Early-Phase Study to Assess Inhibitor Ribociclib in Patients With Recurrent Glioblastoma or Anaplastic Glioma

• Status: Unknown status
• Trial end date: 2020-01-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a single-institution, open-label, early-phase study to assess the ability of ribociclib (LEE011) to inhibit CDK4/CDK6/Rb/E2F signaling and cell proliferation/viability in core and infiltrating tumor tissues obtained from patients with recurrent glioblastoma or anaplastic glioma compared to the baseline/primary pathologic tumor specimen. Abundant preclinical evidence indicates that Rb-deficient cancer cells are resistant to CDK4/6 inhibition and ongoing trials with CDK4/6 inhibitors exclude patients with Rb-deficient tumors. The investigators will evaluate 10 patients with Rb-positive glioblastoma or anaplastic glioma in this study. Given that a minority of glioblastomas ha Rb loss the investigators anticipate enrolling a maximum of 20 patients, to meet our goal of 10 patients with Rb-positive tumors.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Virginia
• Collaborator: Novartis Pharmaceuticals

Criteria

Inclusion criteria:

• Written informed consent must be obtained prior to any screening procedures

• Patients age 18-85 are eligible for study participation

• History of grade III or IV glioma (GBM or AG) with archived FFPE and/or frozen tumor tissue available

• Patient must be a candidate for surgical resection of recurrent high-grade glioma

• Karnofsky Performance Scale score ≥ 70.

• Life expectancy of 4 months or longer.

• Received at least 1 prior systemic therapy for glioma.

• A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies and major surgery) and enrollment, to allow the effects of prior therapy to have abated

• Patients must have adequate organ function

• For continued ribociclib treatment after surgery, immunohistochemical (IHC) confirmation of Rb expression in ≥50% of malignant tumors cells in at least 1 tumor specimen is

Exclusion criteria:

• Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of ribociclib such as patients with a history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastroparesis, unresolved nausea, vomiting, or diarrhea of CTCAE grade > 1

• Impaired cardiac function or clinically significant cardiac diseases

• Patients who are currently receiving treatment (within 5 days prior to starting study drug) with agents that are metabolized predominantly through CYP3A4 and that have a narrow therapeutic window. Agents including vitamins, supplements, and herbal supplements that are either (i) metabolized solely through CYP3A4/5, CYP1A2 or BSEP and have a narrow therapeutic window or (ii) are strong inhibitors of CYP3A4/5, CYP1A2 or BSEP. Agents that are known strong inducers or inhibitors CYP3A4 are prohibited. Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and for 7 days before the first dose.

• Patients with concurrent severe and/or uncontrolled concurrent medical conditions that the investigator believes could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection)

• Pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).

• Women of childbearing potential, defined as all women physically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception must be used by both sexes (female patients and their male partners) during study treatment and for 30 days after the last dose of study medication

• Fertile males must be willing to use contraception. Fertile males must use condom with spermicide (double barrier method). Effective contraception, as defined above, must be used by both sexes (male patients and their female partners) during study treatment and for 30 days after the last dose of study medication. A condom is required to be used by vasectomized men in order to prevent delivery of the study drug via seminal fluid.

• Patients unwilling or unable to comply with the protocol

• Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not mandatory)