A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma

European Organisation for Research and Treatment of Cancer - EORTC749 enrolled

Overview

The standard of care for newly diagnosed glioblastoma includes surgery, involved-field radiotherapy, and concomitant and six cycles of maintenance temozolomide chemotherapy, however the prognosis remains dismal. Marizomib has been tested in patients with newly diagnosed and recurrent glioblastoma in phase I and phase II studies. In patients with recurrent glioblastoma, marizomib was administered as a single agent or in combination with bevacizumab (NCT02330562). Based on encouraging observations, a phase I/II trial of marizomib in combination with Temozolomide+Radiotherapy(TMZ/RT) followed by Temozolomide (TMZ) in newly diagnosed glioblastoma has been launched (NCT02903069) which explores safety and tolerability of this triple combination and which shall help to determine the dose for further clinical trials in glioblastoma. In this context, given that marizomib has been established as a safe addition to the standard TMZ/RT --\>TMZ, a phase III study is considered essential to establishing its impact on overall survival.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

749

Conditions

Newly Diagnosed Glioblastoma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically confirmed newly diagnosed glioblastoma (WHO grade IV) * Tumor resection (gross total or partial), or biopsy only * Availability of formalin-fixed paraffin-embedded (FFPE) tumor block or 24 unstained slides for o6-methylguanine-DNA-methyltransferase (MGMT) analysis * Patient must be eligible for standard TMZ/RT + TMZ * Karnofsky performance score (KPS) ≥ 70 * Recovered from effects of surgery, postoperative infection and other complications of surgery (if any) * The patient is at least 18 years of age on day of signing informed consent * Stable or decreasing dose of steroids for at least 1 week prior to inclusion * The patient has a life expectancy of at least 3 months * Patient has undergone a brain MRI within 14 days of randomization but after intervention (resection or biopsy) * The patient shows adequate organ functions as assessed by the specified laboratory values within 2 weeks prior to randomization defined as adequate bone marrow, renal and hepatic function within the following ranges: * white blood cell count (WBC) ≥ 3×10\*9/L * absolute neutrophil count (ANC) ≥ 1.5×10\*9/L * Platelet count of ≥ 100×10\*9/L independent of transfusion * Hemoglobin ≥ 10 g/dl * Total Bilirubin ≤ 1.5 upper limit of normal (ULN) * Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) ≤ 2.5 × ULN * Serum creatinine \< 1.5 x ULN or creatinine clearance (CrCl) \> 30 mL/min(using the Cockcroft-Gault formula) * Women of child bearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to the first dose of study treatment. * Patients of childbearing / reproductive potential must agree to use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1 percent per year) when used consistently and correctly. Patients must also agree not to donate sperm during the study and for 6 months after receiving the last dose of study treatment. * Women who are breast feeding must agree to discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment. * Ability to take oral medication * Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments. * Before patient registration/randomization, written informed consent must be given according to International Council for Harmonisation (ICH) / Good clinical practice (GCP), and national/local regulations.

Locations (82)

Mayo Clinic Scottsdale

Scottsdale, Arizona, United States

University of California at Irvine

Orange, California, United States

University of California

San Francisco, California, United States

John Wayne Cancer Institute

Santa Monica, California, United States

University of Florida

Gainesville, Florida, United States

Outcomes

Primary Outcomes

Overall Survival (OS)

Overall Survival (OS): OS is defined as the number of days from date of randomization to the date of death due to any cause. If a patient has not died, the data will be censored at the last date documented to be alive.

Time frame: From the date of randomization up to the date of death, assessed up to 49 months

Secondary Outcomes

Progression Free Survival (PFS)

PFS is defined as the number of days from date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology criteria (by investigator) or to the date of death due to any cause, if disease progression does not occur. Patients for whom neither death nor progression have been documented were censored on the date of the last radiological assessment that the patient was progression-free. If a patient with no post-baseline radiological assessment then the data were censored at the date of randomization. Patients with two or more missing response assessments prior to a visit with documented disease progression (or death) were censored at the last visit where the patient was documented to be progression free. Patients who received new anti-cancer therapy or cancer-related surgery prior to progression or death were not censored at the last assessment where the patient was documented as progression free prior to the new therapy.

Time frame: From the date of randomization until the date of first objective progression or the date of patient's death whichever occurs first, assessed up to 49 months

Health-related Quality of Life (HRQol)

HRQoL was assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. The primary HRQol score is Physical Functioning. It is reported at week 16 during the Temozolomide (TMZ) maintenance phase. Physical functioning score is ranging 0 to 100. A large scores indicate a good physical functioning. A negative difference indicates a worsening physical functioning.

Time frame: From randomization until progression or death which ever occurs first, reported at week 16 by the mean difference from baseline assessment.

Mini Mental State Examination (MMSE)

MMSE is a brief, standardized tool to grade patients' neurocognitive function. It is an 11-question measure that tests five areas of neurocognitive function: orientation, registration, attention and calculation, recall, and language. A large MMSE score indicates a good cognitive functioning. The maximum MMSE score is 30 which corresponds to the best neurocognitive function and minimum MMSE score is 0 the worst neurocognitive function.The patient's neurocognitive function are considered 'impaired' if MMSE is 26 or less and 'normal' if it is 27 or more. MMSE has been validated and extensively used in both clinical practice and research. It is reported at week 16 during the Temozolomide (TMZ) maintenance phase. A negative difference indicates a worsening cognitive functioning. Difference range reported in the data table is min -19 and max 10. The mean difference is reported with 95% confidence interval (CI). A CI which excludes 0 indicates a significant mean MMSE score change.

Time frame: From the date of randomization until end of treatment. It is reported at week 16 by the mean difference from baseline assessment.