LY3214996 Plus Abemaciclib in Recurrent Glioblastoma Patients

NCT04391595 | Completed Early Phase 1 DMC FDA Drug

• 1 other identifier: 2019-07
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 3

Brief Summary

This trial is an open-label, multicenter, Phase 0/2 trial that will enroll up to 50 participants with recurrent glioblastoma which are schedule for resection. In the lead-in cohort, a total of 10 participants will be enrolled into the proposed phase 0 clinical trial. Participants will be administered LY3214996 plus Abemaciclib prior to surgical resection of their tumor. If positive PK results are demonstrated in ≥50% of Phase 0 participants and at least 5 participants are enrolled into Phase 2, up to approximately 40 additional participants will be enrolled in the dose expansion cohort in order to achieve a total of 25 participants enrolled into Phase 2 (lead-in cohort + dose expansion).

Conditions

Glioblastoma; GBM; Glioma

Outcome Measures

Primary Outcomes (4)

• Phase 0: Pharmacokinetic analysis of tumor tissue

  Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in enhancing and non-enhancing tumor tissue

  8 hour

• Phase 0: Pharmacokinetic analysis of cerebrospinal fluid (CSF)

  Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in CSF

  8 hour

• Pharmacokinetic analysis of plasma

  Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in plasma

  Day 6 at 0, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose

• Phase 2: Progression-free survival

  Phase 2: 6-month progression-free survival (PFS6) rate measured from time of surgery to date of recurrence

  up to 60 months

Secondary Outcomes (6)

• Phase 0: PD Analysis

  Intraoperatively

• Number of Adverse Events

  up to 30 days after the last study dose

• Incidence of drug-related toxicity

  up to 30 days after the last study dose

• Incidence of treatment-emergent adverse events

  up to 30 days after the last study dose

• Deaths

  up to 60 months

Study Arms (1)

Arm 1

EXPERIMENTAL

400 mg of LY3214996 QD for 6 doses and 100 mg of Abemaciclib BID for 11 doses over 5.5 days prior to surgical resection. On Day 6, participants will receive Abemaciclib + LY3214996 dose 7 to 9 hours prior to craniotomy for tumor resection.

Drug: Abemaciclib; Drug: LY3214996

Interventions

Abemaciclib DRUG

100 mg of Abemaciclib BID for 11 doses over 5.5 days prior to surgical resection. Participants with tumors demonstrating PK-response in Phase 0 will continue treatment with recommended Phase 2 dose (RP2D) continuously in 21d cycles after surgery.

Arm 1

LY3214996 DRUG

400 mg of LY3214996 daily for 6 doses over 5.5 days prior to surgical resection. Participants with tumors demonstrating PK-response in Phase 0 will continue treatment with recommended Phase 2 dose (RP2D) continuously in 21d cycles after surgery.

Arm 1

Eligibility Criteria

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

You may qualify if:

• Prior resection of histologically diagnosed WHO Grade IV glioma defined as glioma participants who have progressed on or following standard (Stupp regimen) therapy, which included maximal surgical resection, temozolomide, and fractionated radiotherapy.
• Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-enhanced MRI.
• Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria.
• Sufficient archival tissue available to confirm eligibility.
• For gliomas, archival tissue must demonstrate: (a) RB positivity (≥20%) on immunohistochemistry (IHC); or, no RB mutations on next-generation sequencing (NGS), (b) Chromosomal loss of CDKN2A/B/C; or, CDK4/6 amplification on array CGH or NGS, (c) pERK positivity (\>30%) on IHC.
• Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable).
• Participant has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
• Age ≥18 at time of consent
• Have a performance status (PS) ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale (Oken et al. 1982)
• Ability to swallow oral medications.
• Participant has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):
• Adequate bone marrow function:
• absolute neutrophil count ≥1,000/mcL
• platelets (at time of surgery) ≥100,000/mcL

You may not qualify if:

• Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.
• Pregnancy or lactation.
• Known allergic reactions to components of the abemaciclib or LY3214996.
• Active infection or fever \>38.5°C requiring systemic antibiotic, antifungal or antiviral therapy within 4 weeks of Day 1.
• Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis.
• Known active systemic bacterial infection (requiring intravenous \[IV\] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\]. Screening is not required for enrollment.
• Have history of central or branch retinal artery or venous occlusion with significant vision loss or other retinal diseases that cause current visual impairment or would likely cause visual impairment over the time period of the study.
• Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment \[e.g. estimated creatinine clearance \<30ml/min\], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Prior therapy with any CDK4/6 inhibitor or any ERK1/2 inhibitor. Prior therapy is defined as a therapeutic dosing.
• Treatment with another investigational drug or other intervention within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.
• Have a mean QT interval corrected for heart rate (QTc) of ≥470 milliseconds on screening electrocardiogram (ECG) as calculated using the Bazett's formula.
• The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.

Sponsors & Collaborators

• Nader Sanai: lead
• Barrow Neurological Institute: collaborator
• Ivy Brain Tumor Center: collaborator
• Eli Lilly and Company: collaborator

Study Sites (3)

Chandler Regional Medical Center

Chandler, Arizona, 85224, United States

Location

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

Location

HonorHealth Scottsdale Osborn Medical Center

Scottsdale, Arizona, 85251, United States

Location

Related Links

• Ivy Brain Tumor Center Website

MeSH Terms

Conditions

Glioblastoma; Glioma

Interventions

abemaciclib; LY3214996

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

• Nader Sanai, MD

  Deputy Director of the Ivy Brain Tumor Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Deputy Director, Ivy Brain Tumor Center

Study Record Dates

• First Submitted: May 12, 2020
• First Posted: May 18, 2020
• Study Start: July 11, 2020
• Primary Completion: July 27, 2023
• Study Completion: September 3, 2025
• Last Updated: March 6, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)