Clinical trial NCT03776071: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Glioblastoma
Lead sponsor: Denovo Biopharma LLC
Sponsor class: INDUSTRY
First posted: 2018-12-14
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: Up to 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center - Duarte
state: California
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Orange
country: United States
facility: University of California Irvine Health Chao Family Comprehensive Cancer Center
state: California
city: Pasadena
country: United States
facility: The University of Southern California
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Helen Diller Family Comprehensive CA Ctr
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital Anschutz Cancer Pavilion
state: Colorado
city: Englewood
country: United States
facility: Blue Sky Neurology
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital - New Haven
state: Connecticut
city: Boca Raton
country: United States
facility: Lynn Cancer Institute
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Markey Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute - Multidisciplinary Clinic
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan Rogel Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: John Nasseff Neuroscience Institute
state: Minnesota
city: Minneapolis
country: United States
facility: Masonic Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine Center for Advanced Medicine
state: Missouri
city: Edison
country: United States
facility: Hackensack Meridian Health - JFK Medical Center
state: New Jersey
city: New York
country: United States
facility: New York University Medical Oncology Associates
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: New York - Presbyterian - Weill Cornell Medical Center
state: New York
city: Asheville
country: United States
facility: Messino Cancer Centers
state: North Carolina
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health - Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University - The James Cancer Hospital and Solove Research Institute
state: Ohio
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Medicine - Perelman Center for Advanced Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: SCRI - Tennessee Oncology - Nashville - Centennial
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt - Ingram Cancer Center
state: Tennessee
city: Austin
country: United States
facility: Austin Cancer Center - Park St. David's
state: Texas
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: Lynn Cancer Institute
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston (UT Health)
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Abbotsford
country: Canada
facility: British Columbia Cancer Agency - Abbotsford
state: British Columbia
city: Victoria
country: Canada
facility: British Columbia Cancer Agency - Victoria
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Sherbrooke
country: Canada
facility: Hôpital Fleurimont
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Center
state: Saskatchewan
city: Hefei
country: China
facility: First Affiliated Hospital of USTC - Anhui Provincial Hospital
state: Anhui
city: Beijing
country: China
facility: Beijing Tian Tan Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Sanbo Brain Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center
state: Guangdong
city: Shenzhen
country: China
facility: Shenzhen Second People's Hospital
state: Guangdong
city: Wuhan
country: China
facility: Tongji Hospital
state: Hubei
city: Shenyang
country: China
facility: Shengjing Hospital - Nanhu Campus
state: Liaoning
city: Xian
country: China
facility: Tangdu Hospital
state: Shaanxi
city: Shanghai
country: China
facility: Huashan Hospital Affiliated to Fudan University
state: Shanghai
city: Jinnan
country: China
facility: Tianjin Huanhu Hospital
state: Tianjin
city: Tianjin
country: China
facility: General Hospital of Tianjin Medical University
state: Tianjin
Study officials:
References: