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

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. An observed 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.

Details