Stage 1: Marizomib + Bevacizumab in WHO Gr IV GBM; Stage 2: Marizomib Alone; Stage 3: Combination of Marizomib and Bevacizumab

NCT02330562 | Completed Phase 1 Results

• 1 other identifier: MRZ-108
• Study Type: interventional
• Target: 121
• Locations: 2 countries
• Sites: 5

Brief Summary

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.

Conditions

Malignant Glioma; Glioblastoma

Keywords

Marizomib; Bevacizumab; Avastin; Grade IV malignant glioma; proteasome inhibitor; glioblastoma; brain tumor; malignant glioma; brain cancer; gliosarcoma; BEV

Outcome Measures

Primary Outcomes (2)

• 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).

  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

  From first dose to death, assessed up approx. 42 weeks

Secondary Outcomes (7)

• Number of Participants Experiencing Adverse Events

  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)

  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)

  From first dose to 28 days first dose (during Cycle 1 of study treatment)

• Number of Participants Experiencing Dose-Limiting Adverse Events (DLAEs)

  From first dose to 28 days following last dose (up to approx. 46 weeks)

• Radiographic Objective Response Rate (ORR)

  From first dose to end of study treatment (up to approx. 68 weeks for Part 1, and approx. 42 weeks for Part 3)

Study Arms (1)

Phase 1: MRZ + BEV; Phase 2: MRZ alone

EXPERIMENTAL

Part1-Phase1: MRZ 10 minute IV infusion on Days 1, 8, and 15 plus BEV IV infusion on Days 1 and 15 of each 28-day cycle. Part2-Phase2: MRZ 10 minute IV infusion administered on Days 1, 8, and 15 of each 28-day cycle. Part3-Phase2: All subjects will receive IV MRZ infusion and IV BEV infusion. MRZ will be administered as a 10-minute, IV infusion on Days 1, 8, and 15 of every 28-day cycle using intra-patient dose escalation. Starting dose will be 0.8 mg/m2. Part4- Phase1: All subjects will receive MRZ enterally by NG tube as a bolus on Days 1, 8 and 15 of the first 28-day cycle and BEV IV infusion on Day 15 of the first 28-day cycle. For subsequent 28-day treatment cycles, MRZ will be administered as an IV at the recommended dose and schedule determined in Part 1, with BEV IV on Days 1 and 15. Part5-Phase1: All subjects will receive IV MRZ infusion and IV BEV infusion. MRZ will be administered as a 10-minute, IV infusion at 0.8 mg/m2 on Days 1, 8, and 15 of every 28-day cycle 0.8 mg/m2

Drug: MRZ; Drug: BEV

Interventions

MRZ DRUG

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.

Also known as: Marizomib, CC-92763, NPI-0052

Phase 1: MRZ + BEV; Phase 2: MRZ alone

BEV DRUG

BEV 10 mg/kg IV infusion administered for all cohorts in Phase 1 only.

Also known as: Avastin, Bevacizumab

Phase 1: MRZ + BEV; Phase 2: MRZ alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understand and voluntarily sign and date an informed consent document prior to any study related assessments/procedures are conducted.
• Males and females at least 18 years of age at the time of signing of the informed consent document.
• All subjects must have histologic evidence of G4 MG (including glioblastoma and gliosarcoma) and radiographic evidence of recurrence or disease progression (defined as either a greater than 25% increase in the largest bidimensional product of enhancement, a new enhancing lesion, or significant increase in T2 FLAIR).
• Subjects must have previously completed standard radiation therapy and been exposed to temozolomide. Patients must be in first or second relapse.
• No prior treatment with MRZ or any other proteasome inhibitors or any other anti-angiogenic agents.
• No investigational agent within 4 weeks prior to first dose of study drug.
• At least 4 weeks from surgical resection and 12 weeks from end of radiotherapy prior to enrollment in this study, unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are two MRIs confirming progressive disease that are 8 weeks apart.
• Subjects with a history of seizures must be on a stable dose of anti-epileptic drugs (AEDs) and without seizures for 14 days prior to enrollment in patients enrolled prior to Amendment 2. Subjects enrolled after Amendment 2 is approved with a history of seizures must be on a stable dose of anti-epileptic drugs (AEDs) for 7 days prior to enrollment.
• All AEs resulting from prior chemotherapy, surgery, or radiotherapy, must have resolved to at least NCI-CTCAE (v. 4.03) Grade 1 (except for laboratory parameters outlined below).
• Laboratory results within 7 days prior to MRZ administration (transfusions and/or growth factor support may not be used to meet this criteria):
• Platelet count at least 100,000/mm3
• Hemoglobin at least 9 g/dL
• Absolute neutrophil count (ANC) at least 1,500/mm3
• Serum bilirubin at least 1.5 × upper limit of normal (ULN) or at least 3 × ULN if Gilbert's disease is documented
• Aspartate transaminase (AST) at least 2.5 ULN

