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
- Conditions
- Glioblastoma
- Interventions
- Registration Number
- NCT03776071
- Lead Sponsor
- Denovo Biopharma LLC
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 260
Patients must meet all the following inclusion criteria to be eligible for enrollment into the study:
-
Signed informed consent
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Age ≥ 18 years with life expectancy > 12 weeks
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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
-
Randomization must occur within approximately 6 weeks after resection (patients undergoing biopsy only are excluded from the study)
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Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment
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DGM1 biomarker status (positive or negative) is available prior to randomization
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Availability of tumor tissue representative of glioblastoma from surgery, and MGMT promoter methylation status is determined prior to study randomization
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Karnofsky performance status (KPS) ≥ 70 (Appendix 1)
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Stable or decreasing corticosteroids within 5 days prior to study treatment start
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Willing to forego the use of Tumor Treating Fields therapy (Optune®)
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Adequate organ function within 14 days prior to randomization:
Bone marrow
-
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
-
Platelet count ≥ 100 x 109/L;
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Hemoglobin ≥ 10 g/dL (eligibility level for hemoglobin may be met by transfusion) Renal
-
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
-
Total serum bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert syndrome;
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Aspartate and Alanine transaminase (AST/SGOT and ALT/SGPT) ≤ 2.5 x ULN;
-
Alkaline phosphatase (ALP) ≤ 2.5 x ULN
-
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Negative serum pregnancy test (for females of childbearing potential) within 7 days prior to the first study treatment
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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
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Willing and able to comply with the protocol
Patient
Patients with any of the following characteristics/conditions will be excluded from study:
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Unable to swallow tablets or capsules
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Pregnant or breastfeeding
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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)
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Glioblastoma IDH mutant
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Prior radiation therapy to the brain
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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
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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
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Use of warfarin that cannot be stopped prior to the study.
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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
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Active bacterial, fungal or viral infection requiring systemic treatment
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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
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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)
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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)
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Persistent electrolyte abnormalities such as hypokalemia or hypomagnesemia that do not respond to treatment
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History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)
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Evidence of chronic hepatitis C infection as indicated by antibody to hepatitis C virus (HCV) with positive HCV ribonucleic acid (RNA)
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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)
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Any contraindication to temozolomide listed in the local product label
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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
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Participation in other studies involving investigational product(s) within 30 days prior to randomization
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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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RT plus TMZ and ENZ; ENZ alone; TMZ and ENZ Enzastaurin Hydrochloride Radiotherapy (RT) plus temozolomide (TMZ) and enzastaurin (ENZ) (Concurrent Phase) followed by enzastaurin alone (Single-Agent Phase), then temozolomide and enzastaurin (Adjuvant Phase) RT plus TMZ and placebo; placebo; TMZ and placebo Placebo Radiotherapy (RT) plus temozolomide (TMZ) and placebo followed placebo then by temozolomide and placebo RT plus TMZ and placebo; placebo; TMZ and placebo Temozolomide Radiotherapy (RT) plus temozolomide (TMZ) and placebo followed placebo then by temozolomide and placebo RT plus TMZ and ENZ; ENZ alone; TMZ and ENZ Temozolomide Radiotherapy (RT) plus temozolomide (TMZ) and enzastaurin (ENZ) (Concurrent Phase) followed by enzastaurin alone (Single-Agent Phase), then temozolomide and enzastaurin (Adjuvant Phase) RT plus TMZ and ENZ; ENZ alone; TMZ and ENZ Radiotherapy Radiotherapy (RT) plus temozolomide (TMZ) and enzastaurin (ENZ) (Concurrent Phase) followed by enzastaurin alone (Single-Agent Phase), then temozolomide and enzastaurin (Adjuvant Phase) RT plus TMZ and placebo; placebo; TMZ and placebo Radiotherapy Radiotherapy (RT) plus temozolomide (TMZ) and placebo followed placebo then by temozolomide and placebo
- Primary Outcome Measures
Name Time Method Overall Survival Up to 3 years
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (64)
New York University Medical Oncology Associates
🇺🇸New York, New York, United States
University of Kentucky Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Messino Cancer Centers
🇺🇸Asheville, North Carolina, United States
Mayo Clinic - Arizona
🇺🇸Scottsdale, Arizona, United States
The University of Southern California
🇺🇸Pasadena, California, United States
City of Hope Comprehensive Cancer Center - Duarte
🇺🇸Duarte, California, United States
First Affiliated Hospital of USTC - Anhui Provincial Hospital
🇨🇳Hefei, Anhui, China
University of California San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
The Ottawa Hospital - General Campus
🇨🇦Ottawa, Ontario, Canada
Mayo Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
Penn State Health Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
General Hospital of Tianjin Medical University
🇨🇳Tianjin, Tianjin, China
British Columbia Cancer Agency - Abbotsford
🇨🇦Abbotsford, British Columbia, Canada
Tongji Hospital
🇨🇳Wuhan, Hubei, China
Lynn Cancer Institute
🇺🇸Houston, Texas, United States
The Ohio State University - The James Cancer Hospital and Solove Research Institute
🇺🇸Columbus, Ohio, United States
University of Texas Health Science Center at Houston (UT Health)
🇺🇸Houston, Texas, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
University of California Irvine Health Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
Washington University School of Medicine Center for Advanced Medicine
🇺🇸Saint Louis, Missouri, United States
University of Pittsburgh Medical Center - Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Huashan Hospital Affiliated to Fudan University
🇨🇳Shanghai, Shanghai, China
Beijing Tian Tan Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Sanbo Brain Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Peking Union Medical College Hospital
🇨🇳Beijing, Beijing, China
Shenzhen Second People's Hospital
🇨🇳Shenzhen, Guangdong, China
Tangdu Hospital
🇨🇳Xian, Shaanxi, China
Tianjin Huanhu Hospital
🇨🇳Jinnan, Tianjin, China
Sun Yat-Sen University Cancer Center
🇨🇳Guangzhou, Guangdong, China
Shengjing Hospital - Nanhu Campus
🇨🇳Shenyang, Liaoning, China
Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
John Nasseff Neuroscience Institute
🇺🇸Minneapolis, Minnesota, United States
Miami Cancer Institute
🇺🇸Miami, Florida, 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
University of Utah
🇺🇸Salt Lake City, Utah, United States
SCRI - Tennessee Oncology - Nashville - Centennial
🇺🇸Nashville, Tennessee, United States
Vanderbilt - Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Blue Sky Neurology
🇺🇸Englewood, Colorado, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Hôpital Fleurimont
🇨🇦Sherbrooke, Quebec, Canada
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
Saskatoon Cancer Center
🇨🇦Saskatoon, Saskatchewan, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Hackensack Meridian Health - JFK Medical Center
🇺🇸Edison, New Jersey, United States
British Columbia Cancer Agency - Victoria
🇨🇦Victoria, British Columbia, Canada
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Winship Cancer Institute of Emory University
🇺🇸Atlanta, Georgia, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
New York - Presbyterian - Weill Cornell Medical Center
🇺🇸New York, New York, United States
Penn Medicine - Perelman Center for Advanced Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
University of Michigan Rogel Cancer Center
🇺🇸Ann Arbor, Michigan, United States
University of Colorado Hospital Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Norton Cancer Institute - Multidisciplinary Clinic
🇺🇸Louisville, Kentucky, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
Smilow Cancer Hospital - New Haven
🇺🇸New Haven, Connecticut, United States
The University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Wake Forest Baptist Health - Comprehensive Cancer Center
🇺🇸Winston-Salem, North Carolina, United States
Austin Cancer Center - Park St. David's
🇺🇸Austin, Texas, United States