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

Study Overview
=================
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Phase 1, Multicenter, Open-label, Dose-escalation, Combination Study of Marizomib and Bevacizumab in Bevacizumab-Naïve Subjects With WHO Grade IV Malignant Glioma Followed by Phase 2 Studies of Single Agent Marizomib and Combination Marizomib and Bevacizumab, and Phase 1 Dose-Escalation Study of Enterally-administered Marizomib With Bevacizumab

Conditions
-----------------
Malignant Glioma, Glioblastoma

Intervention / Treatment
-----------------
* Drug: MRZ
* Drug: BEV


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Alanine transaminase (ALT) at least 2.5 ULN Serum creatinine at least 1.5 × ULN Urine protein: creatinine ratio ≤ 1.0 at screening Karnofsky Performance Status (KPS) score at least 70%. For women of child-bearing potential and for men with partners of child-bearing potential, subject must agree to take contraceptive measures for duration of treatments and 6 months after the last dose of BEV. A female subject of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). Willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: 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. BEV-Specific Concerns (Note: These exclusion criteria apply to the Part 2 Phase 2 portion of the study even though BEV is not administered so that the subject populations among Part 1, Part 2, Part 3, Part 4, and Part 5 are similar): 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. Clinically significant peripheral vascular disease. Evidence of bleeding diathesis, coagulopathy as documented by an elevated (≥ 1.5 x ULN) prothrombin time (PT), partial thromboplastin time (PTT), or bleeding time. The use of full-dose oral or parenteral anticoagulants is permitted as long as the PT or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the subject has been on a stable dose of anticoagulants for at least 2 weeks prior to the first study treatment. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during course of the study. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1. History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 1. Serious, non-healing wound, ulcer, or bone fracture requiring surgical intervention.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: MRZ + BEV; Phase 2: MRZ alone<br>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<br>* 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.<br>* Other names: Marizomib, CC-92763, NPI-0052;Drug: BEV<br>* BEV 10 mg/kg IV infusion administered for all cohorts in Phase 1 only.<br>* Other names: Avastin, Bevacizumab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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) | 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. | 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. | 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 | 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. | 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 | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Marizomib, Bevacizumab, Avastin, Grade IV malignant glioma, proteasome inhibitor, glioblastoma, brain tumor, malignant glioma, brain cancer, gliosarcoma, BEV