ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of Marizomib With Temozolomide and Radiotherapy in Patients With Newly Diagnosed Brain Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02903069
Recruitment Status : Recruiting
First Posted : September 16, 2016
Last Update Posted : April 27, 2018
Sponsor:
Collaborator:
Triphase
Information provided by (Responsible Party):
Celgene

Brief Summary:
This study is for newly diagnosed WHO Grade IV malignant glioma patients to determine whether an investigational drug known as marizomib (MRZ) will improve the treatment of newly diagnosed glioblastoma patients by delaying the growth of the cancer, reducing the size of the tumor, and/or improving survival. Marizomib (MRZ) is being added to standard-of-care treatments of radiotherapy (RT), temozolomide (TMZ), and Optune.

Condition or disease Intervention/treatment Phase
Glioblastoma Malignant Glioma Drug: MRZ Drug: TMZ Radiation: RT Device: Optune Phase 1

Detailed Description:

Gliomas account for ~80% of primary malignant tumors in the Central Nervous System (CNS), with WHO Grade IV malignant glioma (G4 MG; including glioblastoma and gliosarcoma) constituting the majority of gliomas, and are essentially incurable. Currently only surgical resection and radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) are standard-of-care treatment strategies for newly diagnosed G4 MG. However, resistance to chemotherapy and RT results in a high recurrence rate, with median survival of ~15-16 months. Since no survival advantage has been demonstrated for the addition of bevacizumab (BEV) to TMZ and RT (Chinot 2014) in newly diagnosed G4 MG, alternative promising investigational agents need to be tested.

Targeting the proteasome is a well-validated target for the treatment of multiple myeloma (MM), and preclinical evidence suggests that targeting the proteasome in glioma cells shows significant anti-tumor activity. Proteasome activity is elevated in patient-derived glioblastoma (GBM) tissue in comparison with normal human brain. Importantly, preclinical evidence demonstrates that proteasome inhibition sensitizes GBM cell lines to irradiation and to TMZ. Further, the combination of bortezomib (BTZ, one of three proteasome inhibitors [PI] currently approved for the treatment of MM) with TMZ resulted in synergistic glioblastoma cell death in vitro, and BTZ reduces glioma cell survival in vitro in cell lines sensitive and resistant to TMZ.

Despite the activity against GBM cells in vitro, BTZ does not cross the blood brain barrier, and thus has proven ineffective in animal models and in the clinic. In contrast, marizomib (MRZ) - a potent and irreversible 20S PI possesses the unique attribute among PIs to cross the blood brain barrier as shown in previous clinical studies. These data prompted examination of the combination of MRZ and BEV in an ongoing clinical trial in patients with recurrent G4 MG. In the dose-escalation portion of this ongoing study (MRZ-108), 12 patients were dosed with MRZ once weekly for 3 weeks (0.55, 0.7, and 0.8 mg/m2 infused intravenously (IV) over 10 minutes) and with BEV on weeks 1 and 3 (10 mg/kg IV) of a 28-day cycle. As of April 2016, of these 12 patients, 7 were on study for over 4 months - 5 with a partial response (including 2 patients with no radiologic evidence of tumor on 2 or more consecutive MRI scans) and 2 patients whose best response was stable disease. Four of these 12 patients were treated for over 6 months, 3 of whom remain on study. The recommended Phase 2 dose (RP2D) of MRZ was determined to be 0.8 mg/m2. Currently, an expansion cohort of 24 patients has been enrolled in the Phase 2 portion of the study. The next phase involves treatment with MRZ alone (no BEV) in patients with recurrent G4 MG, and has begun enrolling patients in the second quarter of 2016.

Together, the demonstrated activity of PIs in preclinical glioma models, and the synergistic activity of PIs with TMZ on glioblastoma cells, along with the ability of MRZ to access the CNS, provides compelling rationale to assess the therapeutic benefit of the combination of MRZ with TMZ in patients with G4 MG, for whom no brain-penetrant options for proteasome inhibition are currently available.

Very recently, the FDA has approved a novel treatment device using tumor treating fields (Optune) in addition to standard of care RTand TMZ as an option to standard of care. Optune has been shown to significantly improve both progression-free and overall survival in GBM patients. An additional cohort of 12 patients will be treated with Optune in combination with MRZ and TMZ


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b, Multicenter, Open-Label Study of Marizomib Combined With Temozolomide and Radiotherapy in Patients With Newly Diagnosed WHO Grade IV Malignant Glioma
Actual Study Start Date : April 15, 2016
Estimated Primary Completion Date : June 18, 2019
Estimated Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Stage 1: Concomitant Treatment

MRZ + TMZ + RT

Patients who complete Concomitant Treatment may continue on to Adjuvant Treatment.

Drug: MRZ

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15, 29, and 36 during Concomitant Treatment.

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15 every 28 days during Adjuvant Treatment.

IV hydration will be given prior to the MRZ infusion.

Other Name: NPI-0052

Drug: TMZ

TMZ will be administered once daily, 7 days/week, for 6 weeks, starting on Day 1, at a dose of 75 mg/m2 during Concomitant Treatment.

TMZ will be administered once daily on Days 1-5 every cycle, dose range 150 to 200 mg/m2 during Adjuvant Treatment.

Other Names:
  • temozolomide
  • Temodar

Radiation: RT
Focal RT will be administered once daily, 5 days/week, for 30 doses over 6 weeks to a total dose of 60 Gy, starting on Day 1 during Concomitant Treatment.
Other Name: radiation therapy

Experimental: Stage 1: Adjuvant Treatment
MRZ + TMZ
Drug: MRZ

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15, 29, and 36 during Concomitant Treatment.

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15 every 28 days during Adjuvant Treatment.

IV hydration will be given prior to the MRZ infusion.

Other Name: NPI-0052

Drug: TMZ

TMZ will be administered once daily, 7 days/week, for 6 weeks, starting on Day 1, at a dose of 75 mg/m2 during Concomitant Treatment.

TMZ will be administered once daily on Days 1-5 every cycle, dose range 150 to 200 mg/m2 during Adjuvant Treatment.

Other Names:
  • temozolomide
  • Temodar

Experimental: Stage 2: Dose-Expansion

MRZ + TMZ + RT followed by MRZ + TMZ

In Stage 2 (dose-expansion): a minimum of 12 and up to approximately 18 additional evaluable patients will be enrolled in a cohort in which Concomitant Treatment (MRZ + TMZ + RT) is followed by Adjuvant Treatment (MRZ + TMZ) to confirm the MTD for each treatment regimen as determined in the Dose-Escalation (Stage 1), and to assess preliminary activity of the recommended Phase 2 dose (RP2D).

Drug: MRZ

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15, 29, and 36 during Concomitant Treatment.

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15 every 28 days during Adjuvant Treatment.

IV hydration will be given prior to the MRZ infusion.

Other Name: NPI-0052

Drug: TMZ

TMZ will be administered once daily, 7 days/week, for 6 weeks, starting on Day 1, at a dose of 75 mg/m2 during Concomitant Treatment.

TMZ will be administered once daily on Days 1-5 every cycle, dose range 150 to 200 mg/m2 during Adjuvant Treatment.

Other Names:
  • temozolomide
  • Temodar

Radiation: RT
Focal RT will be administered once daily, 5 days/week, for 30 doses over 6 weeks to a total dose of 60 Gy, starting on Day 1 during Concomitant Treatment.
Other Name: radiation therapy

Experimental: Optune Arm
MRZ + TMZ + Optune
Drug: MRZ

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15, 29, and 36 during Concomitant Treatment.

MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15 every 28 days during Adjuvant Treatment.

IV hydration will be given prior to the MRZ infusion.

Other Name: NPI-0052

Drug: TMZ

TMZ will be administered once daily, 7 days/week, for 6 weeks, starting on Day 1, at a dose of 75 mg/m2 during Concomitant Treatment.

TMZ will be administered once daily on Days 1-5 every cycle, dose range 150 to 200 mg/m2 during Adjuvant Treatment.

Other Names:
  • temozolomide
  • Temodar

Device: Optune
Tumor Treating Fields Therapy device to be worn ≥ 18 hours per day.
Other Name: NovoTTF-100A




Primary Outcome Measures :
  1. Determine MRZ maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for both concomitant treatment (MRZ + TMZ + RT) and adjuvant treatment (MRZ + TMZ) [ Time Frame: 42-day concomitant treatment and 28-day Cycle 1 adjuvant treatment ]
    Assess dose-limiting toxicities (DLTs) in each dose-escalation arm

  2. To assess adverse events during the adjuvant treatment [ Time Frame: From the first dose of study drug through 28 days after the last dose ]
    To assess the safety of the combination of MRZ and TMZ with the addition of Optune™ in patients entering Adjuvant Treatment


Secondary Outcome Measures :
  1. To confirm the MRZ RP2D for concomitant and adjuvant treatment in an expanded group of patients [ Time Frame: Assessments made during the concomitant (dosing for 42 days of a 10-week treatment period) and adjuvant (one or more 28-day cycles) treatment periods in the dose-expansion stage of the study ]
    Assess adverse events

  2. Assess adverse events during concomitant and adjuvant treatment [ Time Frame: From the first dose of study drug through 28 days after the last dose ]
    Assess adverse events

  3. Evaluate the activity (overall survival [OS]) of MRZ + TMZ + RT [ Time Frame: Survival monitored throughout the concomitant and adjuvant treatment periods and every three months during long-term follow-up for 2 years ]
    Includes death due to any cause

  4. Evaluate the activity (progression-free survival [PFS]) of MRZ + TMZ + RT [ Time Frame: MRI assessments at Week 10 during concomitant trt and every even Cycle during adjuvant treatment, death monitored throughout the treatment periods, and disease progression and death monitored every three months during long-term follow-up for 2 years ]
    RANO criteria used to assess tumor response

  5. MRZ pharmacokinetics - Maximum Serum Concentration (Cmax) [ Time Frame: Day 1 and Day 8 during Stage 1 (dose-escalation) ]
    Measured after stopping the MRZ infusion

  6. MRZ pharmacokinetics - Elimination Half-Life (t1/2) [ Time Frame: Day1 and Day 8 during Stage 1 (dose-escalation) ]
    Calculated from MRZ serum concentrations measured through 60 minutes after the stopping the infusion

  7. MRZ pharmacokinetics - Area Under the Blood Concentration-Time Curve (AUC0-t, AUC0-inf) [ Time Frame: Day1 and Day 8 during Stage 1 (dose-escalation) ]
    Calculated from MRZ serum concentrations measured through 60 minutes after the stopping the infusion

  8. MRZ pharmacokinetics - Clearance (CL) [ Time Frame: Day1 and Day 8 during Stage 1 (dose-escalation) ]
    Calculated from MRZ serum concentrations measured through 60 minutes after the stopping the infusion

  9. MRZ pharmacokinetics - Volume of Distribution (Vd) [ Time Frame: Day1 and Day 8 during Stage 1 (dose-escalation) ]
    Calculated from MRZ serum concentrations measured through 60 minutes after the stopping the infusion

  10. TMZ serum concentration [ Time Frame: On Day 1 of Week 1 (D1) and on Day 1 of Week 2 (D8), TMZ serum concentration will be measured before treatment, and 60 minutes after the dose and 24 hrs after the dose (prior to the Day 9 TMZ dose) ]
    Peak and trough TMZ serum concentrations will be measured to see if MRZ affects TMZ serum concentration

  11. Assess neurological coordination using the Scale for the Assessment and Rating for Ataxia (SARA) [ Time Frame: Assessments made at baseline and then weeks 1, 5, and 8 during concomitant treatment, on Day 1 of each Cycle during adjuvant treatment, and at the end of treatment visit (28 days after last dose of study drug) ]
    Investigator evaluation of neurologic coordination using a standardized rating scale

  12. Evaluate the activity (overall survival [OS]) of MRZ + TMZ + Optune [ Time Frame: Survival monitored throughout the concomitant and adjuvant treatment periods and every three months during long-term follow-up for 2 years ]
    Includes death due to any cause

  13. Evaluate the activity (progression-free survival [PFS]) of MRZ + TMZ + Optune [ Time Frame: MRI assessments at Week 10 during concomitant treatment and every even Cycle during adjuvant treatment, death monitored throughout the treatment periods, and disease progression and death monitored every 3 months during long-term follow-up for 2 years ]
    RANO 2010 criteria used to assess tumor response



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Signed Informed Consent Form
  • Males and females of age ≥ 18 years or of age ≥ 22 years for those assigned to Optune™ at the time of signing of the informed consent document.
  • Histologically confirmed newly diagnosed G4 MG
  • Karnofsky Performance Status (KPS) score ≥ 70%
  • For Concomitant Treatment: Prior tumor resection or biopsy up to 8 weeks prior to first MRZ dose
  • For Adjuvant Treatment: All AEs resulting from surgery must have resolved to NCI-CTCAE (v. 4.03) Grade ≤ 1
  • Stable or decreasing dose of corticosteroids over 14 days prior to first MRZ dose
  • For Concomitant Treatment: No prior treatment with MRZ or any other PIs, including BTZ, carfilzomib (CFZ), or ixazomib (IXZ)
  • For Adjuvant Treatment: No prior treatment with BTZ, CFZ, or IXZ
  • No investigational agent within 4 weeks prior to first dose of study drug
  • Adequate hematological, renal, and hepatic function
  • Patients must be without seizures for at least 14 days prior to enrollment, and patients who receive treatment with AEDs must be on stable doses for at least 14 days prior to enrollment
  • Absence of known HIV infection, chronic hepatitis B, or hepatitis C infection; absence of any other serious medical condition which could interfere with oral medication intake
  • Patients with archival tumor tissue suitable for measurement of proteasome activity and biomarker status must give permission to access and test the tissue. Patients without archival tumor tissue are eligible for the Dose-Escalation stage, but not the Dose-Expansion stage of the study
  • For women of child-bearing potential and for men with partners of child-bearing potential, patient must agree to take contraceptive measures for duration of treatments and for one month after last study treatment
  • Willing and able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

