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

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ClinicalTrials.gov Identifier: NCT02330562
Recruitment Status : Active, not recruiting
First Posted : January 5, 2015
Last Update Posted : April 12, 2018
Sponsor:
Collaborator:
Triphase
Information provided by (Responsible Party):
Celgene

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. Phase 1 evaluates the combination of MRZ and BEV, while 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.

Condition or disease Intervention/treatment Phase
Malignant Glioma Glioblastoma Drug: MRZ Drug: BEV Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 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 a Phase 2 Studies of Single Agent Marizomib and Combination Marizomib and Bevacizumab
Actual Study Start Date : April 15, 2015
Estimated Primary Completion Date : October 1, 2018
Estimated Study Completion Date : October 1, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Experimental: Phase 1: MRZ + BEV; Phase 2: MRZ alone

Part 1 (Phase 1): 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.

Part 2 (Phase 2): MRZ 10 minute IV infusion administered on Days 1, 8, and 15 of each 28-day cycle.

Part 3 (Phase 2): 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.

Drug: MRZ

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.

Other Names:
  • Marizomib
  • NPI-0052

Drug: BEV
BEV 10 mg/kg IV infusion administered for all cohorts in Phase 1 only.
Other Names:
  • Avastin
  • Bevacizumab




Primary Outcome Measures :
  1. Part 1 (Phase 1): Maximum Tolerated Dose (MTD) / Maximum Administered Dose (MAD) [ Time Frame: First 28 days (Cycle 1) ]
    To determine the MTD/MAD of MRZ + BEV

  2. Part 1 (Phase 1): Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 28 days after last dose of study drug ]
    To determine the RP2D of MRZ + BEV

  3. Part 2 (Phase 2): MRZ single agent tumor activity [ Time Frame: Up to 2 years; Subjects may continue on study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or termination of the study. ]
    Assess tumor response by RANO criteria, progression-free survival, and overall survival

  4. Part 3 (Phase 2): activity of MRZ + BEV with intra-patient dose escalation [ Time Frame: Up to 2 years; Subjects may continue on study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or termination of the study. ]
    Assess tumor response by RANO criteria, progression-free survival, and overall survival


Secondary Outcome Measures :
  1. Part 1 (Phase 1): Tumor activity [ Time Frame: Up to 2 years; Subjects may continue on study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or termination of the study. ]
    Assess tumor response by progression-free survival

  2. Part 1 (Phase 1): Tumor activity [ Time Frame: Up to 2 years; Subjects may continue on study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or termination of the study. ]
    Assess tumor response by overall survival

  3. Part 1 (Phase 1): Tumor activity [ Time Frame: Up to 2 years; Subjects may continue on study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or termination of the study. ]
    Assess tumor response by RANO criteria

  4. Parts 1, 2 & 3 (Phase 1 and Phase 2): Assess safety and tolerance [ Time Frame: Up to 28 days after last dose of study drug ]
    Evaluate adverse events, serious adverse events, deaths, laboratory tests, and vital signs

  5. Part 1 (Phase 1): MRZ pharmacokinetics [ Time Frame: Days 1 and 15 of Cycle 1. ]
    Measure MRZ and BEV serum concentration to calculate MRZ Maximum Concentration (Cmax), Elimination Half-Life (t1/2), Area Under the Blood Concentration-Time Curve (AUC0-t, AUC0-inf), Clearance (CL), Volume of Distribution (Vd) and to see if MRZ affects BEV serum concentration

  6. Part 1 (Phase 1): Proteasome Activity in Packed Whole Blood (PWB) [ Time Frame: Days 1, 8, and 15 of Cycle 1; Days 1 and 15 of each cycle thereafter; and up to 28 days after last dose of study drug ]
    Assess the whole blood proteasome pharmacodynamic (PD) activity of MRZ + BEV in Phase 1 and for MRZ alone in Phase 2

  7. Parts 1, 2 & 3 (Phase 1 and Phase 2): Neurological Coordination Assessment [ Time Frame: Up to 28 days after last dose of study drug ]
    Evaluation using the Scale for the Assessment and Rating for Ataxia (SARA)

  8. Parts 1, 2 & 3 (Phase 1 and Phase 2): Quality of Life Assessment [ Time Frame: Up to 28 days after last dose of study drug ]
    Evaluation using the Functional Assessment of Cancer Therapy (FACT) questionnaire



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Understand and voluntarily sign and date an informed consent document prior to any study related assessments/procedures are conducted.
  2. Males and females at least 18 years of age at the time of signing of the informed consent document.
  3. 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).
  4. Subjects must have previously completed standard radiation therapy and been exposed to temozolomide. Patients must be in first or second relapse.
  5. Subjects with archival tumor tissue suitable for proteasome activity and genetic testing must give permission to access and test the tissue; subjects without archival tumor tissue are eligible.
  6. No prior treatment with MRZ or any other proteasome inhibitors or any other anti-angiogenic agents.
  7. No investigational agent within 4 weeks prior to first dose of study drug.
  8. 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.
  9. 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.
  10. 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).
  11. 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
  12. Karnofsky Performance Status (KPS) score at least 70%.
  13. 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.
  14. Willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

  1. Co-medication that may interfere with study results, e.g., 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.)
  2. 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).
  3. History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months.
  4. Chemotherapy administered within 4 weeks (except 6 weeks for nitrosoureas, 12 weeks for an implanted nitrosoureas wafer, and 1 week from metronomic chemotherapy, like daily temozolomide and etoposide) prior to Day 1 of study treatment, unless the subject has recovered from all expected toxicities from the chemotherapy.
  5. Pregnancy or breast feeding.
  6. 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.
  7. 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.
  8. 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 Phase 2 portion of the study even though BEV is not administered so that the patient populations between Phase 1 and Phase 2 are similar):

  9. Any prior history of hypertensive crisis or hypertensive encephalopathy.
  10. Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg.
  11. Unstable angina.
  12. New York Heart Association Grade ≥ II congestive heart failure.
  13. History of myocardial infarction within 6 months.
  14. Subjects with mean QTcF interval > 500 ms.
  15. Clinically significant peripheral vascular disease
  16. 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.
  17. 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.
  18. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1.
  19. History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 1.
  20. Serious, non-healing wound, ulcer, or bone fracture requiring surgical intervention.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02330562


Locations
United States, California
Comprehensive Brain Tumor Program at the University of California, Irvine Medical Center
Irvine, California, United States, 92697
John Wayne Cancer Institute at the Providence Saint John's Health Center
Santa Monica, California, United States, 90404
United States, New York
Brain Tumor Center at NewYork Presbyterian Hospital/Weill Cornell Medical Center
New York, New York, United States, 10021
United States, North Carolina
The Preston Robert Tisch Brain Tumor Center at the Duke University Medical Center
Durham, North Carolina, United States, 27710
Canada, Ontario
Gerry and Nancy Pencer Brain Tumour Centre at Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Celgene
Triphase
Investigators
Study Director: Ileana Elias, MD Celgene Corporation

Additional Information:
Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02330562     History of Changes
Other Study ID Numbers: MRZ-108
First Posted: January 5, 2015    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: April 2018

Keywords provided by Celgene:
Marizomib
Bevacizumab
Avastin
Grade IV malignant glioma
proteasome inhibitor
glioblastoma
brain tumor
malignant glioma
brain cancer
gliosarcoma
BEV

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents