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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03776071
• Other study ID #: DB102-01
• Status: Completed
• Phase: Phase 3
• Start date: December 16, 2020
• Est. completion date: February 29, 2024

Study information

• Verified date: April 2024
• Source: Denovo Biopharma LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 260
• Est. completion date: February 29, 2024
• Est. primary completion date: February 29, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Drug:
• Enzastaurin Hydrochloride
mg

Other:
• Placebo
mg

Drug:
• Temozolomide
mg/m^2

Radiation:
• Radiotherapy
Gy

Locations

Country	Name	City	State
Canada	British Columbia Cancer Agency - Abbotsford	Abbotsford	British Columbia
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	The Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	Saskatoon Cancer Center	Saskatoon	Saskatchewan
Canada	Hôpital Fleurimont	Sherbrooke	Quebec
Canada	British Columbia Cancer Agency - Victoria	Victoria	British Columbia
China	Beijing Tian Tan Hospital, Capital Medical University	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Sanbo Brain Hospital, Capital Medical University	Beijing	Beijing
China	Sun Yat-Sen University Cancer Center	Guangzhou	Guangdong
China	First Affiliated Hospital of USTC - Anhui Provincial Hospital	Hefei	Anhui
China	Tianjin Huanhu Hospital	Jinnan	Tianjin
China	Huashan Hospital Affiliated to Fudan University	Shanghai	Shanghai
China	Shengjing Hospital - Nanhu Campus	Shenyang	Liaoning
China	Shenzhen Second People's Hospital	Shenzhen	Guangdong
China	General Hospital of Tianjin Medical University	Tianjin	Tianjin
China	Tongji Hospital	Wuhan	Hubei
China	Tangdu Hospital	Xian	Shaanxi
United States	University of Michigan Rogel Cancer Center	Ann Arbor	Michigan
United States	Messino Cancer Centers	Asheville	North Carolina
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	University of Colorado Hospital Anschutz Cancer Pavilion	Aurora	Colorado
United States	Austin Cancer Center - Park St. David's	Austin	Texas
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Lynn Cancer Institute	Boca Raton	Florida
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	The Ohio State University - The James Cancer Hospital and Solove Research Institute	Columbus	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center - Duarte	Duarte	California
United States	Hackensack Meridian Health - JFK Medical Center	Edison	New Jersey
United States	Blue Sky Neurology	Englewood	Colorado
United States	Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Lynn Cancer Institute	Houston	Texas
United States	University of Texas Health Science Center at Houston (UT Health)	Houston	Texas
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of California San Diego Moores Cancer Center	La Jolla	California
United States	University of Kentucky Markey Cancer Center	Lexington	Kentucky
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Norton Cancer Institute - Multidisciplinary Clinic	Louisville	Kentucky
United States	Miami Cancer Institute	Miami	Florida
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	John Nasseff Neuroscience Institute	Minneapolis	Minnesota
United States	Masonic Cancer Center	Minneapolis	Minnesota
United States	SCRI - Tennessee Oncology - Nashville - Centennial	Nashville	Tennessee
United States	Vanderbilt - Ingram Cancer Center	Nashville	Tennessee
United States	Smilow Cancer Hospital - New Haven	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	New York - Presbyterian - Weill Cornell Medical Center	New York	New York
United States	New York University Medical Oncology Associates	New York	New York
United States	University of California Irvine Health Chao Family Comprehensive Cancer Center	Orange	California
United States	The University of Southern California	Pasadena	California
United States	Penn Medicine - Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of Pittsburgh Medical Center - Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine Center for Advanced Medicine	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Mays Cancer Center	San Antonio	Texas
United States	University of California San Francisco Helen Diller Family Comprehensive CA Ctr	San Francisco	California
United States	Mayo Clinic - Arizona	Scottsdale	Arizona
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida
United States	Wake Forest Baptist Health - Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Denovo Biopharma LLC

Countries where clinical trial is conducted

United States,  Canada,  China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival		Up to 3 years