Clinical Trials /

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

NCT02330562

Description:

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.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Stage 1: Marizomib + Bevacizumab in WHO Gr IV GBM; Stage 2: Marizomib Alone
  • 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 Trial of Single Agent Marizomib

Clinical Trial IDs

  • ORG STUDY ID: MRZ-108
  • NCT ID: NCT02330562

Conditions

  • Malignant Glioma
  • Glioblastoma

Interventions

DrugSynonymsArms
MRZMarizomib, NPI-0052Phase 1: MRZ + BEV; Phase 2: MRZ alone
BEVAvastin, BevacizumabPhase 1: MRZ + BEV; Phase 2: MRZ alone

Purpose

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.

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.

      Phase 1 of this trial has been completed with the Recommended Phase 2 Dose (RP2D)
      established at 0.8 mg/m2. Phase 2 of this trial is enrolling at the MRZ RP2D determined in
      Phase 1 to assess single-agent activity and safety.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: MRZ + BEV; Phase 2: MRZ aloneExperimentalPhase 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. Phase 2: MRZ 10 minute IV infusion administered on Days 1, 8, and 15 of each 28-day cycle.
  • MRZ
  • BEV

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Maximum Tolerated Dose (MTD) / Maximum Administered Dose (MAD)
Time Frame:First 28 days (Cycle 1)
Safety Issue:
Description:To determine the MTD/MAD of MRZ + BEV

Secondary Outcome Measures

Measure: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.
Safety Issue:
Description:Assess tumor response by RANO criteria, progression-free survival, and overall survival
Measure:Phase 1 and Phase 2: Assess safety and tolerance
Time Frame:Up to 28 days after last dose of study drug
Safety Issue:
Description:Evaluate adverse events, serious adverse events, deaths, laboratory tests, and vital signs
Measure:Phase 1: MRZ pharmacokinetics
Time Frame:Days 1 and 15 of Cycle 1.
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description:Assess the whole blood proteasome pharmacodynamic (PD) activity of MRZ + BEV in Phase 1 and for MRZ alone in Phase 2
Measure:Phase 1 and Phase 2: Neurological Coordination Assessment
Time Frame:Up to 28 days after last dose of study drug
Safety Issue:
Description:Evaluation using the Scale for the Assessment and Rating for Ataxia (SARA)
Measure:Phase 1 and Phase 2: Quality of Life Assessment
Time Frame:Up to 28 days after last dose of study drug
Safety Issue:
Description:Evaluation using the Functional Assessment of Cancer Therapy (FACT) questionnaire

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Triphase Research and Development I Corporation

Trial Keywords

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

Last Updated

January 4, 2017