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Phase 2 Clinical Trial of NPI-0052 in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT00461045
Recruitment Status : Completed
First Posted : April 17, 2007
Results First Posted : September 13, 2017
Last Update Posted : December 19, 2017
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE April 13, 2007
First Posted Date  ICMJE April 17, 2007
Results First Submitted Date  ICMJE March 29, 2017
Results First Posted Date  ICMJE September 13, 2017
Last Update Posted Date December 19, 2017
Study Start Date  ICMJE March 2007
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 14, 2017)
Number of Patients Exhibiting a Given Overall Response as Determined by Investigator [ Time Frame: Through study completion, an average of 6.09 weeks. ]
Disease response and progression were determined by the investigator using the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). Overall response rate includes patients with a best response of PR of better. Stringent complete response (CR) includes immunophenotypic CR and molecular CR in addition to stringent CR.
Original Primary Outcome Measures  ICMJE
 (submitted: April 13, 2007)
Maximum Tolerated Dose (MTD)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 14, 2017)
  • Duration of MRZ Treatment [ Time Frame: Through study completion, an average of 6.09 weeks. ]
    Duration of treatment is defined as the last dose date minus the first dose date of the dose cohort plus 1 expressed in weeks.
  • Number of Cycles of Marizomib (MRZ) [ Time Frame: Through study completion, an average of 6.09 weeks. ]
  • Number of Patients Receiving Marizomib (MRZ) in Each Cycle [ Time Frame: Through study completion, an average of 6.09 weeks. ]
    A patient was counted in a cycle if the patient received at least one dose of study drug during the cycle.
  • Number of Patients With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Through study completion, an average of 6.09 weeks. ]
    Adverse events were graded using NCI-CTCAE (version 4.3). TEAEs are defined as any adverse event with an onset date between the date of first dose and 30 days after the date of last dose of any study drug. Treatment-related adverse events are adverse events considered related to at least one study drug by the investigator (NPI-002, dexamethasone), including those with unknown relationship.
  • Number of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Through study completion, an average of 6.09 weeks. ]
    Adverse events were graded using NCI-CTCAE (version 4.3). TEAEs are defined as any adverse event with an onset date between the date of first dose and 30 days after the date of last dose of any study drug. Treatment-related adverse events are adverse events considered related to at least one study drug by the investigator (NPI-002, dexamethasone), including those with unknown relationship.
  • Maximum Observed Blood Drug Concentration (Cmax) [ Time Frame: Samples collected on Cycle 1 Day 1 and Cycle 1 Day 11. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 13, 2007)
  • safety and toxicity profile
  • pharmacokinetics
  • biological activity
  • Recommended Phase 2 Dose
  • Response (EBMT criteria)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 2 Clinical Trial of NPI-0052 in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma
Official Title  ICMJE Phase 2 Clinical Trial of NPI-0052 in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma
Brief Summary This is a Phase 2, open-label, multicenter study examining the safety, pharmacokinetics and pharmacodynamics, and best overall response to escalating doses of the proteasome inhibitor NPI-0052 (also known as marizomib) in patients with relapsed or relapsed/refractory multiple myeloma. NPI-0052 is a novel, second generation proteasome inhibitor that prevents the breakdown of proteins involved in signal transduction which blocks growth and survival in cancer cells. The study is a Phase 2 study and is a 2-stage efficacy design in a selected subgroup of patients (Arm C) treated with the recommended phase 2 dose of NPI-0052, as determined in a previously completed Phase 1 study. The study is to evaluate the safety and any preliminary evidence of efficacy of NPI-0052 in multiple myeloma patients who have previously received carfilzomib (PR-171, Kyprolis™) and subsequently had disease progression.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE Drug: MRZ 0.5 mg/m^2
NPI-0052 0.5 mg/m2 administered IV over 2 hours on Days 1, 4, 8, and 11 in each 21-day cycle
Other Names:
  • Marizomib
  • NPI-0052
Study Arms  ICMJE Experimental: MRZ 0.5 mg/m^2
Twice-weekly dosing with 2-hour IV infusions on days 1,4,8, and 11 of 3-week cycles
Intervention: Drug: MRZ 0.5 mg/m^2
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 14, 2017)
15
Original Enrollment  ICMJE
 (submitted: April 13, 2007)
35
Actual Study Completion Date  ICMJE October 2014
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria: Prior to Amendment 13:

  • Age 18 years.
  • Karnofsky Performance Status (KPS) score 70%.
  • All patients must have histologic evidence of multiple myeloma. Evidence of relapsed or relapsed/refractory disease for which no other approved treatment is available and clinically indicated. In addition, patients may have undergone prior bone marrow transplantation. For patients treated at the Recommended Phase 2 Dose patients are required to have measurable relapsed or relapsed/refractory disease. Disease must be assessed within 28 days prior to treatment initiation.

    1. Measurable disease is defined as one of the following:

      • Serum M-protein ≥0.5 g/dL
      • Urine M-protein ≥200 mg/24 hours
      • Involved serum free light chain (FLC) level ≥10 mg/dL, provided the serum FLC ratio is abnormal
    2. Relapsed and Refractory are defined as:

      • Must have received at least 2 prior treatment regimens.
      • Must have received prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of bortezomib (either in separate regimens or within the same regimen).
      • Must have received a cytotoxic chemotherapy agent (eg, alkylating agent).
      • Relapsed Disease: Must have progressive disease after having achieved at least stable disease for at least one cycle of treatment during at least one prior regimen.
      • Refractory Disease: Must have documented evidence of progressive disease during or within 60 days (measured from the end of the last cycle) of completing the most recently received anti-myeloma drug regimen prior to study entry
  • All AEs resulting from prior chemotherapy, surgery, or radiotherapy must have resolved to NCI-CTCAE Grade 1 (except for hematologic parameters outlined below).
  • The following laboratory results, within 7 days prior to NPI-0052 administration (transfusions and/or growth factor support may be used with discretion by the Investigator during Screening):

