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

November 20, 2017 updated by: Celgene
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago, School of Medicine
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Dana Farber Cancer Institute
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
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:
  • NPI-0052
  • Marizomib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Through study completion, an average of 6.09 weeks.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Through study completion, an average of 6.09 weeks.
Number of Cycles of Marizomib (MRZ)
Time Frame: Through study completion, an average of 6.09 weeks.
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.
Through study completion, an average of 6.09 weeks.
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.
Through study completion, an average of 6.09 weeks.
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.
Through study completion, an average of 6.09 weeks.
Maximum Observed Blood Drug Concentration (Cmax)
Time Frame: Samples collected on Cycle 1 Day 1 and Cycle 1 Day 11.
Samples collected on Cycle 1 Day 1 and Cycle 1 Day 11.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Celgene

Investigators

  • Study Director: Steven D Reich, MD, Triphase Research and Development I Corp

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2007

Primary Completion (Actual)

September 1, 2014

Study Completion (Actual)

October 1, 2014

Study Registration Dates

First Submitted

April 13, 2007

First Submitted That Met QC Criteria

April 13, 2007

First Posted (Estimate)

April 17, 2007

Study Record Updates

Last Update Posted (Actual)

December 19, 2017

Last Update Submitted That Met QC Criteria

November 20, 2017

Last Verified

November 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NPI-0052-101

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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