| Eligibility |
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.
- 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-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 .
Exclusion Criteria:
Pathology
- Prior evidence of 1p/19q co-deletion.
- IDH1/2 mutation in any prior biopsy.
Previous therapies
- 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).
Concomitant medications
- 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. A list of EIAEDs and other inducers of CYP3A4 can be
found.
- 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.
- 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.
Other illnesses
- 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 P.I., Eudocia Quant Lee, MD, at 617-632-2166 or
eqlee@partners.org.
- 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.
- 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).
- Participants with diarrhea = CTCAE grade 2
- Participant has active cardiac disease including any of the following:
- Angina pectoris that requires the use of anti-anginal medications
- Ventricular arrhythmias except for benign premature ventricular contractions
- Supraventricular and nodal arrythmias 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 LVEF function
- History of documented congestive heart failure (New York Heart Association
functional classification III-IV, see Appendix B)
- Documented cardiomyopathy
- Congenital long QT syndrome
- 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.
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