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Clinical Trial 21084

Cancer Type: Neurologic Oncology
Study Type: Treatment
NCT#: NCT03776071

Phase: Phase III
Prinicipal Investigator: Michael Vogelbaum

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Overview

Study 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 DGM1PI

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.

Objective

Primary: To assess whether there is superiority of overall survival (OS) when enzastaurin rather than placebo is added to the regimen of temozolomide with radiation therapy followed by temozolomide for the treatment of patients with newly diagnosed glioblastoma in DGM1 biomarker-positive patients, regardless of MGMT methylation status. Secondary: To compare progression free survival (PFS) in DGM1 biomarker-positive patients between treatment arms, regardless of MGMT methylation status To compare objective response rate (ORR) in DGM1 biomarker-positive patients between treatment arms, regardless of MGMT methylation status To further evaluate the safety profile of enzastaurin in combination with radiation therapy plus temozolomide and in combination with temozolomide Exploratory: To evaluate OS in DGM1 biomarker-negative patients To determine if the presence of chromaturia (orange/red discoloration of urine) correlates with improved survival in patients taking enzastaurin To analyze for the presence of enzastaurin and enzastaurin metabolites in urine (urine pharmacokinetics [PK]) To evaluate if the presence of other somatic or tumor biomarkers correlates with improved efficacy in patients taking enzastaurin To determine enzastaurin and enzastaurin metabolite(s) concentrations for incorporation into a subsequent population PK analysis

Treatments

Therapies

Medications

Placebo (); Radiotherapy (); Temodal (Temozolomide); Temozolomide (); enzastaurin (LY317615)

Inclusion Criteria

  • Signed informed consent
  • Age > 18 years with life expectancy > 12 weeks
  • Histologically proven, newly diagnosed supratentorial glioblastoma based on the World Health Organization (WHO) classification (2016); prior diagnosis of lower grade astrocytoma that has been upgraded to histologically confirmed glioblastoma is eligible if chemotherapy and radiotherapy treatment-naïve
  • Randomization must occur within approximately 6 weeks after resection (subjects undergoing biopsy only are excluded)
  • Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment
  • Available and willing to submit sufficient and of adequate quality tumor tissue representative of glioblastoma to perform MGMT promoter methylation status is determined prior study randomization
  • Karnofsky performance status (KPS) > 60
  • Stable or decreasing corticosteroids within 5 days prior to study treatment start
  • Willing to forego the use of Tumor Treating Fields therapy (Optune®)
  • Adequate organ function within 14 days prior to randomization defined per protocol
  • 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
  • Willing and able to comply with protocol

  • Exclusion Criteria

  • Unable to swallow tablets or capsules
  • Pregnant or breastfeeding
  • 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)
  • Prior radiotherapy to the brain
  • Unable to discontinue use of EIAEDs, if previously taking EIAEDs, must have been discontinued ≥ 2 weeks prior to randomization
  • Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior to randomization or expected requirement for use on study therapy
  • Use of warfarin that cannot be stopped prior to the study
  • Use of any medication that can prolong the QT/QTc interval within 7 days prior to randomization or expected requirement for use on study therapy, or plan to use such medication during the study
  • Active bacterial, fungal or viral infection requiring systemic treatment
  • Personal or immediate family history of abnormal long QT interval, QTc interval > 450 msec (males) or > 470 msec (females) at screening (recommended that QTc be calculated using Fridericia correction formula, QTcF), or a history of unexplained syncope
  • Unstable angina; myocardial infarction or coronary artery bypass graft/percutaneous stent placement within 6 months of starting study treatment, congestive heart failure requiring treatment
  • 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)
  • Persistent electrolyte abnormalities such as hypokalemia or hypomagnesemia that do not respond to treatment
  • History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)
  • Evidence of chronic hepatitis C infection as indicated by antibody to hepatitis C virus (HCV) with positive HCV-ribonucleic acid (RNA)
  • 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)
  • Any contraindication to temozolomide listed in the local product label
  • Another malignancy except adequately treated non-melanoma skin cancer; subjects who have had another primary malignancy in the past, but have been disease-free for more than 5 years, and subjects who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible
  • Participation in other studies involving investigational product(s) within 30 days prior to randomization
  • 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

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