A Trial of Enzastaurin Plus Temozolomide During and Following Radiation Therapy in Patients With Newly Diagnosed Glioblastoma With or Without the Novel Genomic Biomarker, DGM1

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Enzastaurin Added to Temozolomide During and Following Radiation Therapy in Newly Diagnosed Glioblastoma Patients Who Possess the Novel Genomic Biomarker DGM1

This study will be conducted as a randomized, double-blind, placebo-controlled, multi-center Phase 3 study. Approximately 300 subjects with newly diagnosed glioblastoma who meet all eligibility criteria will be enrolled.

Patient Inclusion Criteria:

Patients must meet all the following inclusion criteria to be eligible for enrollment into the study:

1. Signed informed consent

2. Age ≥ 18 years with life expectancy > 12 weeks

3. Histologically proven, newly diagnosed supratentorial glioblastoma (IDH mutant is excluded) based on the WHO classification (2016) which includes gliosarcoma (GS); prior diagnosis of lower grade astrocytoma that has been upgraded to histologically confirmed glioblastoma is eligible if chemotherapy and radiation therapy treatment-naïve

4. Randomization must occur within approximately 6 weeks after resection (patients undergoing biopsy only are excluded from the study)

5. Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment

6. DGM1 biomarker status (positive or negative) is available prior to randomization

7. Availability of tumor tissue representative of glioblastoma from surgery, and MGMT promoter methylation status is determined prior to study randomization

8. Karnofsky performance status (KPS) ≥ 70 (Appendix 1)

9. Stable or decreasing corticosteroids within 5 days prior to study treatment start

10. Willing to forego the use of Tumor Treating Fields therapy (Optune®)

11. Adequate organ function within 14 days prior to randomization:

    Bone marrow

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L;

    2. Platelet count ≥ 100 x 109/L;

    3. Hemoglobin ≥ 10 g/dL (eligibility level for hemoglobin may be met by transfusion) Renal

    4. Serum creatinine < 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min as calculated using an appropriately validated prediction equation for the estimation of eGFR (eg, Cockcroft-Gault or MDRD method).

       Hepatic

    5. Total serum bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert syndrome;

    6. Aspartate and Alanine transaminase (AST/SGOT and ALT/SGPT) ≤ 2.5 x ULN;

    7. Alkaline phosphatase (ALP) ≤ 2.5 x ULN

12. Negative serum pregnancy test (for females of childbearing potential) within 7 days prior to the first study treatment

13. Male and female patients of reproductive potential must agree to use an effective method of contraception (eg, oral contraceptives, intrauterine device, barrier method) throughout the study and for at least 3 months after the last dose of study treatment, or 6 months for female patients in regard to the last dose of temozolomide (TMZ), whichever is later

    • Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis
    • Male patients must agree not to donate their semen during treatment with temozolomide and for at least 6 months after their last dose of temozolomide
    • Women are considered of reproductive potential unless they have undergone hysterectomy and/or surgical sterilization (at least 6 weeks following a bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive procedure that has been confirmed in accordance with the device's label), have medically confirmed ovarian failure, or achieved postmenopausal status (defined as cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women

14. Willing and able to comply with the protocol

Patient Exclusion Criteria:

Patients with any of the following characteristics/conditions will be excluded from study:

1. Unable to swallow tablets or capsules

2. Pregnant or breastfeeding

3. Prior chemotherapy (including carmustine-containing wafers (Gliadel®), immunotherapy (including vaccine therapy), or investigational products for GBM or GS (previous 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) administered prior to surgery to aid in optimal surgical resection is permitted)

4. Glioblastoma IDH mutant

5. Prior radiation therapy to the brain

6. Unable to discontinue use of enzyme-inducing anti-epileptic drugs (EIAEDs), see Section 5.1.2.4.1; if previously taking EIAEDs, must have been discontinued ≥ 2 weeks prior to randomization

7. Use of a strong inducer or moderate or strong inhibitor of CYP3A4 (Appendix 2) within 7 days prior to randomization or expected requirement for use on study therapy

8. Use of warfarin that cannot be stopped prior to the study.

9. Use of any medication that can prolong the QT/QTc interval (Appendix 3) within 7 days prior to start of study therapy, or plan to use such a medication during the study

10. Active bacterial, fungal or viral infection requiring systemic treatment

11. Personal or family history of abnormal long QT interval, QTc interval > 450 msec (males) or > 470 msec (females) as read on the printout of the electrocardiogram (ECG) at screening (recommended that QTc be calculated using Fridericia's correction formula, QTcF: see Section 7.3.2.2), or a history of unexplained syncope

12. Unstable angina; myocardial infarction or coronary artery bypass graft/percutaneous stent placement within 6 months of starting study treatment, congestive heart failure requiring treatment (New York Heart Association [NYHA] Grade ≥2)

13. History of significant cardiac arrhythmia (ventricular tachycardia or fibrillation, Torsades de Pointe) or second- or third-degree A-V block, symptomatic bradycardia (unless controlled with a pacemaker)

14. Persistent electrolyte abnormalities such as hypokalemia or hypomagnesemia that do not respond to treatment

15. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)

16. Evidence of chronic hepatitis C infection as indicated by antibody to hepatitis C virus (HCV) with positive HCV ribonucleic acid (RNA)

17. Evidence of active or chronic hepatitis B infection as indicated by either:

    hepatitis B surface antigen (HBsAg) positive, or hepatitis B core antibody (HBcAb) positive with hepatitis B virus-deoxyribonucleic acid (HBV-DNA) positive (any detectable amount is considered positive)

18. Any contraindication to temozolomide listed in the local product label

19. Another malignancy except adequately treated non-melanoma skin cancer; patients who have had another primary malignancy in the past, but have been disease-free for more than 5 years, and patients who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible

20. Participation in other studies involving investigational product(s) within 30 days prior to randomization

21. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for participation in this study