Inclusion Criteria:
- - Histologically confirmed GBM at first or second recurrence after concurrent
chemoradiotherapy.
Patients with an initial diagnosis of a lower-grade glioma are
eligible if a subsequent biopsy was determined to be GBM. GBMs either from the
initial resection or at repeat resection at recurrence must be analyzed by
next-generation exome sequencing (NES) and RNA-sequencing and must have the
following aberrations:
- - Heterozygous or homozygous loss of CDKN2A and/or CDKN2B.
OR.
- - Gain or amplification of CDK4 and/or 6.
NOTE: Patients with GBMs having loss of function of RB1 are EXCLUDED.
- - Imaging confirmation of first tumor progression or regrowth as defined by the RANO
criteria.
A minimum of 12 weeks must have elapsed from the completion of
radiotherapy to study entry to minimize the potential for magnetic resonance imaging
(MRI) changes related to radiation necrosis that might be misdiagnosed as
progression of disease, unless there is a new lesion outside the radiation field or
unequivocal evidence of viable tumor on histopathological sampling.
- - Karnofsky performance status (KPS) ≥ 60%.
- - Stable or decreasing dose of corticosteroids within 5 days prior to randomization.
- - For women who are of child-bearing potential or surgically sterile (absence of
ovaries and/or uterus) and who are sexually active: to use an adequate method of
contraception (oral contraceptives, intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal jelly) during the treatment
period and for at least 6 months after last dose of study drug.
Should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.
For male patients who are partners of premenopausal women: agreement to use a barrier
method of contraception during the treatment period and for at least 6 months after the
last dose of study drug.
- - A female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy; or.
- - Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
- - Patients who have undergone recent surgery for recurrent or progressive tumor are
eligible provided that:
- Surgery must have confirmed the recurrence.
- - A minimum of 28 days must have elapsed from the day of surgery to study entry.
For
core or needle biopsy, a minimum of 7 days must have elapsed prior to study entry.
- - Craniotomy or intracranial biopsy site must be adequately healed and free of
drainage or cellulitis, and the underlying cranioplasty must appear intact at the
time of randomization.
- - Patients must be willing and able to provide written informed consent and to comply
with the study protocol as judged by the investigator.
- - Patients must have recovered (Common Terminology Criteria for Adverse Events CTCAE]
Grade ≤1) from the acute effects of chemotherapy prior to study entry.
Minimum times
from prior therapies include:
- - ≥ 28 days elapsed from the administration of any investigational agent.
- - ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except ≥ 42
days from nitrosoureas.
NOTE: Prior treatment with Novo-TTF therapy is allowed at initial diagnosis, but must be
discontinued prior to study entry.
- - Patients must be able to swallow oral medications.
- - Ability to understand and the willingness to sign a written informed consent.
- - Patients must have adequate organ and marrow function.
Exclusion Criteria:
- - Prior treatment with Bevacizumab, Abemaciclib, or any other CDK4/6 inhibitor or
other systemic VEGF- or VEGF-receptor-targeted agent.
- - Prior treatment with prolifeprospan 20 with carmustine wafer.
- - Evidence of recent hemorrhage on baseline MRI of the brain.
However, patients with
clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes
related to surgery, or presence of punctuate hemorrhage in the tumor are eligible.
- - Concurrent investigational agents.
- - History of allergic reactions attributed to compounds of similar chemical or
biologic composition to Agent(s) or other agents used in study.
- - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance
with study requirements.
- - Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
- - Patients unable to undergo brain MRI scans with IV gadolinium.
- - Screening laboratory values outside of the values listed on Table 2.
- - Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
and/or diastolic blood pressure > 100 mmHg while on antihypertensive medication).
- - Uncontrolled diabetes despite maximal medical management.
- - Prior history of hypertensive crisis or hypertensive encephalopathy.
- - New York Heart Association Grade II or greater congestive cardiac failure.
- - History of myocardial infarction (within 12 months) or unstable angina (within 6
months) prior to study entry.
- - History of stroke or transient ischemic attacks within 6 months prior to study
entry.
- - Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to study entry.
- - Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
anticoagulation).
- - History of abdominal fistula or gastrointestinal perforation within 6 months prior
to study entry.
- - History of intracranial abscess within 6 months prior to randomization or active
bacterial infection (requiring intravenous [IV] antibiotics within 2 weeks from
initiation of study treatment), fungal infection, or detectable viral infection
(such as known human immunodeficiency virus positivity or with known active
hepatitis B or C [for example, hepatitis B surface antigen positive].
- - Serious non-healing wound, active ulcer, or untreated bone fracture.
- - History of another malignancy in the previous 3 years, with a disease-free interval
of < 3 years.
Patients with prior history of in situ cancer or basal or squamous
cell skin cancer are ELIGIBLE.
- - Hypersensitivity to Chinese hamster ovary cell products or other recombinant human
or humanized antibody.
- - Taking any treatments listed in the Prohibited Concomitant Medications.
