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

NCT00461045 | Completed Phase 2 Results

• 1 other identifier: NPI-0052-101
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 6

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.

Conditions

Multiple Myeloma

Keywords

multiple myeloma; proteasome inhibitor; relapsed; refractory

Outcome Measures

Primary Outcomes (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.

  Through study completion, an average of 6.09 weeks.

Secondary Outcomes (6)

• Duration of MRZ Treatment

  Through study completion, an average of 6.09 weeks.

• Number of Cycles of Marizomib (MRZ)

  Through study completion, an average of 6.09 weeks.

• Number of Patients Receiving Marizomib (MRZ) in Each Cycle

  Through study completion, an average of 6.09 weeks.

• Number of Patients With Treatment Emergent Adverse Events (TEAEs)

  Through study completion, an average of 6.09 weeks.

• Number of Treatment Emergent Adverse Events (TEAEs)

  Through study completion, an average of 6.09 weeks.

Study Arms (1)

MRZ 0.5 mg/m^2

EXPERIMENTAL

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

Interventions

MRZ 0.5 mg/m^2 DRUG

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

Also known as: Marizomib, NPI-0052

MRZ 0.5 mg/m^2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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):

You may not qualify if:

• 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.

Sponsors & Collaborators

• Celgene: lead

Study Sites (6)

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

University of Chicago, School of Medicine

Chicago, Illinois, 60637, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (34)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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

  BACKGROUND

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

  BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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

  BACKGROUND

• 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.

  PMID: 12548698 BACKGROUND

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

  PMID: 7082756 BACKGROUND

• 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.

  PMID: 15613697 BACKGROUND

• Hamilton AL, Eder JP, Pavlick AC, Clark JW, Liebes L, Garcia-Carbonero R, Chachoua A, Ryan DP, Soma V, Farrell K, Kinchla N, Boyden J, Yee H, Zeleniuch-Jacquotte A, Wright J, Elliott P, Adams J, Muggia FM. Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle. J Clin Oncol. 2005 Sep 1;23(25):6107-16. doi: 10.1200/JCO.2005.01.136.

  PMID: 16135477 BACKGROUND

• Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001 Aug;8(8):739-58. doi: 10.1016/s1074-5521(01)00056-4.

  PMID: 11514224 BACKGROUND

• Kondagunta GV, Drucker B, Schwartz L, Bacik J, Marion S, Russo P, Mazumdar M, Motzer RJ. Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol. 2004 Sep 15;22(18):3720-5. doi: 10.1200/JCO.2004.10.155.

  PMID: 15365068 BACKGROUND

• KYPROLIS™ (carfilzomib) for Injection Prescribing Information. Onyx Pharmaceuticals, Inc., South San Francisco, CA; 07/2012. http://www.kyprolis.com/Areas/Hcp/content/pdfs/PI.pdf

  BACKGROUND

• Macherla VR, Mitchell SS, Manam RR, Reed KA, Chao TH, Nicholson B, Deyanat-Yazdi G, Mai B, Jensen PR, Fenical WF, Neuteboom ST, Lam KS, Palladino MA, Potts BC. Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor. J Med Chem. 2005 Jun 2;48(11):3684-7. doi: 10.1021/jm048995+.

  PMID: 15916417 BACKGROUND

• Anderson KC, Alsina M, Bensinger W, Biermann JS, Chanan-Khan A, Cohen AD, Devine S, Djulbegovic B, Gasparetto C, Huff CA, Jagasia M, Medeiros BC, Meredith R, Raje N, Schriber J, Singhal S, Somlo G, Stockerl-Goldstein K, Tricot G, Vose JM, Weber D, Yahalom J, Yunus F; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw. 2009 Oct;7(9):908-42. doi: 10.6004/jnccn.2009.0061. No abstract available.