  • Co-medication or concomitant therapy that may interfere with study results
  • History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months
  • Other chemotherapy or anti-tumor treatment for brain tumor (other than therapies required by the inclusion criteria of this protocol)
  • Pregnant or breast feeding
  • Uncontrolled intercurrent illness that would limit compliance with study requirements, or disorders associated with significant immunocompromised state
  • Known other previous/current malignancy requiring treatment within ≤ 3 years except for liited disease treated with curative intent
  • Any comorbid condition that confounds the ability to interpret data from the study as judged by the Investigator or Medial Monitor
  • For those enrolled in Adjuvant Treatment with Optune™, patients are excluded if they are < 22 years of age, have an active implanted medical device, a skull defect, bullet fragments in the head, sensitivity to conductive hydrogels, a scalp condition that might interfere with wearing the device, or GBM that is not supratentorial.

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): NCT02903069


Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
United States, California
University of California, Irvine Medical Center Comprehensive Brain Tumor Program Recruiting
Irvine, California, United States, 92697
Contact: Jinah Chung    714-456-8442    jinahec@uci.edu   
Principal Investigator: Daniela Bota, MD, PhD         
University of California, San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92037
Contact: Brian Churas    858-534-7996    bchuras@ucsd.edu   
Principal Investigator: David Piccioni, MD, PhD         
John Wayne Cancer Institute at the Providence Saint John's Health Center Recruiting
Santa Monica, California, United States, 90404
Contact: Najee Boucher    310-582-7460    najee.boucher@providence.org   
Principal Investigator: Santosh Kesari, MD, PhD         
United States, Illinois
Northwestern Brain Tumor Institute at Northwestern University Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Anne Mendelke       anne.mendelke@northwestern.edu   
Contact: Roger Stupp, MD    (855) 695-6284      
United States, North Carolina
Duke University Medical Center, Preston Robert Tisch Brain Tumor Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Sarah Woodring    919-684-2527    sarah.woodring@duke.edu   
Contact: Denise Jaggers    919-613-6803    denise.jaggers@dm.duke.edu   
Principal Investigator: Annick Desjardins, MD         
United States, Pennsylvania
Penn State Health Milton S. Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Scott Murphy    717-531-0003 ext 283114    smurphy6@pennstatehealth.psu.edu   
Principal Investigator: Dawit G Aregawi, MD         
Canada, Ontario
Princess Margaret Hospital, Gerry and Nancy Pencer Brain Tumour Centre Recruiting
Toronto, Ontario, Canada
Contact: Mariya Bakalets    416-946-4603    mariya.bakalets@uhn.ca   
Contact: Elena Chizhov    416-946-4624    elena.chizhov@uhn.ca   
Principal Investigator: Warren Mason, MD         
Switzerland
University Hospital Zurich Brain Tumor Center Recruiting
Zurich, Switzerland, 8091
Contact: Carola Keding    +41 44 255 55 00    carola.keding@usz.ch   
Principal Investigator: Patrick Roth, MD         
Sponsors and Collaborators
Celgene
Triphase
Investigators
Study Director: Ileana Elias, M.D. Celgene Corporation

Additional Information:
Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02903069     History of Changes
Other Study ID Numbers: MRZ-112
First Posted: September 16, 2016    Key Record Dates
Last Update Posted: April 27, 2018
Last Verified: April 2018

Keywords provided by Celgene:
newly diagnosed
malignant glioma
WHO Grade 4
WHO Grade IV
marizomib
MRZ
TMZ
RT
brain cancer
proteasome inhibitor
radiation
temozolomide
temodar
chemotherapy
concurrent
adjuvant
Optune
Novocure
NovoTTF

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
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents