This is a Phase 1/2 clinical trial to evaluate a new combination of drugs, marizomib (MRZ) and bevacizumab (BEV; Avastin®), for the treatment of WHO Grade IV malignant glioma. The study population includes subjects who are in first or second relapse and who have not previously received any bevacizumab or other anti-angiogenic agent or proteasome inhibitor for treatment of malignant glioma. Part 1 Phase 1 evaluates the combination of MRZ and BEV, while Part 2 Phase 2 evaluates single-agent MRZ. Part 3 (Phase 2) includes a combination MRZ using intra-patient dose escalation, and BEV at a fixed dose. Part 4 Phase 1 evaluates MRZ through enteral administration, and BEV at a fixed dose. Part 5 Phase 1 evaluates the repeat-dose pharmacokinetics of MRZ administered IV with ECG.
One of the few treatment options currently FDA approved for recurrent WHO Grade IV malignant glioma is BEV. Additional treatment options are needed for these subjects. Published literature indicates that targeting the proteasome in glioma cells has shown significant anti-tumor activity. MRZ is a novel, second generation proteasome inhibitor that prevents the breakdown of proteins involved in signal transduction which blocks growth and survival of cancer cells. In-vitro studies of multiple glioma cell lines were highly sensitive to MRZ. MRZ had relatively little effect on neural stem/progenitor cells suggesting minimal neurotoxicity while significantly affecting both malignant glioma stem cells and glioma cell lines. Parts 1 and 2 of this trial have been completed with the Recommended Part 3 (Phase 2) Dose established at 0.8 mg/m2. Part 3 of this trial is enrolling at the MRZ RP2D determined in Phase 1 to assess the combination of MRZ and BEV activity and safety. Parts 1, 2, 3 and 4 of this trial have been completed with the Recommended Dose established at 0.8 mg/m2. Part 5 of this trial is enrolling.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
121
MRZ dosing in Phase 1 to range from 0.55 to 0.8 mg/m2. Dose Escalation: MRZ dose-escalation will occur using a standard 3+3 study design. The RP2D of MRZ (0.8.mg/m2) will be used in a two stage design, with fifteen response-evaluable patients entered in the first stage. If 1 or more responses are observed at the MRZ RP2D, then the second stage will be implemented with an additional 15 response-evaluable patients treated.
BEV 10 mg/kg IV infusion administered for all cohorts in Phase 1 only.
University of Californai, Irvine
Orange, California, United States
John Wayne Cancer Institute
Santa Monica, California, United States
Weill Cornell Medical College
New York, New York, United States
Duke Univ Medical Center
Durham, North Carolina, United States
Princess Margaret Hospital, Medical Oncology
Toronto, Ontario, Canada
Radiographic Objective Response Rate (ORR) - Part 2 Cohort
Radiographic ORR is defined as the percentage of participants achieving a Complete Response (CR) or Partial Response (PR), as assessed by the investigator, according to RANO 2010 criteria. Tumor response assessment was conducted every 2 cycles of study therapy. 95% confidence interval from exact binomial distribution (Clopper-Pearson method).
Time frame: From first dose to end of study treatment (up to approx. 48 weeks)
Overall Survival (OS) - Part 3 Cohorts
OS is defined as time from the date of the first dose of study drug to date of death due to any cause. Participants who are alive will be censored at the last follow up visit
Time frame: From first dose to death, assessed up approx. 42 weeks
Number of Participants Experiencing Adverse Events
Number of subjects experiencing at least 1 Treatment-Emergent Adverse Event (TEAE) within the timeframe specified. For Part 4, data are presented separately for Cycle 1 (when Marizomib was enterally-administered) and for Cycles 2 and subsequent cycles (when Marizomib was administered IV)
Time frame: From first dose to 28 days following last dose (up to approx. 72 weeks for Part 1, approx. 52 weeks for Part 2, approx. 46 weeks for Part 3, and approx. 37 weeks for Part 4)
Number of Participants Experiencing Serious Adverse Events (SAEs)
Number of subjects experiencing at least 1 Serious Adverse Event (SAE) within the timeframe specified. For Part 4, data are presented separately for Cycle 1 (when Marizomib was enterally-administered) and for Cycles 2 and subsequent cycles (when Marizomib was administered IV)
Time frame: From first dose to 28 days following last dose (up to approx. 72 weeks for Part 1, approx. 52 weeks for Part 2, approx. 46 weeks for Part 3, and approx. 37 weeks for Part 4)
Number of Participants Experiencing Dose-Limiting Toxicity (DLT)
Number of subjects experiencing at least 1 DLT event within the timeframe specified. DLT is defined as the occurrence of any of the following AEs related to one of the drugs or the combination observed during Cycle 1, using NCI-CTCAE (v 4.03): * ≥ Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding. * Grade 4 neutropenia or anemia lasting for more than 4 days. * Febrile neutropenia. * Any ≥ Grade 2 neurological event lasting more than 4 days. * Grade 3 or 4 non-hematologic toxicity (excluding alopecia), lasting for more than 4 days despite adequate supportive therapy or preventing the next scheduled dose from being administered within 4 days of scheduled day; for ≥ Grade 3 fatigue to be considered a DLT, it must be present for more than 7 days. For Part 4, data are presented separately for Cycle 1 (when Marizomib was enterally-administered) and for Cycles 2 and subsequent cycles (when Marizomib was administered IV). DLT was assessed only for Part 1 and Part 4 cohorts.
Time frame: From first dose to 28 days first dose (during Cycle 1 of study treatment)
Number of Participants Experiencing Dose-Limiting Adverse Events (DLAEs)
Number of subjects experiencing at least 1 DLAE within the timeframe specified. DLAEs are defined as Marizomib-related AEs observed which are: * related to disturbances in the cerebellum (ie, ataxia, dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any grade * any other AEs of Grade ≥ 2. DLAEs were assessed only for Part 3 cohorts.
Time frame: From first dose to 28 days following last dose (up to approx. 46 weeks)
Radiographic Objective Response Rate (ORR)
Radiographic ORR is defined as the percentage of participants achieving a Complete Response (CR) or Partial Response (PR), as assessed by the investigator, according to RANO 2010 criteria. Tumor response assessment was conducted every 2 cycles of study therapy. 95% confidence interval from exact binomial distribution (Clopper-Pearson method). Radiographic ORR was assessed for Part 1 and Part 3 cohorts
Time frame: From first dose to end of study treatment (up to approx. 68 weeks for Part 1, and approx. 42 weeks for Part 3)
Progression Free Survival (PFS)
PFS is defined as the time between start of treatment and first evidence of documented disease progression or death (due to any cause), whichever occurs first. Disease progression will be determined using RANO 2010 criteria as assessed by the investigator. PFS was determined using Kaplan-Meier product-limit estimates.
Time frame: From first dose to disease progression or death, assessed up to approx. 68 weeks for Part 1, approx. 48 weeks for Part 2, approx. 42 weeks for Part 3, and approx. 33 weeks for Part 4
Overall Survival (OS)
OS is defined as time from the date of the first dose of study drug to date of death due to any cause. Participants who are alive will be censored at the last follow up visit
Time frame: From first dose to death, assessed up to approx. 68 weeks for Part 1, approx. 48 weeks for Part 2, and approx. 33 weeks for Part 4
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