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

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ClinicalTrials.gov Identifier: NCT04750928
Recruitment Status : Not yet recruiting
First Posted : February 11, 2021
Last Update Posted : May 18, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Neurofibromatosis 1 Drug: Abemaciclib Phase 1 Phase 2

Show Show detailed description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : May 21, 2021
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2023


Arm Intervention/treatment
Experimental: 1/ Phase I Dose Escalation
Abemaciclib orally twice daily at escalating doses to determine the MTD/RP2D
Drug: Abemaciclib
Abemaciclib is to be administered orally on Days 1 through 28 of each 28-day cycle

Experimental: 2/ Phase II Objective Response Rate
Abemaciclib orally twice daily at the RP2D
Drug: Abemaciclib
Abemaciclib is to be administered orally on Days 1 through 28 of each 28-day cycle




Primary Outcome Measures :
  1. safety of abemaciclib in patients with NF1 and a measurable ANF [ Time Frame: 30 days after treatment ]
    List of adverse event frequency


Secondary Outcome Measures :
  1. Stable disease rate of target ANF [ Time Frame: baseline through 30 days after treatment ]
    Proportion of patients that have progressive disease

  2. Response rate of non-target ANF/DNL [ Time Frame: at progression ]
    Changes in non-target ANF/DNL determined by volumetric MRI analysis

  3. Effect of abemaciclib on CDK4/6 target inhibition [ Time Frame: after Day 7 of Cycle 1 ]
    Measurement of phosphorylated Retinoblastoma (pRB) in tumor biopsy samples

  4. Tolerability of abemaciclib on a prolonged dosing schedule [ Time Frame: 30 days after treatment ]
    List of adverse event frequency

  5. Effect of abemaciclib on ANF related pain and quality of life [ Time Frame: baseline through 30 days after treatment ]
    Patient-Reported Outcome response

  6. Abemaciclib pharmacokinetics and pharmacodynamic [ Time Frame: 30 days after treatment ]
    Drug level in blood



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT04750928


Contacts
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Contact: Anne Goodwin, R.N. (301) 594-4762 goodwina@mail.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: Andrea M Gross, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04750928    
Other Study ID Numbers: 210011
21-C-0011
First Posted: February 11, 2021    Key Record Dates
Last Update Posted: May 18, 2021
Last Verified: April 30, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
distinct nodular lesion
genomic alteration
Additional relevant MeSH terms:
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Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms