Clinical Trials /

Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas

NCT04750928

Description:

Background: NF1 is a genetic disease that causes tumors called atypical neurofibromas. These tumors, which arise from nerves, can cause serious medical problems. The only treatment is surgery. Researchers want to see if a drug called abemaciclib can help. Objective: To find a safe, tolerable dose of abemaciclib for treating atypical neurofibromas. Eligibility: People ages 12 and older who have NF1 and have one or more atypical neurofibromas that cannot or will not be removed with surgery Design: Participants will be screened with: Medical history and physical exam Blood, urine, and heart tests MRI: Participants will lie in a machine that takes pictures of the body. A padding or coil will be placed around their head. They may have a contrast agent injected into a vein. Biopsy sample: A small piece of tumor will be removed using a large needle. Participants will have frequent visits during the study. These will include repeats of the screening tests as well as the following: PET scan: Participants will lie in a machine that takes pictures of the body. They will have a contrast agent injected into their arm. Questionnaires about the effects of abemaciclib on pain and quality of life Possible photographs of tumors Participants will take abemaciclib capsules orally twice daily in 28-day cycles. They will take the drug for up to 2 years. Some may be able to take it for longer. Participants will have a follow-up visit about 30 days after their last dose of the study drug. Then they will have visits every 3 months for 1 year.

Related Conditions:
  • Neurofibromatosis Type 1
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas
  • Official Title: A Phase I/II Study of the Cyclin-Dependent Kinase(CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type 1 (NF1) Related Atypical Neurofibromas

Clinical Trial IDs

  • ORG STUDY ID: 210011
  • SECONDARY ID: 21-C-0011
  • NCT ID: NCT04750928

Conditions

  • Neurofibromatosis 1

Interventions

DrugSynonymsArms
Abemaciclib1/ Phase I Dose Escalation

Purpose

Background: NF1 is a genetic disease that causes tumors called atypical neurofibromas. These tumors, which arise from nerves, can cause serious medical problems. The only treatment is surgery. Researchers want to see if a drug called abemaciclib can help. Objective: To find a safe, tolerable dose of abemaciclib for treating atypical neurofibromas. Eligibility: People ages 12 and older who have NF1 and have one or more atypical neurofibromas that cannot or will not be removed with surgery Design: Participants will be screened with: Medical history and physical exam Blood, urine, and heart tests MRI: Participants will lie in a machine that takes pictures of the body. A padding or coil will be placed around their head. They may have a contrast agent injected into a vein. Biopsy sample: A small piece of tumor will be removed using a large needle. Participants will have frequent visits during the study. These will include repeats of the screening tests as well as the following: PET scan: Participants will lie in a machine that takes pictures of the body. They will have a contrast agent injected into their arm. Questionnaires about the effects of abemaciclib on pain and quality of life Possible photographs of tumors Participants will take abemaciclib capsules orally twice daily in 28-day cycles. They will take the drug for up to 2 years. Some may be able to take it for longer. Participants will have a follow-up visit about 30 days after their last dose of the study drug. Then they will have visits every 3 months for 1 year.

Detailed Description

      Background:

      Neurofibromatosis type 1 (NF1) is a genetic tumor predisposition syndrome (incidence of
      1:3000), which results in the development of progressive tumor and non-tumor manifestations,
      the majority of which have no effective medical therapies. 25-50% of individuals with
      neurofibromatosis type 1 (NF1) develop histologically benign plexiform neurofibromas (PN),
      which can cause substantial morbidity. Recently, the POB identified that MEK inhibitors cause
      shrinkage of the majority of PN and that PN shrinkage is associated with clinical benefit.

      A natural history study of NF1 at the NCI has gathered comprehensive imaging information
      using longitudinal whole-body MRI with volumetric measurements. By this approach, distinct
      nodular lesions (DNL) were identified, many of which are atypical neurofibromas (ANF) based
      on pathology review.

      The NCI POB and others have described ANF as precursor lesions for aggressive soft tissue
      sarcomas called malignant peripheral nerve sheath tumors (MPNST), which show poor response to
      chemotherapy and have poor survival. Of note, ANF appear to be less responsive to treatment
      with MEK inhibitors indicating a different biology.

      Exome sequencing of 16 ANF resected at the National Cancer Institute, Pediatric Oncology
      Branch (NCI POB) and Belgium revealed that 90% of the cases had heterozygous loss of CDKN2A/B
      as the only new somatic change in addition to biallelic NF1 deletion, consistent with prior
      reports. These results demonstrate that transformation of NF1 nerve tumors may genetically
      proceed through the premalignant ANF by a common mechanism that might be a point of
      intervention.

      CDKN2A is the primary inhibitory brake on CDK4/6 driven signaling and is commonly deleted in
      glioblastoma, pancreas, bladder, breast and prostate cancer. The specific CDK4/6 inhibitor,
      abemaciclib, has FDA approval for the treatment of metastatic breast cancer.

