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

NCT02345824 | Unknown Phase 1 DMC

• 2 other identifiers: D1322318729
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Glioblastoma; Glioma

Keywords

CDK4/6 Inhibitor; LEE011; Recurrent Glioblastoma; Anaplastic Glioma; Ribociclib

Outcome Measures

Primary Outcomes (1)

• Inhibition of CDK4/CDK6 Signaling Pathway in Cell Proliferation

  Levels of phospho-Rb in tumor cells, the fraction of Ki67-positive tumor cells, and the fraction of TUNEL-positive tumor cells in primary (baseline) vs. recurrent (post-LEE011) tumor samples will be assessed via laboratory practices as a means of studying Inhibition of CDK4/CDK6 Signaling Pathway in Cell Proliferation.

  an expected average of 1 year to allow laboratory quality assessment of tumor proliferation

Secondary Outcomes (5)

• Ribociclib Concentration in Tissues

  1 Day Collection as the time of initial surgery

• Ribociclib Concentration in Plasma

  time of Pharmacokinetic draws

• Tumor Progression

  Over 1 year, which is expected average length of participation per patient

• Survival Outcomes

  Over 1 year, which is expected average length of participation per patient

• Ribociclib Safety Profile

  30 days post last dose of LEE011 per patient

Other Outcomes (2)

• Identifying Treatment Induced Changes in Oncogenic Pathways

  Over 1 year, which is expected average length of participation per patient

• Ribociclib Concentrations in Cerebrospinal Fluid (CSF)

  1 Day Collection as the time of initial surgery

Study Arms (1)

Ribociclib (LEE011) Treatment

EXPERIMENTAL

Patients will be treated with ribociclib (LEE011) (recommended phase 2 dose of 600 mg/day) for 8-21 days prior to surgery. For preliminary evaluation of efficacy and toxicity, patients with Rb-positive tumors will resume treatment with ribociclib at 14-28 days post-surgery on a schedule of 21 days on, 7 days off in a 28-day cycle. Patients will be treated until unacceptable toxicity is observed, or until disease progression as assessed by radiographic or clinical metrics.

Drug: Ribociclib

Interventions

Ribociclib DRUG

CDK4/6 INHIBITOR

Also known as: LEE011

Ribociclib (LEE011) Treatment

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Virginia: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Related Publications (1)

• Miller TW, Traphagen NA, Li J, Lewis LD, Lopes B, Asthagiri A, Loomba J, De Jong J, Schiff D, Patel SH, Purow BW, Fadul CE. Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma. J Neurooncol. 2019 Sep;144(3):563-572. doi: 10.1007/s11060-019-03258-0. Epub 2019 Aug 9.

  PMID: 31399936 DERIVED

MeSH Terms

Conditions

Glioblastoma; Glioma

Interventions

ribociclib

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Camilo Fadul, MD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 2, 2015
• First Posted: January 26, 2015
• Study Start: March 1, 2016
• Primary Completion: September 1, 2019
• Study Completion: January 1, 2020
• Last Updated: June 7, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)