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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Enzastaurin Hydrochloride; Drug: Temozolomide; Radiation: Radiotherapy; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Abbotsford, British Columbia, Canada, V2S OC2
      • British Columbia Cancer Agency - Abbotsford
    • Victoria, British Columbia, Canada, V8R 6V5
      • British Columbia Cancer Agency - Victoria
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Hôpital Fleurimont
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Center
• China
  • Anhui
    • Hefei, Anhui, China, 230071
      • First Affiliated Hospital of USTC - Anhui Provincial Hospital
  • Beijing
    • Beijing, Beijing, China, 100730
      • Peking Union Medical College Hospital
    • Beijing, Beijing, China, 100070
      • Beijing Tian Tan Hospital, Capital Medical University
    • Beijing, Beijing, China, 100093
      • Sanbo Brain Hospital, Capital Medical University
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center
    • Shenzhen, Guangdong, China, 518035
      • Shenzhen Second People's Hospital
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital
  • Liaoning
    • Shenyang, Liaoning, China, 110004
      • Shengjing Hospital - Nanhu Campus
  • Shaanxi
    • Xian, Shaanxi, China, 710038
      • Tangdu Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital affiliated to Fudan University
  • Tianjin
    • Jinnan, Tianjin, China, 300350
      • Tianjin Huanhu Hospital
    • Tianjin, Tianjin, China, 300052
      • General Hospital of Tianjin Medical University
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic - Arizona
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center - Duarte
    • La Jolla, California, United States, 92093
      • University of California San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Orange, California, United States, 92868
      • University of California Irvine Health Chao Family Comprehensive Cancer Center
    • Pasadena, California, United States, 91105
      • The University of Southern California
    • San Francisco, California, United States, 94143
      • University of California San Francisco Helen Diller Family Comprehensive CA Ctr
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital Anschutz Cancer Pavilion
    • Englewood, Colorado, United States, 80220
      • Blue Sky Neurology
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Smilow Cancer Hospital - New Haven
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Lynn Cancer Institute
    • Jacksonville, Florida, United States, 32224-1865
      • Mayo Clinic - Jacksonville
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Markey Cancer Center
    • Louisville, Kentucky, United States, 40202
      • Norton Cancer Institute - Multidisciplinary Clinic
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Rogel Cancer Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • John Nasseff Neuroscience Institute
    • Minneapolis, Minnesota, United States, 55455-4800
      • Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Center for Advanced Medicine
  • New Jersey
    • Edison, New Jersey, United States, 08820
      • Hackensack Meridian Health - JFK Medical Center
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • New York University Medical Oncology Associates
    • New York, New York, United States, 10065
      • New York - Presbyterian - Weill Cornell Medical Center
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Messino Cancer Centers
    • Chapel Hill, North Carolina, United States, 27599-7055
      • The University of North Carolina at Chapel Hill
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health - Comprehensive Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University - The James Cancer Hospital and Solove Research Institute
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Health Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Medicine - Perelman Center for Advanced Medicine
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center - Hillman Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203-1625
      • SCRI - Tennessee Oncology - Nashville - Centennial
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt - Ingram Cancer Center
  • Texas
    • Austin, Texas, United States, 78705
      • Austin Cancer Center - Park St. David's
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Lynn Cancer Institute
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston (UT Health)
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98109--1023
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RT plus TMZ and ENZ; ENZ alone; TMZ and ENZ; Radiotherapy (RT) plus temozolomide (TMZ) and enzastaurin (ENZ) (Concurrent Phase) followed by enzastaurin alone (Single-Agent Phase), then temozolomide and enzastaurin (Adjuvant Phase)	Drug: Enzastaurin Hydrochloride; mg; Other Names: Kinenza; Drug: Temozolomide; mg/m^2; Other Names: Temodar; Radiation: Radiotherapy; Gy
Placebo Comparator: RT plus TMZ and placebo; placebo; TMZ and placebo; Radiotherapy (RT) plus temozolomide (TMZ) and placebo followed placebo then by temozolomide and placebo	Drug: Temozolomide; mg/m^2; Other Names: Temodar; Radiation: Radiotherapy; Gy; Other: Placebo; mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	Up to 3 years

Collaborators and Investigators

• Sponsor: Denovo Biopharma LLC

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2020
• Primary Completion (Actual): February 29, 2024
• Study Completion (Actual): February 29, 2024

Study Registration Dates

• First Submitted: December 12, 2018
• First Submitted That Met QC Criteria: December 13, 2018
• First Posted (Actual): December 14, 2018

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: DB102-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No