You may not qualify if:

• Co-medication that may interfere with study results, eg, immuno-suppressive agents other than corticosteroids. (Steroid therapy for control of cerebral edema is allowed at the discretion of the Investigator. Subjects should be on a stable dose of steroids for at least 1 week prior to first dose of MRZ. Co-medications must not be taken for 2 hours prior to and up to 2 hours after enteral administration of MRZ (Part 4 Phase 1).
• Evidence of CNS hemorrhage on baseline MRI or CT scan (except for post-surgical, asymptomatic Grade 1 hemorrhage that has been stable for at least 3 months for subjects enrolled prior to Amendment 2 and for at least 4 weeks in subjects enrolled after Amendment 2 is approved).
• History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months.
• Chemotherapy administered within 4 weeks (except 6 weeks for nitrosoureas, 12 weeks for an implanted nitrosoureas wafer, and 1 week from metronomic chemotherapy, such as daily temozolomide and etoposide) prior to Day 1 of study treatment, unless the subject has recovered from all expected toxicities from the chemotherapy.
• (Part 4 Phase 1) Recent nasal or esophageal surgery, history of GI-related medical conditions, or any other condition which, in the opinion of the investigator, would interfere or cause undue risk with insertion of NG tube or enteral administration of marizomib through the NG tube.
• Pregnancy or breast feeding.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics \& psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state.
• Known previous/current malignancy requiring treatment within ≤ 3 years except for cervical carcinoma in situ, squamous or basal cell skin carcinoma, and superficial bladder carcinoma.
• Any comorbid condition that confounds the ability to interpret data from the study as judged by the Investigator or Medical Monitor.
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• Systolic blood pressure (BP) \> 150 mmHg or diastolic BP \> 100 mmHg.
• Unstable angina.
• New York Heart Association Grade ≥ II congestive heart failure.
• History of myocardial infarction within 6 months.
• Subjects with mean QTcF interval \> 500 ms.

Sponsors & Collaborators

• Celgene: lead
• Triphase Research and Development III Corp.: collaborator

Study Sites (5)

University of Californai, Irvine

Orange, California, 92868, United States

Location

John Wayne Cancer Institute

Santa Monica, California, 90404, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Duke Univ Medical Center

Durham, North Carolina, 27710, United States

Location

Princess Margaret Hospital, Medical Oncology

Toronto, Ontario, M5G 2M9, Canada

Location

Related Links

• UC Irvine Health Comprehensive Brain Tumor Program
• The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center
• Brain Tumor Center at New York-Presbyterian Hospital/Weill Cornell Medical Center
• John Wayne Cancer Institute at Providence Saint John's Health Center

MeSH Terms

Conditions

Glioma; Glioblastoma; Brain Neoplasms; Gliosarcoma

Interventions

marizomib; Bevacizumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email

Study Officials

• Ileana Elias, MD

  Celgene Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2014
• First Posted: January 5, 2015
• Study Start: April 15, 2015
• Primary Completion: June 2, 2021
• Study Completion: June 2, 2021
• Last Updated: June 8, 2022
• Results First Posted: June 8, 2022

Record last verified: 2022-05

Locations

CA (1); US (4)