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NCT00461045 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE2
Status at capture
COMPLETED
Registry last update
2017-12-19

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Patients Exhibiting a Given Overall Response as Determined by Investigator

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outcome · POSTED

Duration of MRZ Treatment

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outcome · POSTED

Number of Cycles of Marizomib (MRZ)

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outcome · POSTED

Number of Patients Receiving Marizomib (MRZ) in Each Cycle

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outcome · POSTED

Number of Patients With Treatment Emergent Adverse Events (TEAEs)

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outcome · POSTED

Number of Treatment Emergent Adverse Events (TEAEs)

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outcome · POSTED

Maximum Observed Blood Drug Concentration (Cmax)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
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.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Twice-weekly dosing with 2-hour IV infusions on days 1,4,8, and 11 of 3-week cycles
    intervention Names
    1. Drug: MRZ 0.5 mg/m^2
    label
    MRZ 0.5 mg/m^2
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. MRZ 0.5 mg/m^2
    description
    NPI-0052 0.5 mg/m2 administered IV over 2 hours on Days 1, 4, 8, and 11 in each 21-day cycle
    name
    MRZ 0.5 mg/m^2
    other Names
    1. Marizomib
    2. NPI-0052
    type
    DRUG
Study design
allocation
NA
intervention Model
SINGLE_GROUP
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
15
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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.
    measure
    Number of Patients Exhibiting a Given Overall Response as Determined by Investigator
    time Frame
    Through study completion, an average of 6.09 weeks.
secondary Outcomes
  1. description
    Duration of treatment is defined as the last dose date minus the first dose date of the dose cohort plus 1 expressed in weeks.
    measure
    Duration of MRZ Treatment
    time Frame
    Through study completion, an average of 6.09 weeks.
  2. measure
    Number of Cycles of Marizomib (MRZ)
    time Frame
    Through study completion, an average of 6.09 weeks.
  3. description
    A patient was counted in a cycle if the patient received at least one dose of study drug during the cycle.
    measure
    Number of Patients Receiving Marizomib (MRZ) in Each Cycle
    time Frame
    Through study completion, an average of 6.09 weeks.
  4. description
    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.
    measure
    Number of Patients With Treatment Emergent Adverse Events (TEAEs)
    time Frame
    Through study completion, an average of 6.09 weeks.
  5. description
    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.
    measure
    Number of Treatment Emergent Adverse Events (TEAEs)
    time Frame
    Through study completion, an average of 6.09 weeks.
  6. measure
    Maximum Observed Blood Drug Concentration (Cmax)
    time Frame
    Samples collected on Cycle 1 Day 1 and Cycle 1 Day 11.
Full study description
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.
Source references
references
  1. citation
    Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. doi: 10.1046/j.1365-2141.1998.00930.x. No abstract available.
    pmid
    9753033
    type
    BACKGROUND
  2. citation
    Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, Pazdur R. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3954-64. doi: 10.1158/1078-0432.CCR-03-0781. No abstract available.
    pmid
    15217925
    type
    BACKGROUND
  3. citation
    Chauhan D, Li G, Podar K, Hideshima T, Mitsiades C, Schlossman R, Munshi N, Richardson P, Cotter FE, Anderson KC. Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells. Blood. 2004 Oct 15;104(8):2458-66. doi: 10.1182/blood-2004-02-0547. Epub 2004 Jun 24.
    pmid
    15217830
    type
    BACKGROUND
  4. citation
    Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, Anderson KC. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003 Oct 1;63(19):6174-7.
    pmid
    14559800
    type
    BACKGROUND
  5. citation
    Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao TH, Neuteboom ST, Richardson P, Palladino MA, Anderson KC. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell. 2005 Nov;8(5):407-19. doi: 10.1016/j.ccr.2005.10.013.
    pmid
    16286248
    type
    BACKGROUND
  6. citation
    Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999 Apr;17(4):1244. doi: 10.1200/JCO.1999.17.4.1244.
    pmid
    10561185
    type
    BACKGROUND
  7. citation
    Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant Lymphomas. From the Members of the International Harmonization Project (IHP) of the Competence Network Malignant Lymphoma, 47th Annual Meeting of the American Society of Hematology. Blood. 2005 Nov;106: abstract #18
    type
    BACKGROUND
  8. citation
    ClinicalTrials.gov. Phase 3 Study With Carfilzomib and Dexamethasone Versus Velcade and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR). ClinicalTrials.gov Identifier: NCT01568866.
    type
    BACKGROUND
  9. citation
    DeGeorge JJ, Ahn CH, Andrews PA, Brower ME, Giorgio DW, Goheer MA, Lee-Ham DY, McGuinn WD, Schmidt W, Sun CJ, Tripathi SC. Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother Pharmacol. 1998;41(3):173-85. doi: 10.1007/s002800050726.
    pmid
    9443633
    type
    BACKGROUND
  10. citation
    Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. doi: 10.1038/sj.leu.2404284. Epub 2006 Jul 20.
    pmid
    16855634
    type
    BACKGROUND
  11. citation
    Dy GK, Thomas JP, Wilding G, Bruzek L, Mandrekar S, Erlichman C, Alberti D, Binger K, Pitot HC, Alberts SR, Hanson LJ, Marnocha R, Tutsch K, Kaufmann SH, Adjei AA. A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer. Clin Cancer Res. 2005 May 1;11(9):3410-6. doi: 10.1158/1078-0432.CCR-04-2068.
    pmid
    15867242
    type
    BACKGROUND
  12. citation
    12. Facon T, Dimopoulos M, Dispenzieri A, et al. Initial Phase 3 Results Of The First (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) In Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible For Stem Cell Transplantation (SCT). 2013; ASH Annual Meeting Plenary Session, Sunday, December 8, 2013: 2:55 PM
    type
    BACKGROUND
Source notices and limitations
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