LY3214996 Plus Abemaciclib in Recurrent Glioblastoma Patients

Inclusion Criteria:

1. Prior resection of histologically diagnosed WHO Grade IV glioma defined as gliomaparticipants who have progressed on or following standard (Stupp regimen) therapy,which included maximal surgical resection, temozolomide, and fractionatedradiotherapy.

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

3. Participants must have measurable disease preoperatively, defined as at least 1contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, asper RANO criteria.

4. Sufficient archival tissue available to confirm eligibility.

5. For gliomas, archival tissue must demonstrate: (a) RB positivity (≥20%) onimmunohistochemistry (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 consentdocument (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 screeningprocedures. If consent cannot be expressed in writing, it must be formallydocumented and witnessed, ideally via an independent trusted witness.

8. Willingness and ability to comply with scheduled visits, treatment plans, laboratorytests 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 followinglaboratory 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 toachieve this hemoglobin level at the discretion of the investigator. Initialtreatment must not begin earlier than the day after the erythrocytetransfusion. Adequate hepatic function:

• total bilirubin ≤1.5 X ULN Participants with Gilbert's syndrome with a totalbilirubin ≤2.0 times ULN and direct bilirubin within normal limits arepermitted.

• AST(SGOT) ≤3 X institutional ULN

• ALT(SGPT) ≤3 X institutional ULN

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

14. For females of reproductive potential: use of highly effective contraception for atleast 1 month prior to screening and agreement to use such a method during studyparticipation and for an additional 6 months after the end of treatmentadministration.

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

16. Agreement to adhere to Lifestyle Considerations throughout study duration

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

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

Exclusion Criteria:

1. Current use of coumarin-derived anticoagulant for treatment, prophylaxis orotherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinuxis 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 orantiviral therapy within 4 weeks of Day 1.

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

6. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics attime of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known activehepatitis B or C [for example, hepatitis B surface antigen positive]. Screening isnot required for enrollment.

7. Have history of central or branch retinal artery or venous occlusion withsignificant vision loss or other retinal diseases that cause current visualimpairment or would likely cause visual impairment over the time period of thestudy.

8. Participant has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this study (forexample, interstitial lung disease, severe dyspnea at rest or requiring oxygentherapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],history of major surgical resection involving the stomach or small bowel, orpreexisting Crohn's disease or ulcerative colitis or a preexisting chronic conditionresulting in baseline Grade 2 or higher diarrhea).

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

10. Treatment with another investigational drug or other intervention within 30 daysprior to enrollment or within 5 half-lives of the investigational product, whicheveris longer.

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

12. The patient has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest.