A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

[1]  H. van de Velde,et al.  Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma , 2012, Haematologica.

[2]  M. Kaminski,et al.  A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. , 2012, Blood.

[3]  S. Trudel,et al.  A Phase I Single-Agent Study of Twice-Weekly Consecutive-Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma or Lymphoma , 2012, Clinical Cancer Research.

[4]  P. L. Bergsagel,et al.  A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma. , 2012 .

[5]  H. Goldschmidt,et al.  Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study , 2012, Leukemia.

[6]  I. Yakoub-Agha,et al.  Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents , 2012, Leukemia.

[7]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[8]  D. Siegel,et al.  A Phase 1b/2 Study of Prolonged Infusion Carfilzomib in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma: Updated Efficacy and Tolerability From the Completed 20/56mg/m2 Expansion Cohort of PX-171-007 , 2011 .

[9]  M. Buyse,et al.  Multivariate Modelling Reveals Evidence of a Dose-Response Relationship in Phase 2 Studies of Single-Agent Carfilzomib , 2011 .

[10]  S. Jagannath,et al.  Integrated Safety From Phase 2 Studies of Monotherapy Carfilzomib in Patients with Relapsed and Refractory Multiple Myeloma (MM): An Updated Analysis , 2011 .

[11]  M. Kersten,et al.  Carfilzomib Combined with Thalidomide and Dexamethasone (CARTHA-DEX) As Induction Treatment Prior to High-Dose Melphalan (HDM) in Newly Diagnosed Patients With Multiple Myeloma (MM). A Trial of the European Myeloma Network EMN , 2011 .

[12]  H. Goldschmidt,et al.  Treatment of relapsed and refractory multiple myeloma in the era of novel agents. , 2011, Cancer treatment reviews.

[13]  J. Laubach,et al.  Future directions of next-generation novel therapies, combination approaches, and the development of personalized medicine in myeloma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D. Esseltine,et al.  Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. , 2011, The Lancet. Oncology.

[15]  T. Muchamuel,et al.  Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: a Link to Clinical Adverse Events , 2011, Clinical Cancer Research.

[16]  A. Palumbo,et al.  Outcome and toxicity in the modern era of new drugs for multiple myeloma: a reappraisal for comparison with future investigational trials. , 2010, Clinical lymphoma, myeloma & leukemia.

[17]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[18]  X. Navarro,et al.  Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice , 2010, Experimental Neurology.

[19]  F. Gay,et al.  Management of disease- and treatment-related complications in patients with multiple myeloma , 2010, Medical oncology.

[20]  N. Munshi,et al.  Tailoring treatment for multiple myeloma patients with relapsed and refractory disease. , 2010, Oncology.

[21]  D. Weber,et al.  Advances in treatment for relapses and refractory multiple myeloma , 2010, Medical oncology.

[22]  A. Jemal,et al.  Annual report to the nation on the status of cancer, 1975‐2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates , 2010, Cancer.

[23]  I. Yakoub-Agha,et al.  Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations , 2010, Haematologica.

[24]  M. Lenardo,et al.  The nuclear signaling of NF-κB: current knowledge, new insights, and future perspectives , 2010, Cell Research.

[25]  S. Jagannath,et al.  Final results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  R. Orlowski,et al.  A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies , 2009, Clinical Cancer Research.

[27]  J. Vose,et al.  NCCN clinical practice guidelines in oncology: multiple myeloma. , 2009, Journal of the National Comprehensive Cancer Network : JNCCN.

[28]  Tilman Grune,et al.  The proteasomal system. , 2009, Molecular aspects of medicine.

[29]  D. Esseltine,et al.  Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose‐modification guideline , 2009, British journal of haematology.

[30]  R A Kyle,et al.  Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma , 2009, Leukemia.

[31]  M. Aujay,et al.  The Selective Proteasome Inhibitor Carfilzomib Is Well Tolerated in Experimental Animals with Dose Intensive Administration , 2008 .

[32]  T. Fojo,et al.  Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: A possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition , 2008, Cell cycle.

[33]  P. Richardson,et al.  Clinically relevant end points and new drug approvals for myeloma , 2008, Leukemia.

[34]  S. Demo,et al.  Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. , 2007, Cancer research.

[35]  S. Demo,et al.  Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. , 2005, Blood.

[36]  B. Barlogie,et al.  International uniform response criteria for multiple myeloma , 2006, Leukemia.

[37]  R. Pazdur,et al.  United States Food and Drug Administration Approval Summary: Bortezomib for the Treatment of Progressive Multiple Myeloma after One Prior Therapy , 2006, Clinical Cancer Research.

[38]  D. Esseltine,et al.  Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. , 2005, Blood.

[39]  Hartmut Goldschmidt,et al.  Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. , 2005, The New England journal of medicine.

[40]  Aaron Ciechanover,et al.  Proteolysis: from the lysosome to ubiquitin and the proteasome , 2005, Nature Reviews Molecular Cell Biology.

[41]  Hui-Chen Hsu,et al.  Regulation of apoptosis proteins in cancer cells by ubiquitin , 2004, Oncogene.

[42]  Richard Pazdur,et al.  Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. , 2003, The oncologist.

[43]  D. Fishman,et al.  Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—Neurotoxicity (Fact/GOG‐Ntx) questionnaire for patients receiving systemic chemotherapy , 2003, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[44]  Bart Barlogie,et al.  A phase 2 study of bortezomib in relapsed, refractory myeloma. , 2003, The New England journal of medicine.

[45]  S. Jagannath,et al.  CRITERIA FOR EVALUATING DISEASE RESPONSE AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA TREATED BY HIGH‐DOSE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION , 1998, British journal of haematology.

[46]  M. Pagano,et al.  The ubiquitin-mediated proteolytic pathway as a therapeutic area , 1997, Journal of Molecular Medicine.

[47]  M Schemper,et al.  A note on quantifying follow-up in studies of failure time. , 1996, Controlled clinical trials.

[48]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[49]  R Simon,et al.  A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. , 1984, Statistics in medicine.

[50]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .