A Study of Abemaciclib in Recurrent Glioblastoma

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved abemaciclib as a treatment
for any disease.

Many brain cancers show over expression of a protein called cyclin D1. That means that the
body makes too much cyclin D1, which affects enzymes called CDK 4 and CDK 6. Enzymes are
substances in the body that help reactions between cells happen. Too much cyclin D1 triggers
CDK 4 and CDK 6 to make more cells than normal. This extra cell production leads to the
growth of tumors.

In laboratory studies, Abemaciclib was able to enter the brain, stop CDK 4 and CDK 6 from
making cells, and slow growth of mice Glioblastoma.

In this research study, the investigators are looking to see how safe and effect Abemaciclib
is with the participant type of cancer. In the surgical participants, the investigators are
looking to see if Abemaciclib reached the brain tumor.

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. Nature of illness and treatment history

- 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 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).

- 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.

- 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).

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.

- 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 tissue is required:

- 25 unstained formalin fixed paraffin embedded (FFPE) sections (standard 4-5 micrometer
thickness)

- AND 1 H&E stained slide (or 1 additional unstained 4-5 um slide for staining)

- AND 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

- At least 200 mg of frozen tissue

- 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);

- 6 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 109/L

- Platelet count ≥ 100 x 109/L

- 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 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.

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.

- 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.

- 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 documents 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.