  PMID: 19878637 BACKGROUND

• National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Multiple Myeloma (Version 2.2013). Accessed 29 August 2013

  BACKGROUND

• O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2005 Feb 1;23(4):676-84. doi: 10.1200/JCO.2005.02.050. Epub 2004 Dec 21.

  PMID: 15613699 BACKGROUND

• Palumbo A, Mina R. Management of older adults with multiple myeloma. Blood Rev. 2013 May;27(3):133-42. doi: 10.1016/j.blre.2013.04.001. Epub 2013 Apr 25.

  PMID: 23623929 BACKGROUND

• Penta JS, Rozencweig M, Guarino AM, Muggia FM. Mouse and large-animal toxicology studies of twelve antitumor agents: relevance to starting dose for phase I clinical trials. Cancer Chemother Pharmacol. 1979;3(2):97-101. doi: 10.1007/BF00254979. No abstract available.

  PMID: 116778 BACKGROUND

• Pfistner B, Diehl V, Greb A, Cheson B. International harmonization of trial parameters in malignant lymphoma. Eur J Haematol Suppl. 2005 Jul;(66):53-4. doi: 10.1111/j.1600-0609.2005.00455.x.

  PMID: 16007869 BACKGROUND

• Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J; International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 May 5;117(18):4691-5. doi: 10.1182/blood-2010-10-299487. Epub 2011 Feb 3.

  PMID: 21292775 BACKGROUND

• Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. doi: 10.1056/NEJMoa043445.

  PMID: 15958804 BACKGROUND

• Ruiz S, Krupnik Y, Keating M, Chandra J, Palladino M, McConkey D. The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. Mol Cancer Ther. 2006 Jul;5(7):1836-43. doi: 10.1158/1535-7163.MCT-06-0066.

  PMID: 16891470 BACKGROUND

• Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. doi: 10.1182/blood-2012-05-425934. Epub 2012 Jul 25.

  PMID: 22833546 BACKGROUND

• Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997 Aug 6;89(15):1138-47. doi: 10.1093/jnci/89.15.1138.

  PMID: 9262252 BACKGROUND

• Suzuki E, Jazirehi A, Palladino M, Bonavida B. Chemosensitization of Drug and Rituximab Resistant Daudi B-NHL Clones to Drug-Induced Apoptosis by the Proteasome Inhibitor NPI-0052. 47th Annual Meeting of the American Society for Hematology. Blood. 2005;106: abstract #1521

  BACKGROUND

• Yasui H, Hideshima T, Hamasaki M, Roccaro AM, Shiraishi N, Kumar S, Tassone P, Ishitsuka K, Raje N, Tai YT, Podar K, Chauhan D, Leoni LM, Kanekal S, Elliott G, Munshi NC, Anderson KC. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood. 2005 Jul 15;106(2):706-12. doi: 10.1182/blood-2005-02-0838. Epub 2005 Mar 31.

  PMID: 15802527 BACKGROUND

• Richardson PG, Zimmerman TM, Hofmeister CC, Talpaz M, Chanan-Khan AA, Kaufman JL, Laubach JP, Chauhan D, Jakubowiak AJ, Reich S, Trikha M, Anderson KC. Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1. Blood. 2016 Jun 2;127(22):2693-700. doi: 10.1182/blood-2015-12-686378. Epub 2016 Mar 23.

  PMID: 27009059 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Recurrence

Interventions

marizomib

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Associate Director of Clinical and Regulatory Operations
• Organization: Triphase Accelerator

jennifer.ki@triphaseco.com

858-295-4337

Study Officials

• Steven D Reich, MD

  Triphase Research and Development I Corp

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 13, 2007
• First Posted: April 17, 2007
• Study Start: March 1, 2007
• Primary Completion: September 1, 2014
• Study Completion: October 1, 2014
• Last Updated: December 19, 2017
• Results First Posted: September 13, 2017

Record last verified: 2017-11

Data Sharing

• IPD Sharing: Will share

Locations

US (6)