A Phase 2 Study of Abemaciclib in Recurrent Glioblastoma
The goal of this clinical research study is to learn if abemaciclib can help to control glioblastoma that is recurrent (has returned after treatment) in patients who are and are not receiving surgery as part of their standard care. The safety of this drug will also be studied.
Disease Group: Malignant neoplasms of eye brain and other parts of central nervous system
Treatment Agent: Abemaciclib
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Dana-Farber/Partners Cancer Care, Inc.,Eli Lilly and Company
1. Primary Objectives 1.1 Cohort 1 To evaluate abemaciclib concentration in tumor tissue. 1.2 Cohort 2 To investigate the treatment efficacy of abemaciclib in participants with recurrent Glioblastoma (GBM) as measured by 6-month progressive-free survival (PFS6). 2. Secondary Objectives 2.1 Cohort 1 To evaluate effects of abemaciclib on phospho-Retinoblastoma (RB) (S807/811), tumor cell proliferation (Ki67) and tumor cell death (CC3, p21) by immunohistochemistry (IHC). To investigate pharmacokinetics of abemaciclib in participants with recurrent GBM. To investigate the safety profile of abemaciclib in participants with recurrent GBM. 2.2 Cohort 2 To investigate the radiographic response (RR) to abemaciclib. To investigate median progression free survival (PFS) and overall survival (OS) of participants with recurrent GBM receiving treatment with abemaciclib. To investigate pharmacokinetics (PK) of abemaciclib in participants with recurrent GBM. To investigate the safety profile of abemaciclib in participants with recurrent GBM. 3. Exploratory Objectives 3.1 Cohort 1 To investigate the effects of abemaciclib on patient-derived cells lines (PDCL) and xenografts (PDX) established from patients on the study. To investigate the effects of abemaciclib on live cells obtained from patients and using a novel biomarker of single cell mass accumulation rate (MAR) of acutely studied live tumor cells derived from treated patients. 3.2 Cohort 2 To correlate response to treatment with molecular phenotype of pre-treatment tumor (Oncopanel sequencing and array comparative genomic hybridization (CGH) copy number analysis) To investigate the mechanisms of resistance to abemaciclib by examining tumor tissue obtained from patients who progress on treatment, when available, with pretreatment tumor.
IRB Review and Approval Date: 08/17/2017
Recruitment Status: Open
Projected Accrual: 47
1) Participants must be able to understand and willing to sign a written
informed consent document.
2) 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.
3) Participants must be at least 18 years old on day of signing informed consent.
4) Participants must have a Karnofsky Performance Status (KPS) >/= 60.
5) Participants must be able to swallow capsules.
6) Participants must undergo central pathology review to histologically confirm the diagnosis of glioblastoma or variants (1 unstained slide or 1 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). Participants will not be eligible if the prior diagnosis was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants was made (e.g. secondary GBM).
7) 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 that demonstrate the following 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. 1) 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 log2 ratio of <0.3 by array CGH; or from sequencing data with sufficient coverage for evaluation). 2) 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).
8) 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.
9) 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. 1) 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.
10) ( 9. continued) 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.
11) 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 tissue is required: 1) 25 unstained FFPE sections (standard 4-5 micrometer thickness). AND 2) 1 H&E stained slide (or 1 additional unstained 4-5 um slide for staining). AND 3) one of the following for genomics/nucleic acid extraction: At least 10 (preferably 20) unstained FFPE sections of 10 micrometer thickness, OR At least 8 tissue cores from an FFPE block (200 micrometer total thickness of tissue from a block with a total surface area of 0.5 cm2), OR o At least 200 mg of frozen tissue.
12) 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.
13) 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).
14) 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); 6 weeks from antibodies; 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies. 2 days from Novo-TTF.
15) 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.
16) 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: 1) They have recovered from the effects of surgery.
17) (15. continued) 2) 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.
18) Hematology: Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L; Platelet count >/= 100 x 10^9/L; Hemoglobin >/= 8.0 g/dL.
19) Biochemistry: Total serum calcium (corrected for serum albumin as needed) or ionized calcium within institution’s normal range; Magnesium within institution’s normal range; Aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/SGOT) and Alanine aminotransferase/glutamic pyruvic transaminase (ALT/SGPT) </= 3.0 x institution’s Upper Limit of Normal (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.
20) Coagulation studies: INR < 2.0; Partial Thromboplastin Time (PTT) </= institution’s ULN, unless receiving therapeutic low molecular weight heparin
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
1) Prior evidence of 1p/19q co-deletion.
2) IDH1/2 mutation in any prior biopsy.
3) Participants who have received prior treatment with a CDK4/6 inhibitor.
4) Participants who have received anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL184, sunitinib etc).
5) 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.
6) 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, pummelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment period due to potential CYP3A4 interaction.
7) Participants receiving any other investigational agents.
8) 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.
9) 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.
10) History of allergic reactions attributed to compounds of similar chemical or biologic composition to abemaciclib.
11) 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 P.I..
12) Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 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.
13) Individuals with a history of a different malignancy except for the following circumstances: if they have been disease-free for at least 2 years prior to starting study drug and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 2 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
14) Participant has an active systemic fungal and/or known viral infection (for example, human immunodeficiency virus antibodies, hepatitis B surface antigen or hepatitis C antibodies).
15) Participants with diarrhea >/= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
16) Participant has active cardiac disease including any of the following: a. Angina pectoris that requires the use of anti-anginal medications b. Ventricular arrhythmias except for benign premature ventricular contractions c. Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication d. Conduction abnormality requiring a pacemaker e. Valvular disease with document compromise in cardiac function f. Symptomatic pericarditis
17) 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 documents congestive heart failure (New York Heart Association functional classification III-IV); Documented cardiomyopathy; Congenital long QT syndrome.
18) 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.
19) 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.
20) Participants who are pregnant or breastfeeding.
21) 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.
Information and next steps
Malignant neoplasms of eye brain and other parts of central nervous system
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