Overview

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

Status:
Recruiting
Trial end date:
2023-12-01
Target enrollment:
0
Participant gender:
All
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. ...
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
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