      ANF is a prototypic premalignant lesion for testing experimental intervention, as these
      lesions are at risk for transformation, and share a common potentially druggable genomic
      alteration (CDKN2A/B deletion). We propose a clinical trial of abemaciclib in children and
      adults with NF1 and unresectable ANF.

      Objectives:

      Phase I: To determine the recommended Phase II dose (RP2D) of abemaciclib in patients with
      NF1 and a measurable ANF.

      Phase II: To determine the objective response rate (ORR) in the target ANF; complete and
      partial response (CR + PR), response determined by volumetric MRI analysis (^3 20% volume
      reduction) compared to baseline.

      Eligibility:

      Patients must be at least 12 years of age with a diagnosis of NF1 with associated age-related
      requirements as follows:

      Willingness of patients >= 12 years old and <18 years old to undergo pre-treatment
      percutaneous biopsy of ANF if deemed feasible with minimal morbidity

      Willingness of patients >=18 years old to undergo pre-treatment and on-treatment percutaneous
      biopsy of ANF if deemed feasible with minimal morbidity

      Presence of >= 1 measurable ANF (biopsy confirmed) for which surgical removal could cause
      significant morbidity OR for which patient is unwilling to undergo surgical resection OR the
      presence of more than one distinct nodular lesion (DNL) including at least 1 biopsy proven
      ANF

      For patients of all ages with ANF who cannot be safely biopsied with minimal morbidity,
      biopsy requirement to be performed at NIH Clinical Center will be waived from eligibility
      criteria. In this case, review of available archival tissue by NIH Pathology will be
      necessary to confirm diagnosis of ANF, which is mandatory for eligibility.

      Design:

      This is a Phase I/II non-randomized, open label, single institution study of the CDK4/6
      inhibitor, abemaciclib, in children and adults with NF1 and a measurable ANF or with multiple
      ANF/DNL.

      Primarily because the tolerability of investigational agents may differ between the NF1
      population and non-NF1 population and secondarily because abemaciclib has not been evaluated
      in children to date, there will be a limited dose finding phase.

      During the Phase 1 portion of the trial, the first 6 subjects enrolled will be treated at 75%
      of the adult recommended Phase II dose (ARP2D; 150mg PO BID) of abemaciclib used in patients
      with malignancies, in a 28-day cycle. For patients < 18 years of age, dosing will be based on
      body surface area (BSA).

      Cohorts of up to 6 subjects will be enrolled, with dose adjustment depending on dose-limiting
      toxicities (DLT) until the maximum tolerated dose (MTD)/ recommended Phase II dose (RP2D) is
      established.

      The Phase II trial is a Simon minimax two-stage trial design. A response rate of
      approximately 30% or greater would be considered desirable. The first stage of the Phase II
      portion of the trial will enroll 15 evaluable subjects; if 0 to 2 of the 15 have a PR or CR,
      then no further subjects will be accrued. If 3 or more of the 15 subjects have a PR or CR,
      then accrual would continue until a total of 21 evaluable subjects have been enrolled in
      phase II.

      The accrual ceiling will be set at 50 eligible subjects (to include patients who are screened
      but found to not be eligible to undergo treatment).

      All patients will undergo careful toxicity monitoring. Restaging MRI for response will be
      performed pre-cycles 3 and 5, and then every 4 cycles for remainder of the first year.
    

Trial Arms

NameTypeDescriptionInterventions
1/ Phase I Dose EscalationExperimentalAbemaciclib orally twice daily at escalating doses to determine the MTD/RP2D
  • Abemaciclib
2/ Phase II Objective Response RateExperimentalAbemaciclib orally twice daily at the RP2D
  • Abemaciclib

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have a clinical diagnosis of NF1, i.e., patients must have at least two
             of the diagnostic criteria for NF1 listed below (NIH Consensus conference) or a
             confirmed

        NF1 mutation from a CLIA-certified laboratory:

        -- Six or more cafe-au-lait macules (>= 0.5cm in prepubertal subjects or >= 1.5 cm

        in post pubertal subjects)

          -  Freckling in axilla or groin

          -  A neurofibroma or plexiform neurofibroma

          -  Optic glioma

          -  Two or more Lisch nodules

          -  A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of
             long bone cortex)

          -  A first-degree relative with NF1

               -  Presence of >= 1 ANF (biopsy confirmed) for whom surgical removal could cause
                  significant clinical morbidity OR for which patient is unwilling to undergo
                  surgical resection OR the presence of more than one distinct nodular lesion (DNL)
                  including at least 1 biopsy proven ANF

        NOTES: Definition of DNL. In addition, there will not be a requirement for confirmed
        CDKN2A/B deletion for study eligibility due to known biopsy sampling error and tumor
        heterogeneity.

          -  Age >= 12 years old (no maximum age) with associated age-related requirements as
             follows:

          -  Age >= 12 years old with BSA >= 0.71 M^2 and able to swallow whole tablets

          -  Willingness of patients >= 12 years old and <18 years old to undergo pre-treatment
             percutaneous biopsy of ANF if deemed feasible with minimal morbidity

          -  Willingness of patients >=18 years old to undergo pre-treatment and on-treatment
             percutaneous biopsy of ANF if deemed feasible with minimal morbidity

        NOTE: For patients of all ages with ANF that cannot be safely biopsied with minimal
        morbidity, biopsy requirement to be performed at NIH Clinical Center will be waived from
        eligibility criteria. In this case, review of available archival tissue by NIH Pathology
        will be necessary to confirm diagnosis of ANF, which is mandatory for eligibility.

          -  Measurable disease: Patients must have at least one measurable ANF defined as a lesion
             of at least 3 centimeters (cm) measured in one dimension. Measurability and
             suitability for volumetric MRI analysis of the target ANF must be confirmed with the
             NCI POB prior to enrolling a patient. The target ANF will be defined as the clinically
             most relevant ANF, which has to be amenable to volumetric MRI analysis.

             - Prior Therapies:

          -  Since there is no standard effective chemotherapy for patients with NF1 and ANF,
             patients may be treated on this trial without having received prior medical therapy
             directed at their ANF.

          -  Investigational agents/biologic therapies (not chemotherapy): Patients who have
             received previous investigational agents or biologic therapies are eligible for
             enrollment. At least 28 days must have elapsed since receiving medical therapy
             directed at any NF1 related tumor. Patients who received prior medical therapy for a
             NF1 related tumor manifestation must have recovered from the acute toxic effects of
             all prior therapy to <= grade 1 CTCAEv5 except for residual alopecia or Grade 2

        peripheral neuropathy prior to enrollment before entering this study.

          -  Chemotherapy agents: Patients who received chemotherapy must have recovered (CTCAE
             Grade <=1) from the acute effects of chemotherapy except for residual alopecia or
             Grade 2 peripheral neuropathy prior to enrollment. A washout period of at least 28
             days is required between last chemotherapy dose and enrollment (provided the patient
             did not receive radiotherapy).

          -  Patients who received adjuvant radiotherapy must have completed and fully recovered
             from the acute effects of radiotherapy. Patients who have received previous radiation
             therapy are eligible for enrollment. At least 6 weeks must have elapsed since the last
             radiation therapy and start of treatment. The only target ANF cannot have received
             radiation previously.

          -  At least 4 weeks must have elapsed since any major surgeries, with evidence of good
             wound healing. Minimally invasive biopsies and central line placements are not
             considered major surgeries.

          -  Patients who have received prior treatment with abemaciclib or another specific CDK4/6
             inhibitor are not eligible for enrollment

               -  Adequate performance scale (Lansky/Karnofsky >=70%).

               -  Adequate organ function as defined below:

          -  Hematologic Function: Patients must have an absolute neutrophil count =1500/ micro
             lliter, hemoglobin >=9 g/dL (transfusion independent, defined as not receiving blood
             transfusion unless related to trauma or surgeries), and platelets >=100,000/ micro
             liter (transfusion independent, defined as not receiving platelet transfusions unless
             related to trauma or surgeries)

          -  Hepatic Function: Patients must have bilirubin within 1.5 x the upper limit of normal
             for age, with the exception of those with Gilbert syndrome, and AST/ALT within <= 3 x
             upper limit of normal.

          -  Renal Function: Patients must have a creatinine clearance or radioisotope GFR
             >=60ml/min/1.73 m^2 or a normal serum creatinine based on age, described below.

          -  Age (years) is >12 and <=15 then Maximum Serum Creatinine (mg/dL) = 1.2

          -  Age (years) is >15 then Maximum Serum Creatinine (mg/dL) = 1.5

          -  Cardiac Function: Normal ejection fraction (ECHO or cardiac MRI) >= 53% (or the
             institutional normal; if a range is given then the upper value of the range will be
             used); QTC or QTcF <=450 msec.

               -  Willingness to avoid grapefruit or grapefruit juice during abemaciclib
                  administration

               -  Informed Consent: Ability of subject or Legally Authorized Representative (LAR)
                  to understand and the willingness to sign a written informed consent document.
                  All patients or their legal guardians (if the patient is < 18 years old) must
                  sign an IRB-approved document of informed consent to demonstrate their
                  understanding of the investigational nature and the risks of this study before
                  any protocol-related studies are performed. When appropriate, pediatric subjects
                  will be included in all discussions.

               -  Based on animal studies, the effects of abemaciclib can cause fetal harm. For
                  these reasons, women of child-bearing potential and men must agree to use a
                  highly effective contraceptive method during treatment and for at least 3 months
                  after the last dose of abemaciclib. 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. Men treated or enrolled on this
                  protocol must also agree to use adequate contraception prior to the study, for
                  the duration of study participation, and 4 months after completion of abemaciclib
                  administration

          -  Woman subjects of childbearing potential (WOCBP) must have a negative serum pregnancy
             test with a sensitivity of at least 25 mIU/mL within 7 days of the first dose of
             abemaciclib.

          -  A woman is considered to be of childbearing potential if she is postmenarcheal, has
             not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no
             identified cause other than menopause), and has not undergone surgical sterilization
             (removal of ovaries and/or uterus).

          -  Contraceptive methods may include intrauterine devices (IUD), or barrier method, a
             spermicidal agent should be added as a double barrier protection.

          -  Cases of pregnancy that occur during maternal exposures to abemaciclib should be
             reported. If a patient or spouse/partner is determined to be pregnant following
             abemaciclib initiation she must discontinue treatment immediately. Data on fetal
             outcomes and breastfeeding are to be collected for regulatory reporting and drug
             safety evaluation.

        EXCLUSION CRITERIA:

          -  Pregnant women, or women who intent to become pregnant during the study, are excluded
             from this study because of the teratogenic effects of abemaciclib. Because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with these agents, breastfeeding should be discontinued if the
             mother is treated on study.

          -  May not have a NF1-related tumor such as optic pathway glioma or malignant peripheral
             nerve sheath tumor, which requires treatment with chemotherapy or surgery.

          -  Serious preexisting medical condition(s) that would preclude participation in this
             study (for example, interstitial lung disease, severe dyspnea at rest requiring oxygen
             therapy, history of major surgical resection involving the stomach or small bowel that
             would preclude adequate absorption, or preexisting Crohn s disease or ulcerative
             colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher
             diarrhea).

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active
             bleeding diatheses or renal transplant, or psychiatric illness/social situations that
             would limit compliance with study requirements.

          -  Personal history of any of the following conditions: syncope of cardiovascular
             etiology, ventricular arrhythmia of pathological origin (including, but not limited
             to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.

          -  Active bacterial infection (requiring intravenous [IV] antibiotics at time of
             initiating study treatment), fungal infection, or detectable viral infection (such as
             known human immunodeficiency virus positivity or with known active hepatitis B or C
             [for example, hepatitis B surface antigen positive]. Patients with HIV who have
             adequate CD4 counts and who have no requirement for antiviral therapy will be
             eligible. NOTE: Screening is not required for enrollment.

          -  Patients with interstitial lung disease

          -  Requires treatment with strong CYP3A inhibitors or inducers

          -  Inability to swallow tablets, since tablets cannot be crushed or broken.

          -  Inability to undergo MRI and/or contraindication for MRI examinations following the
             MRI protocol (see Study Procedure Manual). Prosthesis or orthopedic or dental braces
             that would interfere with volumetric analysis of target ANF on MRI.

          -  Refractory nausea and vomiting that would limit drug administration in the opinion of
             the Principal Investigator

          -  Known severe hypersensitivity to abemaciclib or any excipient of abemaciclib or
             history of allergic reactions attributed to compounds of similar chemical or biologic
             composition to abemaciclib

          -  Clinical judgment by the investigator that the patient should not participate in the
             study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:safety of abemaciclib in patients with NF1 and a measurable ANF
Time Frame:30 days after treatment
Safety Issue:
Description:List of adverse event frequency

Secondary Outcome Measures

Measure:Stable disease rate of target ANF
Time Frame:baseline through 30 days after treatment
Safety Issue:
Description:Proportion of patients that have progressive disease
Measure:Response rate of non-target ANF/DNL
Time Frame:at progression
Safety Issue:
Description:Changes in non-target ANF/DNL determined by volumetric MRI analysis
Measure:Effect of abemaciclib on CDK4/6 target inhibition
Time Frame:after Day 7 of Cycle 1
Safety Issue:
Description:Measurement of phosphorylated Retinoblastoma (pRB) in tumor biopsy samples
Measure:Tolerability of abemaciclib on a prolonged dosing schedule
Time Frame:30 days after treatment
Safety Issue:
Description:List of adverse event frequency
Measure:Effect of abemaciclib on ANF related pain and quality of life
Time Frame:baseline through 30 days after treatment
Safety Issue:
Description:Patient-Reported Outcome response
Measure:Abemaciclib pharmacokinetics and pharmacodynamic
Time Frame:30 days after treatment
Safety Issue:
Description:Drug level in blood

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • distinct nodular lesion
  • genomic alteration

Last Updated

April 8, 2021