Carfilzomib Based Chemotherapy Mobilization for Autologous Stem Cell Transplants in Multiple Myeloma

Summary

This phase I study utilizes a 3+3 design with escalating cohorts of Carfilzomib at 20mg/m2, 27mg/m2, 36mg/m2, 45mg/m2, 56mg/m2, and 70mg/m2 to be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone and Granulocyte colony-stimulating factor (G-CSF)

Timeline

Start

2019-10-08

Primary completion

2026-09

Completion

2026-09

Publications

• Background Mark T, Stern J, Furst JR, Jayabalan D, Zafar F, LaRow A, Pearse RN, Harpel J, Shore T, Schuster MW, Leonard JP, Christos PJ, Coleman M, Niesvizky R. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. Biol Blood Marrow Transplant. 2008 Jul;14(7):795-8. doi: 10.1016/j.bbmt.2008.04.008.
• Background Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omede P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. doi: 10.1182/blood-2014-03-563759. Epub 2014 May 22.
• Background Berenson JR, Hilger JD, Yellin O, Dichmann R, Patel-Donnelly D, Boccia RV, Bessudo A, Stampleman L, Gravenor D, Eshaghian S, Nassir Y, Swift RA, Vescio RA. Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy. Leukemia. 2014 Jul;28(7):1529-36. doi: 10.1038/leu.2014.27. Epub 2014 Jan 16.
• 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.
• Background Munshi NC, Tricot G, Barlogie B: Plasma cell neoplasms, in De Vita VT, Hellman S, Rosenberg SA (ed): Cancer : Principles & Practice on Oncology, 6th edition, Philadelphia, PA. Lippincott Williams & Wilkins, 2001, pp 2465-2499
• Background Riedel DA, Pottern LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am. 1992 Apr;6(2):225-47.
• Background Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, Reece D, Chun K, Keith Stewart A. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol. 2004 Apr;125(1):64-8. doi: 10.1111/j.1365-2141.2004.04867.x.
• Background Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Lentzsch S, Munshi N, Niesvizky R, San Miguel J, Ludwig H, Bergsagel L, Blade J, Lonial S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H, Richardson PG, Durie BG, Rajkumar SV; International Myeloma Working Group. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood. 2009 Aug 27;114(9):1729-35. doi: 10.1182/blood-2009-04-205013. Epub 2009 Jun 26.
• Background Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Kumar S, Munshi NC, Dispenzieri A, Kyle R, Merlini G, San Miguel J, Ludwig H, Hajek R, Jagannath S, Blade J, Lonial S, Dimopoulos MA, Einsele H, Barlogie B, Anderson KC, Gertz M, Attal M, Tosi P, Sonneveld P, Boccadoro M, Morgan G, Sezer O, Mateos MV, Cavo M, Joshua D, Turesson I, Chen W, Shimizu K, Powles R, Richardson PG, Niesvizky R, Rajkumar SV, Durie BG; IMWG. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009 Oct;23(10):1904-12. doi: 10.1038/leu.2009.127. Epub 2009 Jun 25.
• Background Giralt S, Vesole DH, Somlo G, Krishnan A, Stadtmauer E, Mccarthy P, Pasquini MC; Blood and Marrow Transplant Clinical Trials Network Multiple Myeloma Working Group. Re: Tandem vs single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst. 2009 Jul 1;101(13):964; author reply 966-7. doi: 10.1093/jnci/djp126. Epub 2009 Jun 17. No abstract available.
• Background Niesvizky R, Siegel D, Michaeli J. Biology and treatment of multiple myeloma. Blood Rev. 1993 Mar;7(1):24-33. doi: 10.1016/0268-960x(93)90021-u.
• Background Mark T, Niesvizky R, Coleman M. Novel agents in myeloma: an exciting saga. Cancer. 2009 Jan 15;115(2):236-42. doi: 10.1002/cncr.24040. No abstract available.
• Background Niesvizky R, Siegel D, Glassman J, Straus D, Fine J, Lyons L, Michaeli J. Impact of early response to sequential high-dose chemotherapy on outcome of patients with advanced myeloma and poor prognostic features. Leuk Lymphoma. 2002 Mar;43(3):607-12. doi: 10.1080/10428190210324.
• Background Niesvizky R, Choy CG, Fine J, Glassman J, Reich L, Straus D, Zhu A, Michaeli J: Impact of initial response on disease progression following tandem peripheral blood stem cell transplants in patients with poor prognosis multiple myeloma. ASH December, 1998. Abstract # 2728.
• Background Mazumder A, Kaufman J, Niesvizky R, Lonial S, Vesole D, Jagannath S. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia. 2008 Jun;22(6):1280-1; author reply 1281-2. doi: 10.1038/sj.leu.2405035. Epub 2007 Nov 22. No abstract available.
• Background Demo SD, Buchholz TJ, Laidig GL, Parlati F, Shenk KD, Smyth MS, et al. Biochemical and cellular characterization of the novel proteasome inhibitor PR-171. Blood 2005;106:455a, Abstract 1588.
• Background Velcade® (bortezomib) [full prescribing information]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2008.
• Background Ivancsits D, Nimmanapali R, Sun M, Shenk K, Demo SD, Bennett MK, et al. The proteasome inhibitor PR-171 inhibits cell growth, induces apoptosis, and overcomes de novo and acquired drug resistance in human multiple myeloma cells. Blood 2006;106:452a.
• Background Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, Demo SD, Bennett MK, van Leeuwen FW, Chanan-Khan AA, Orlowski RZ. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007 Nov 1;110(9):3281-90. doi: 10.1182/blood-2007-01-065888. Epub 2007 Jun 25.
• Background Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27. doi: 10.1111/bjh.13296. Epub 2015 Feb 13.
• Background Herve Avet-Loiseau eta al., Evaluation of Minimal Residual Disease (MRD) By Next Generation Sequencing (NGS) Is Highly Predictive of Progression Free Survival in the IFM/DFCI 2009 Trial. ASH annual meeting abstracts. Blood 2015 126:191
• Background Martinez-Lopez J, Lahuerta JJ, Pepin F, Gonzalez M, Barrio S, Ayala R, Puig N, Montalban MA, Paiva B, Weng L, Jimenez C, Sopena M, Moorhead M, Cedena T, Rapado I, Mateos MV, Rosinol L, Oriol A, Blanchard MJ, Martinez R, Blade J, San Miguel J, Faham M, Garcia-Sanz R. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014 May 15;123(20):3073-9. doi: 10.1182/blood-2014-01-550020. Epub 2014 Mar 19.
• Background Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, Dalva K, Fuhler G, Gratama J, Hose D, Kovarova L, Lioznov M, Mateo G, Morilla R, Mylin AK, Omede P, Pellat-Deceunynck C, Perez Andres M, Petrucci M, Ruggeri M, Rymkiewicz G, Schmitz A, Schreder M, Seynaeve C, Spacek M, de Tute RM, Van Valckenborgh E, Weston-Bell N, Owen RG, San Miguel JF, Sonneveld P, Johnsen HE; European Myeloma Network. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica. 2008 Mar;93(3):431-8. doi: 10.3324/haematol.11080. Epub 2008 Feb 11.
• Background Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E, Pui CH, Campana D. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2012 Dec 20;120(26):5173-80. doi: 10.1182/blood-2012-07-444042. Epub 2012 Oct 16.

Drugs

Indications