    • Hemoglobin 8 g/dL
    • Absolute neutrophil count 0.5 × 109/L
    • Platelet count 30 × 109/L
    • Serum bilirubin 1.5 × ULN
    • AST 2.5 × ULN
    • Serum creatinine 1.5 × ULN
    • Creatinine clearance ≥40 mL/min
  • Signed informed consent.
  • Must have previously received at least 2 cycles of carfilzomib (as a single agent or in combination with other agents) and subsequently had disease progression during or within 60 days of carfilzomib therapy. Carfilzomib does not have to be the most recent therapy that the patient has received, but patients must have documented disease progression during or within 60 days of their last anti-myeloma therapy

Inclusion Criteria Amendment 13:

  • Age 18 years.
  • Karnofsky Performance Status score 70%.
  • All patients must have histologic evidence of multiple myeloma and evidence of relapsed or relapsed/refractory disease as defined below Patients are required to have measurable relapsed or relapsed/refractory disease. Disease must be assessed within 28 days prior to treatment initiation.

    1. Measurable disease defined as one of the following:

      • Serum M-protein ≥0.5 g/dL
      • Urine M-protein ≥200 mg/24 hours
      • Involved serum free light chain (FLC) level ≥10 mg/dL provided the serum FLC ratio is abnormal
    2. Relapsed and Refractory are defined as:

      • Must have received at least 2 prior treatment regimens.
      • Must have received prior treatment with at least 2 cycles of an immunomodulator (lenalidomide or pomalidomide or thalidomide).
      • Must have previously received at least 2 cycles of carfilzomib (as a single agent or in combination with other agents) and subsequently had disease progression during or within 60 days of carfilzomib therapy. Carfilzomib does not have to be the most recent therapy that the patient has received, but patients must have documented disease progression during or within 60 days of their last anti-myeloma therapy. Patients may also have received bortezomib.

In addition, patients may have undergone prior cytotoxic chemotherapy, bone marrow transplantation and previously participated in other clinical trials.

  • Relapsed Disease: Must have progressive disease after having achieved at least stable disease for at least one cycle of treatment during at least one prior regimen.
  • Refractory Disease: Must have documented evidence of progressive disease during or within 60 days (measured from the end of the last cycle) of completing the most recently received anti-myeloma drug regimen prior to study entry.

    • All Adverse Events resulting from prior chemotherapy, surgery, or radiotherapy, must have resolved to CTCAE Grade 1 (except for hematologic parameters outlined below).
    • The following laboratory results, within 7 days of NPI-0052 administration (transfusions and/or growth factor support may be used with discretion by the Investigator during the screening period):
  • Hemoglobin 8 g/dL
  • Absolute neutrophil count 0.5 x 109/L
  • Platelet count 30 x 109/L
  • Serum bilirubin 1.5 x ULN
  • AST 2.5 x ULN
  • Serum creatinine 1.5 x ULN
  • Creatinine clearance ≥40 mL/min -Signed informed consent.

Exclusion Criteria:

  • Administration of chemotherapy, biological, immunotherapy, or investigational agent (therapeutic or diagnostic) within 14 days prior to receipt of study medication (this washout period can be reduced to 7 days for biologically targeted therapies (eg, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, and dexamethasone or equivalent), provided the patient has recovered from the toxicity from these regimens per Inclusion Criterion #4). Patients must be 6 weeks from last dose of nitrosourea and 12 weeks from BMT. Patients must be 2 weeks from last dose of radiation.
  • Patients with Grade >1 proteinuria (1 g/24 hour excluding M proteins = urine paraprotein subtracted from total urine protein), untreated urinary tract infection, as well as any pre existing kidney disease (acute or chronic) that in the Investigator's assessment would impose excessive risk to the patient.
  • Patients with evidence of mucosal or internal bleeding and/or platelet refractory (ie, unable to maintain platelet count 30 × 109/L).
  • Significant cardiac disease defined as:

    • Patients with congenital long QT syndrome;
    • Congestive heart failure of Class III or IV of the NYHA classification;
    • History of myocardial infarction or ischemia within 12 months of study enrollment.
  • Abnormal left ventricular ejection fraction (LVEF) (< lower limit of normal as defined by the study site for a patient of that age) by echocardiogram (ECHO) or multiple-gated angiography (MUGA).
  • Patients with a prior hypersensitivity reaction of CTCAE Grade >3 to therapy containing propylene glycol or ethanol.
  • Pregnant or breast-feeding women. Female patients must be postmenopausal or surgically sterile, or they must agree to use acceptable methods of birth control (ie, a hormonal contraceptive with barrier method, intra-uterine device, diaphragm with spermicidal or condom with spermicide, or abstinence) for the duration of the study and for one month following study completion. Female patients with childbearing potential must have a negative serum pregnancy test within the 7 days before the first NPI-0052 administration. Male patients must be surgically sterile or agree to use an acceptable method of contraception.
  • Active uncontrolled bacterial or fungal infection requiring systemic therapy; infection requiring parenteral antibiotics.
  • Known to be HIV positive or positive and active for hepatitis A, B, or C.
  • Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient. Examples of such conditions include infection requiring parenteral or oral anti-infective treatment or any altered mental status or psychiatric condition that would interfere with an understanding of the informed consent.
  • Unwilling or unable to comply with procedures required in this protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00461045
Other Study ID Numbers  ICMJE NPI-0052-101
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Steven D Reich, MD Triphase Research and Development I Corp
PRS Account Celgene
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP