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Abemaciclib and Bevacizumab for the Treatment of Recurrent Glioblastomas with Loss of CDKN2A / B or Gain of CDK4 / 6

Trial Status: Active

This early phase I trial studies the side effects of abemaciclib when giving together with bevacizumab in treating patients with glioblastomas that have come back after a period of improvement (recurrent) with loss of CDKN2A / B or gain of CDK4 / 6. Abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving abemaciclib and bevacizumab may work better in treating patients with recurrent glioblastomas compared to bevacizumab alone.

Inclusion Criteria

  • Histologically confirmed glioblastoma (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 ribonucleic acid (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-tumor treating fields (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
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Hemoglobin >= 8 g/dL * NOTE: Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) * Patients with Gilbert’s syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

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 polifeprosan 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 values listed above
  • Inadequately controlled hypertension (defined as systolic blood pressure > 150mmHg 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: * Antineoplastic systemic chemotherapy or biological therapy * Immunotherapies not specified * Chemotherapies not specified * Investigational agents other than abemaciclib and bevacizumab * Radiation therapy * Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guerin, and typhoid vaccines

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Edward Pan
Phone: 214-645-8186

PRIMARY OBJECTIVE:

I. To describe the safety and adverse events associated with abemaciclib when administered with bevacizumab.

SECONDARY OBJECTIVES:

I. To determine the median overall survival (OS) of the study patients from time of study entry until death or lost to follow-up.

II. To determine the median progression free survival (PFS) of the study patients from time of study entry until progression as determined by the Response Assessment in Neuro-Oncology (RANO) criteria.

EXPLORATORY OBJECTIVE:

I. To evaluate the immune response and the efficacy of abemaciclib used as single agent or in combination with bevacizumab in the patient-derived xenografts (PDXs) established from each tumor sample.

OUTLINE:

Patients receive abemaciclib orally (PO) twice daily (BID) starting on days 1-28 and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of treatment, patients are followed up every 2 months for 3 years.

Trial Phase Phase O

Trial Type Treatment

Lead Organization
UT Southwestern / Simmons Cancer Center-Dallas

Principal Investigator
Edward Pan

  • Primary ID SCCC-06319; STU-2019-1214
  • Secondary IDs NCI-2020-01828
  • Clinicaltrials.gov ID NCT04074785