Clinical Trials /

LY3214996 Plus Abemaciclib in Recurrent Glioblastoma Patients

NCT04391595

Description:

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).

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: LY3214996 Plus Abemaciclib in Recurrent Glioblastoma Patients
  • Official Title: A Phase 0/2 Study of LY3214996 (ERK Inhibitor) in Combination With Abemaciclib (CDK4 and 6 Inhibitor) in Recurrent Glioblastoma Participants Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration

Clinical Trial IDs

  • ORG STUDY ID: 2019-07
  • NCT ID: NCT04391595

Conditions

  • Glioblastoma
  • GBM
  • Glioma

Interventions

DrugSynonymsArms
AbemaciclibArm 1
LY3214996Arm 1

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Arm 1Experimental400 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.
  • Abemaciclib
  • LY3214996

Eligibility Criteria

        Inclusion Criteria:

          1. 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.

          2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or
             contrast-enhanced MRI.

          3. 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.

          4. Sufficient archival tissue available to confirm eligibility.

          5. 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.

          6. Ability to understand and the willingness to sign a written informed consent document
             (personally or by the legally authorized representative, if applicable).

          7. 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.

          8. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
             tests and other procedures.

          9. Age ≥18 at time of consent

         10. Have a performance status (PS) ≤2 on the Eastern Cooperative Oncology (Group (ECOG)
             scale (Oken et al. 1982)

         11. Ability to swallow oral medications.

         12. 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

               -  hemoglobin ≥8.0 g/dL Participants 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.

             Adequate hepatic function:

               -  total bilirubin ≤1.5 X ULN Participants with Gilbert's syndrome with a total
                  bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.

               -  AST(SGOT) ≤3 X institutional ULN

               -  ALT(SGPT) ≤3 X institutional ULN

         13. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or
             participant or participant who is no longer of childbearing potential due to surgical,
             chemical, or natural menopause.

         14. For females of reproductive potential: use of highly effective contraception for at
             least 1 month prior to screening and agreement to use such a method during study
             participation and for an additional 6 months after the end of treatment
             administration.

         15. For males of reproductive potential: use of condoms or other methods to ensure
             effective contraception with partner and for an additional 6 months after the end of
             treatment administration.

         16. Agreement to adhere to Lifestyle Considerations throughout study duration

         17. Participants who received chemotherapy must have recovered (Common Terminology
             Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy
             except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A
             washout period of at least 21 days is required between last chemotherapy dose and Day
             1 (provided the patient did not receive radiotherapy).

         18. Participants who received radiotherapy must have completed and fully recovered from
             the acute effects of radiotherapy. A washout period of at least 14 days is required
             between end of radiotherapy and Day 1.

        Exclusion Criteria:

          1. Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise.
             Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.

          2. Pregnancy or lactation.

          3. Known allergic reactions to components of the abemaciclib or LY3214996.

          4. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal or
             antiviral therapy within 4 weeks of Day 1.

          5. Known to have active (acute or chronic) or uncontrolled severe infection, liver
             disease such as cirrhosis, decompensated liver disease, and active and chronic
             hepatitis.

          6. 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.

          7. 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.

          8. 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).

          9. Prior therapy with any CDK4/6 inhibitor or any ERK1/2 inhibitor. Prior therapy is
             defined as a therapeutic dosing.

         10. 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.

         11. Have a mean QT interval corrected for heart rate (QTc) of ≥470 milliseconds on
             screening electrocardiogram (ECG) as calculated using the Bazett's formula.

         12. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 0: Pharmacokinetic analysis of tumor tissue
Time Frame:8 hour
Safety Issue:
Description:Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in enhancing and non-enhancing tumor tissue

Secondary Outcome Measures

Measure:Phase 0: PD Analysis
Time Frame:Intraoperatively
Safety Issue:
Description:Phase 0: percentage of pRSK+, pERK+, pRB+, pFOXM1, MIB-1+ and Cleaved Caspase 3+ cells from the surgical tissue will be quantified and compared to baseline archival tissue.
Measure:Number of Adverse Events
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Number of Adverse Events
Measure:Incidence of drug-related toxicity
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Drug-related toxicity
Measure:Incidence of treatment-emergent adverse events
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Treatment-emergent adverse events
Measure:Deaths
Time Frame:up to 60 months
Safety Issue:
Description:Deaths
Measure:Incidence of clinical laboratory abnormalities per CTCAE
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Clinical laboratory abnormalities per CTCAE

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nader Sanai

Last Updated

May 26, 2020