Abemaciclib in Treating Patients with 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 have a Karnofsky performance status (KPS) >= 60
• Participants must be able to swallow 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 * NOTE: consultation with the overall principal investigator (PI) is highly recommended if enrollment of a participant with a prior or concurrent malignancy is being pursued
• 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 hematoxylin and eosin [H&E] slide must be submitted to and reviewed by a pathologist at the Dana Farber Cancer Institute [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 Clinical Laboratory Improvement Act (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 comparative genomic hybridization [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; central pathology can provide feedback on reports if requested to help in assessing status as needed * 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 < 10 Mb 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 or rearrangements by sequencing)
• Participants must be at first or second relapse of GBM; relapse is defined as progression following therapy; the intent is that patients had no more than 2 prior therapies
• Participants must have shown unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (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, it is acceptable for this MRI/CT to have been performed greater than 14 days prior to registration if unavoidable; furthermore, 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 > 2 cm^2 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 formalin fixed paraffin embedded (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. If recurrence is outside the radiation field or there is histologic confirmation of tumor progression, then an interval of at least 14 days must have elapsed from completion of radiation therapy to start of study drug and participants must have fully recovered from the acute effects of radiotherapy
• Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide)
• 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-Tumor Treating Fields (TTF)
• Participants with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of progressive disease based upon nuclear imaging, magnetic resonance (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
• Absolute neutrophil count (ANC) >= 1.5 x K/uL (within 14 days prior to registration)
• Platelet count >= 100 x K/uL (within 14 days prior to registration)
• Hemoglobin >= 8.0 g/dL (within 14 days prior to registration)
• Total serum calcium (corrected for serum albumin as needed) or ionized calcium within institution’s normal range (within 14 days prior to registration)
• Magnesium within institution’s normal range (within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institution’s upper limit of normal (ULN) (within 14 days prior to registration)
• Serum bilirubin =< 1.5 x institution’s ULN. Patients with Gilbert’s syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted (within 14 days prior to registration)
• Serum creatinine =< 1.5 x institution’s ULN or calculated 24-hour creatinine clearance >= 50 mL/min (within 14 days prior to registration)
• Serum amylase =< 1.5 x institution’s ULN (within 14 days prior to registration)
• Serum lipase =< 1.5 x institution’s ULN (within 14 days prior to registration)
• International normalized ratio (INR) < 2.0 (within 14 days prior to registration)
• Partial thromboplastin time (PTT) =< institution’s ULN, unless receiving therapeutic low molecular weight heparin or oral factor Xa inhibitors (within 14 days prior to registration)
• Based on findings in animals, abemaciclib can cause fetal harm when administered to a pregnant woman; for this reason, women of child-bearing potential (WOCBP) must agree to use a highly effective contraceptive method during the treatment period and for 3 weeks 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 weeks 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 follicle-stimulating hormone (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

Exclusion Criteria

• Prior evidence of 1p/19q co-deletion
• Participants who have received prior treatment with a CDK4/6 inhibitor
• Participants who have received anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL184, sunitinib etc)
• Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate; participants must be off any EIAEDs for at least 14 days prior to starting study drug
• Participants taking a drug known to be a strong inhibitor or inducer of isoenzyme CYP3A; participant must be off CYP3A inhibitors and inducers for at least 14 days prior to starting study drug; NOTE: participants must avoid consumption of Seville oranges (and juice), grapefruits or grapefruit juice, grapefruit hybrids, pomelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment period
• Participants receiving any other investigational agents
• Current use of herbal preparations/medications, including but not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 7 days prior to first dose of study drug
• Current use of warfarin sodium or any other coumadin-derivative anticoagulant; participants must be off coumadin-derivative anticoagulants for at least 7 days prior to starting study drug; low molecular weight heparin is allowed
• Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of registration
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to abemaciclib
• History of intratumoral or peritumoral hemorrhage if deemed significant by the treating investigator; if there are questions, the treating investigator should contact the study overall principal investigator (P.I.), Eudocia Quant Lee, medical doctor (MD), at 617-632-2166 or eqlee@partners.org
• Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study including, but not limited to interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (e.g. estimated creatinine clearance < 30ml/min), history of major surgical resection involving the stomach or small bowel, preexisting Crohn’s disease or ulcerative colitis, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease, pancreatitis, chronic pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator’s opinion, interfere with the conduct of the study or study evaluations
• Participant has an active systemic bacterial (requiring intravenous antibiotics at time of initiating study treatment), fungal infection, and/or detectable viral infection (for example, human immunodeficiency virus positivity, known active hepatitis B [for example, hepatitis surface antigen positive], or known active hepatitis C). Screening is not required for enrollment
• Participants with diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
• Participant has active cardiac disease including any of the following: * Angina pectoris that requires the use of anti-anginal medications * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication * Conduction abnormality requiring a pacemaker * Valvular disease with document compromise in cardiac function * Symptomatic pericarditis
• Participant has a history of cardiac dysfunction including any of the following: * Myocardial infarction within the last 6 months prior to start of study drug, documents by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function * History of documented congestive heart failure (New York Heart Association functional classification III-IV) * Active cardiomyopathy * Congenital long QT syndrome * History of syncope of cardiovascular etiology * History of sudden cardiac arrest * History of ventricular arrhythmias of pathological origin including, but limited to, ventricular tachycardia and ventricular fibrillation
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of abemaciclib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection); participants with unresolved diarrhea >= CTCAE grade 2 will be excluded as previously indicated
• Participants who have undergone major systemic surgery =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Participants who are pregnant or breastfeeding
• Participants with history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug