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Multiple MyelomaPhase 2NCT00461045

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

A Phase 2 study testing MRZ 0.5 mg/m^2 in people with Multiple Myeloma, run by Celgene at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Multiple Myeloma
What is being tested?
MRZ 0.5 mg/m^2
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
15 participants
Where
6 sitesUnited States
Study dates
Mar 2007to Oct 2014
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • Measurable disease is defined as one of the following:
  • Serum M-protein ≥0.5 g/dL
  • Urine M-protein ≥200 mg/24 hours
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  • Involved serum free light chain (FLC) level ≥10 mg/dL, provided the serum FLC ratio is abnormal
  • 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
  • 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.
  • 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
  • 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.

Who cannot join

  • 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;
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  • 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.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • University of Michigan

    Ann Arbor, Michigan, 48109

  • University of Maryland

    Baltimore, Maryland, 21201

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02115

  • University of Chicago, School of Medicine

    Chicago, Illinois, 60637

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

About this study

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.

Being tested
MRZ 0.5 mg/m^2
Keywords
multiple myeloma, proteasome inhibitor, relapsed, refractory
Medical subject headings
Multiple Myeloma, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MRZ 0.5 mg/m^2Drug

    Also called Marizomib, NPI-0052

    NPI-0052 0.5 mg/m2 administered IV over 2 hours on Days 1, 4, 8, and 11 in each 21-day cycle

Study groups in NCT00461045
Study groupRoleWhat they receive
MRZ 0.5 mg/m^2ExperimentalTwice-weekly dosing with 2-hour IV infusions on days 1,4,8, and 11 of 3-week cycles
Receives: Drug: MRZ 0.5 mg/m^2

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    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.

    Measured: Through study completion, an average of 6.09 weeks.

Secondary outcomes (6)

  1. Duration of MRZ Treatment

    Duration of treatment is defined as the last dose date minus the first dose date of the dose cohort plus 1 expressed in weeks.

    Measured: Through study completion, an average of 6.09 weeks.

  2. Number of Cycles of Marizomib (MRZ)

    Measured: Through study completion, an average of 6.09 weeks.

  3. Number of Patients Receiving Marizomib (MRZ) in Each Cycle

    A patient was counted in a cycle if the patient received at least one dose of study drug during the cycle.

    Measured: Through study completion, an average of 6.09 weeks.

  4. Number of Patients With Treatment Emergent Adverse Events (TEAEs)

    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.

    Measured: Through study completion, an average of 6.09 weeks.

  5. Number of Treatment Emergent Adverse Events (TEAEs)

    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.

    Measured: Through study completion, an average of 6.09 weeks.

  6. Maximum Observed Blood Drug Concentration (Cmax)

    Measured: Samples collected on Cycle 1 Day 1 and Cycle 1 Day 11.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Apr 2007 (estimated)
  2. Study startMar 2007
  3. Primary completionSep 2014
  4. Study completionOct 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00461045
Sponsor's protocol ID
NPI-0052-101
Status last verified
Nov 2017
First submitted
13 Apr 2007
Last updated
19 Dec 2017
Data monitoring committee
No
Individual data sharing
Yes

Publications

  • 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.

    PubMed 9753033

  • 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.

    PubMed 15217925

  • 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.

    PubMed 15217830

  • 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.

    PubMed 14559800

  • 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.

    PubMed 16286248

  • 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.

    PubMed 10561185

  • 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

  • ClinicalTrials.gov. Phase 3 Study With Carfilzomib and Dexamethasone Versus Velcade and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR). ClinicalTrials.gov Identifier: NCT01568866.

  • 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.

    PubMed 9443633

  • 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.

    PubMed 16855634

  • 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.

    PubMed 15867242

  • 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

  • Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl. 2003 Jan 20;42(3):355-7. doi: 10.1002/anie.200390115. No abstract available.

    PubMed 12548698

  • Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982 Mar;38(1):143-51.

    PubMed 7082756

  • Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L, Dang NH, Samaniego F, Wang M, Broglio K, Samuels B, Gilles F, Sarris AH, Hart S, Trehu E, Schenkein D, Cabanillas F, Rodriguez AM. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2005 Feb 1;23(4):667-75. doi: 10.1200/JCO.2005.03.108. Epub 2004 Dec 21.

    PubMed 15613697

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing MRZ 0.5 mg/m^2 in people with Multiple Myeloma, run by Celgene at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 47 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Sep 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Patients Exhibiting a Given Overall Response as Determined by Investigator (time frame: Through study completion, an average of 6.09 weeks.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00461045, which also lists 34 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2017.

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