transfusions.

          -  Adequate renal function defined as:

               -  Maximum serum creatinine based on age/gender or a creatinine clearance or
                  radioisotope GFR ≥ 70 ml/min/1.73 m²

          -  Adequate liver function defined as:

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

               -  SGPT (ALT) ≤ 2.5 x upper limit of normal (ULN) for age

               -  Serum albumin ≥ 2 g/dL

          -  Adequate cardiac function defined as:

               -  Left ventricular fractions (LVEF) ≥ 50% as determined by a multigated acquisition
                  (MUGA) scan or echocardiogram

               -  QTc interval ≤ 480 ms.

        Exclusion Criteria

          -  Chronic treatment with systemic steroids or another immunosuppressive agent.

          -  Evidence of an active optic glioma or other low-grade glioma, requiring treatment with
             chemotherapy or radiation therapy. Patients not requiring treatment are eligible for
             this protocol.

          -  Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other
             malignancy requiring treatment in the last 12 months.

          -  Patients who have received radiation to the orbit at any time previously.

          -  Ophthalmologic conditions:

               -  Current or past history of central serous retinopathy

               -  Current or past history of retinal vein occlusion

               -  Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or
                  uncontrolled glaucoma (irrespective of IOP). Patients with known glaucoma and
                  increased IOP who do not have meaningful vision (light perception only or no
                  light perception) and are not experiencing pain related to the glaucoma, may be
                  eligible after review. Patients with orbital plexiform neurofibromas should have
                  IOP measured prior to enrollment.

               -  Patients with any other significant abnormality on ophthalmic examination will be
                  reviewed for potential eligibility.

               -  Ophthalmological findings secondary to long-standing optic pathway glioma (such
                  as visual loss, optic nerve pallor or strabismus) or long-standing
                  orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a
                  significant abnormality for the purposes of the study

          -  Uncontrolled arterial hypertension despite medical treatment defined as CTCAE grade 3
             or higher.

          -  Impaired cardiovascular function or clinically significant cardiovascular diseases,
             including:

               -  History of acute coronary syndromes (including myocardial infarction, unstable
                  angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
                  months prior to screening

               -  Symptomatic chronic heart failure, history or current evidence of clinically
                  significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to
                  screening except atrial fibrillation and paroxysmal supraventricular tachycardia

          -  Other concurrent severe and/or uncontrolled medical disease, which could compromise
             participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,
             severe infection, severe malnutrition, chronic liver or renal disease, active upper GI
             tract ulceration, congestive heart failure, etc.)

          -  Subjects who have an uncontrolled infection.

          -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
             and/or active hepatitis C infection.

          -  Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
             bowel resection).

          -  History of Gilbert's syndrome or patients who are known to be homozygous for UGT1A1
             (7/7).

          -  Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
             muscular atrophy)

          -  Patients who are planning to embark on a new strenuous exercise regimen after first
             dose of study treatment. NB: muscular activities, such as strenuous exercise, that can
             result in significant increases in plasma CK levels should be avoided while on
             binimetinib treatment.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to binimetinib.

          -  Women who are pregnant or breastfeeding.

          -  Any other condition that would contraindicate, in the Investigator's judgement, the
             patient's participation in the clinical study due to safety concerns or compliance
             with clinical study procedures, e.g. infection/inflammation, intestinal obstruction,
             unable to swallow medication, social/ psychological issues, etc.

          -  History of noncompliance to medical regimens.

          -  Patients unwilling to or unable to comply with the protocol, or who in the opinion of
             the investigator may not be able to comply with the safety monitoring requirements of
             the study.

          -  Prior treatment with a MEK inhibitor of any kind.
      

Gender

All

Ages

1 Year - N/A

Accepts Healthy Volunteers

No

Contacts

Bruce Korf, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03231306

Organization ID

IRB-170616001


Responsible Party

Principal Investigator

Study Sponsor

University of Alabama at Birmingham

Collaborators

 Array BioPharma

Study Sponsor

Bruce Korf, MD, PhD, Study Chair, University of Alabama at Birmingham


Verification Date

January 2021