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).
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
2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or
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
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
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
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.
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
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
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
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