Phase 1/2 Clinical Trial of NPI-0052 in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

This study is currently recruiting participants.
Verified April 2014 by Triphase Research and Development I Corporation
Sponsor:
Information provided by (Responsible Party):
Triphase Research and Development I Corporation
ClinicalTrials.gov Identifier:
NCT00461045
First received: April 13, 2007
Last updated: April 7, 2014
Last verified: April 2014
  Purpose

This is a Phase 1/2, open-label, multicenter study examining the safety, pharmacokinetics and pharmacodynamics, and best overall response to escalating doses of the proteasome inhibitor NPI-0052 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 divided into 2 parts: Part 1 is Phase 1 and explores 2 different schedules of NPI-0052 to determine the maximum tolerated dose and/or recommended phase 2 dose (Schedules A [once weekly dosing] and B [twice-weekly dosing]). Part 2 is Phase 2 and is a 2-stage efficacy design in a selected subgroup of patients treated with Schedule B at the recommended phase 2 dose, as determined in Part 1. Amendment 13 to the protocol is currently recruiting 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. Patients in Part 2 will be followed for survival for up to 5 years from date of first dose.


Condition Intervention Phase
Multiple Myeloma
Drug: NPI-0052
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1/2 Clinical Trial of NPI-0052 in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Triphase Research and Development I Corporation:

Primary Outcome Measures:
  • Part 1: Maximum Tolerated Dose (MTD) and/or recommended phase 2 dose of NPI-0052 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Part 2: Best overall response to recommended phase 2 dose established in Part 1 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adverse events [ Time Frame: Up to 7 years ] [ Designated as safety issue: Yes ]
    Number of patients who experience adverse events


Estimated Enrollment: 100
Study Start Date: March 2007
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NPI-0052
NPI-0052
Drug: NPI-0052
I.V. injection on Days 1, 4, 8 and 11 in 21 day cycles

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Part 1 and Part 2 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.

For patients in Part 2 only:

-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 Part 2 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: Part 1 and Part 2

  • 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.
  • For patients in Part 2 only: 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00461045

Contacts
Contact: Robert Corringham, MD 858-242-1542 bob.corringham@triphase.com

Locations
United States, Illinois
University of Chicago, School of Medicine Recruiting
Chicago, Illinois, United States, 60637
Contact: Kathryn McDonnell    773-702-1835    kmcdonnell@medicine.bsd.uchicago.edu   
Principal Investigator: Todd Zimmerman, M.D.         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Deborah Doss, RN       deborah_doss@dfci.harvard.edu   
Principal Investigator: Paul Richardson, M.D.         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Sabrina Hargrove    734-615-2357    sgomes@med.umich.edu   
Contact: Moshe Talpaz, MD       mtalpaz@med.umich.edu   
Sub-Investigator: Moshe Talpaz, MD         
Principal Investigator: Craig Cole, MD         
United States, Missouri
Washington University School of Medicine Recruiting
St Louis, Missouri, United States, 63110
Contact: Phil Powell    314-747-2740      
Principal Investigator: Ravi Vij, MD         
Sponsors and Collaborators
Triphase Research and Development I Corporation
Investigators
Study Director: Robert Corringham Triphase Research and Development I Corp, Chief Medical Officer
  More Information

Publications:

Responsible Party: Triphase Research and Development I Corporation
ClinicalTrials.gov Identifier: NCT00461045     History of Changes
Other Study ID Numbers: NPI-0052-101
Study First Received: April 13, 2007
Last Updated: April 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Triphase Research and Development I Corporation:
multiple myeloma
proteasome inhibitor
relapsed
refractory

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on April 17, 2014