A Study of Abemaciclib in Recurrent Glioblastoma

Inclusion Criteria

• •Participants must be able to understand and willing to sign a written informed consent document.
• •Participants must be able to adhere to the dosing and visit schedules, and agree to record medication times accurately and consistently in a daily diary.
• •Participants must be at least 18 years old on day of signing informed consent.
• •Participants must have a Karnofsky Performance Status (KPS) ≥ 60
• •Participants must be able to swallow capsules/tablets
• •Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy of the trial are eligible.
• •Nature of illness and treatment history
• •Participants must undergo central pathology review to histologically confirm the diagnosis of glioblastoma, IDH-wildtype; glioblastoma variants; or astrocytoma, IDH-mutant, WHO grade 4 (1 unstained slide or 1 H\&E slide must be submitted to and reviewed by a pathologist at the DFCI Coordinating Center prior to enrollment of the participant for central pathology review).
• •To be eligible for the study all participants (Cohort 1 and 2) are required to provide genomic profiling data from assays performed in a CLIA-certified lab. A sequencing-based assay is required and must include reporting of the RB1 gene in explicit terms within the report. Only sequencing assays that include coverage of all exons of the RB1 gene are able to be utilized (most commonly called a targeted exome assay; e.g. Oncopanel, Impact, FoundationOne). In addition, patients must provide a report of copy assessment which reports status of RB1. The reporting may be from a copy array (ideally Oncoscan SNP array or Agilent array CGH) or can also be from sequencing assay if copy status is explicitly provided with quantitative information regarding the status of relevant genes. Specifically, the reporting should provide the following information with respect to relevant biomarkers required for enrollment to the study as listed below.
• •Results from genomic profiling must be sent to the DFCI Coordinating Center prior to enrollment of the participant for central pathology review.
• •* Inactivation of CDKN2A/B or C in the tumor by homozygous deletion (evidence for more than single copy loss for any of the genes defined as array CGH/SNP log2 ratio of \<0.3 by array CGH; or from sequencing data with sufficient coverage for evaluation). Rearrangement/evidence or intragenic breaks by copy or sequencing assay also will be considered eligible for study (any copy status).
• •* OR
• •* CDK4 or CDK6 high-level amplification. (The amplicon size must be \<10Mb and the magnitude the gain must be log2 ratio \>1.5 or estimated as \>10 copies).
• •* AND
• •* Validation of wild-type RB status (no deletion/losses more than single copy by copy number or sequencing data; and/or no inactivating mutations by sequencing).
• •Participants must be at first relapse of GBM. Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 1 prior therapy (initial treatment). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute 1 relapse.
• •Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.
• •* For Cohort 2 subjects, CT or MRI within 14 days prior to study registration. For Cohort 2, corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required.
• •* For Cohort 1 subjects, CT or MRI should be performed ideally within 14 days prior to study registration, but because the screening MRI for this subset of subjects will not be used for evaluation of response, it is acceptable for this MRI/CT to have been performed greater than 14 days prior to registration if unavoidable. Furthermore, for this same reason, fluctuation in corticosteroid dose around this MRI does not warrant repeat scan so long as there is documented unequivocal evidence of tumor progression available.
• •* For Cohort 1 subjects, there must be \> 2cm2 enhancing tissue available for resection and submission for study correlatives as determined by local treating team.
• •Confirmation of availability of sufficient tissue from a prior surgery for correlative studies is required prior to enrollment; these samples must be sent to the DFCI Coordinating Center within 60 days of registration. Cohort 1 participants must have sufficient FFPE tissue from any surgery. Cohort 2 participants must have tissue from biopsy or resection from the most recent recurrence surgery.
• •The following amount of archived tissue is required:
• •* 20 unstained formalin fixed paraffin embedded (FFPE) sections (standard 4-5 micrometer thickness)
• •* NOTE: if the above-mentioned tissue is not available from the most recent surgery revealing GBM, participants may be enrolled with tissue available from any prior surgery revealing GBM with prospective approval from the Overall PI.
• •An interval of at least 12 weeks from the completion of radiation therapy to start of study drug unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field (defined as the region outside the high-dose region or 80% isodose line) or there is unequivocal histologic confirmation of tumor progression.
• •From the projected start of scheduled study treatment, the following time periods must have elapsed:
• •* 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent;
• •* 4 weeks from cytotoxic therapy (except 23 days for temozolomide; 6 weeks from nitrosoureas);
• •* 4 weeks from antibodies;
• •* 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies.
• •* 2 days from Novo-TTF
• •Participants with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of progressive disease based upon nuclear imaging, MR spectroscopy, perfusion imaging or histopathology.
• •Participants having undergone recent resection or open biopsy or stereotactic biopsy of recurrent or progressive tumor will be eligible for Cohort 2 as long as the following conditions apply:
• •* They have recovered from the effects of surgery.
• •* Residual disease following resection of recurrent tumor is not mandated for eligibility. To best assess the extent of residual disease post-operatively, an MRI or CT scan should ideally have been performed no later than 96 hours following surgery, or at least 28 days post-operatively, but scans performed outside of this window are considered acceptable if no alternative is available. In either case, the baseline/screening MRI must be performed within 14 days prior to registration. If the participant is taking corticosteroids, the dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required.
• •Clinical labs - performed within 14 days prior to registration
• •Hematology:
• •* Absolute neutrophil count (ANC) ≥ 1.5 x K/µL
• •* Platelet count ≥ 100 x K/µL
• •* Hemoglobin ≥ 8.0 g/dL
• •Biochemistry:
• •* Total serum calcium (corrected for serum albumin as needed) or ionized calcium within institution's normal range.
• •* Magnesium within institution's normal range.
• •* AST (SGOT) and ALT (SGPT) ≤ 3.0 x institution's ULN
• •* Serum bilirubin ≤ 1.5 x institution's ULN
• •* Serum creatinine ≤ 1.5 x institution's ULN or calculated 24-hour creatinine clearance ≥ 50 mL/min
• •* Serum amylase ≤ 1.5 x institution's ULN
• •* Serum lipase ≤ 1.5 x institution's ULN
• •Coagulation studies:
• •* INR \< 2.0
• •* PTT ≤ institution's ULN, unless receiving therapeutic low molecular weight heparin or oral factor Xa inhibitors Pregnancy and Reproduction
• •The effects of abemaciclib on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) must agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of abemaciclib. Men must agree to use a reliable method of birth control and to not donate sperm during the study and for at least 3 months following the last dose of abemaciclib. Contraceptive methods may include an intrauterine device \[IUD\] or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection.
• •NOTE: Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL and estradiol \< 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• •Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first dose of abemaciclib .