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Robert G Hawley - One of the best experts on this subject based on the ideXlab platform.

  • identification of an abcb1 p glycoprotein positive Carfilzomib resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye cdy1
    American Journal of Hematology, 2013
    Co-Authors: Teresa S Hawley, Wenjing Yang, Yoshiyuki Wakabayashi, Louis Depalma, Youngtae Chang, Weiqun Peng, Robert G Hawley
    Abstract:

    Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor Carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to Carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to Carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with Carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur. Am. J. Hematol. 88:265–272, 2013. © 2013 Wiley Periodicals, Inc.

  • identification of an abcb1 p glycoprotein positive Carfilzomib resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye cdy1
    American Journal of Hematology, 2013
    Co-Authors: Teresa S Hawley, Wenjing Yang, Yoshiyuki Wakabayashi, Louis Depalma, Youngtae Chang, Weiqun Peng, Irene Riz, Jun Zhu, Robert G Hawley
    Abstract:

    Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor Carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to Carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to Carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with Carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur.

Meletios A Dimopoulos - One of the best experts on this subject based on the ideXlab platform.

  • Carfilzomib dexamethasone and daratumumab versus Carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma candor results from a randomised multicentre open label phase 3 study
    The Lancet, 2020
    Co-Authors: Meletios A Dimopoulos, Ola Landgren, Xavier Leleu, Katja Weisel, Mariavictoria Mateos, Hang Quach, David Siegel, Hui Yang, Zandra Klippel, Anita Zahltenkumeli
    Abstract:

    Summary Background Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of Carfilzomib, dexamethasone, and daratumumab versus Carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to Carfilzomib, dexamethasone, and daratumumab (KdD) or Carfilzomib and dexamethasone (Kd). All patients received twice per week Carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. Findings Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46–0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). Interpretation KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit–risk profile. Funding Amgen.

  • isatuximab plus Carfilzomib dexamethasone versus Carfilzomib dexamethasone in patients with relapsed refractory multiple myeloma ikema phase iii study design
    Future Oncology, 2020
    Co-Authors: Philippe Moreau, Kwee Yong, Meletios A Dimopoulos, Joseph Mikhael, Marielaure Risse, Gaelle Asset, Thomas Martin
    Abstract:

    Although the treatment of relapsed/refractory multiple myeloma has improved dramatically over the past decade, the disease remains incurable; therefore, additional therapies are needed. Novel combination therapies incorporating monoclonal antibodies have shown significant promise. Here we describe the design of a Phase III study (NCT03275285, IKEMA), which is evaluating isatuximab plus Carfilzomib and low-dose dexamethasone, versus Carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. The primary end point is progression-free survival. Responses are being determined by an independent review committee using 2016 International Myeloma Working Group criteria, and safety will be assessed throughout. The first patient was recruited in November 2017, and the last patient was recruited in March 2019; 302 patients have been randomized, and the study is ongoing. Clinical trial registration: NCT03275285.

  • once weekly versus twice weekly Carfilzomib dosing in patients with relapsed and refractory multiple myeloma a r r o w interim analysis results of a randomised phase 3 study
    Lancet Oncology, 2018
    Co-Authors: Philippe Moreau, Meletios A Dimopoulos, James R Berenson, Katja Weisel, Mariavictoria Mateos, Antonio Lazzaro, Kevin W Song, Mei Huang, Anita Zahltenkumeli, Keith A Stewart
    Abstract:

    Summary Background Twice a week Carfilzomib at 27 mg/m 2 is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly Carfilzomib dosing, established the maximum tolerated dose at 70 mg/m 2 in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly Carfilzomib or twice weekly Carfilzomib. Methods In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1:1) to receive Carfilzomib once a week (70 mg/m 2 ) or twice a week (27 mg/m 2 ). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received Carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m 2 day 1 [cycle 1]; 70 mg/m 2 thereafter). The twice weekly group received Carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m 2 days 1 and 2 during cycle 1; 27 mg/m 2 thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1–9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02412878, and is no longer enrolling patients. Findings Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly Carfilzomib; 238 to receive twice weekly Carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6–13·0] vs 7·6 months [5·8–9·2]; hazard ratio [HR] 0·69, 95% CI 0·54–0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly Carfilzomib vs twice weekly Carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff. Interpretation Once weekly Carfilzomib at 70 mg/m 2 significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly Carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma. Funding Amgen, Inc.

  • Carfilzomib or bortezomib in relapsed or refractory multiple myeloma endeavor an interim overall survival analysis of an open label randomised phase 3 trial
    Lancet Oncology, 2017
    Co-Authors: Meletios A Dimopoulos, Albert Oriol, Ruben Niesvizky, Heinz Ludwig, Robert Z Orlowski, Hartmut Goldschmidt, Douglas E Joshua, Wee Joo Chng, Thierry Facon
    Abstract:

    Summary Background The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with Carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups. Methods ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive Carfilzomib and dexamethasone (Carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m 2 on days 1 and 2 of cycle 1; 56 mg/m 2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m 2 ) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the Carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients. Findings Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the Carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5–not evaluable) in the Carfilzomib group versus 40·0 months (32·6–42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648–0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the Carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the Carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the Carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the Carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two ( Interpretation Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, Carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease. Funding Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary.

  • Carfilzomib lenalidomide and dexamethasone in patients with relapsed multiple myeloma categorised by age secondary analysis from the phase 3 aspire study
    British Journal of Haematology, 2017
    Co-Authors: Meletios A Dimopoulos, Keith A Stewart, Roman Hajek, Tamas Masszi, Ivan Spicka, Albert Oriol, Laura Rosinol, David A Siegel, Georgi Mihaylov, Vesselina Goranovamarinova
    Abstract:

    Summary A primary analysis of the ASPIRE study found that the addition of Carfilzomib to lenalidomide and dexamethasone (Carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the Carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the Carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the Carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (Carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (Carfilzomib group) and 66·1% (control group). Within the Carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. Trial Registration: clinicaltrials.gov identifier: NCT01080391.

Lori Kunkel - One of the best experts on this subject based on the ideXlab platform.

  • phase ib dose escalation study px 171 006 of Carfilzomib lenalidomide and low dose dexamethasone in relapsed or progressive multiple myeloma
    Clinical Cancer Research, 2013
    Co-Authors: Ruben Niesvizky, David S Siegel, Melissa Alsina, Lori Kunkel, Alvin F Wong, Susan Lee, William I Bensinger, Robert Z Orlowski, Thomas G Martin, Michael Wang
    Abstract:

    Purpose: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of Carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study. Experimental Design: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: Carfilzomib 15 to 27 mg/m 2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly. Results: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. Conclusion: The maximum planned CRd dose, Carfilzomib 27 mg/m 2 , lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy. Clin Cancer Res; 19(8); 2248–56. ©2013 AACR .

  • Carfilzomib in multiple myeloma patients with renal impairment pharmacokinetics and safety
    Leukemia, 2013
    Co-Authors: Ashraf Badros, Lori Kunkel, Zhengping Wang, Alvin F Wong, Susan Lee, Ravi Vij, Thomas Martin, Jeffrey A Zonder, Ruben Niesvizky
    Abstract:

    This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of Carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50–80 ml/min, 30–49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m2 (Cycle 1), 20 mg/m2 (Cycle 2) and 27 mg/m2 (Cycles 3+). There were no differences in Carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m2, proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of Carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and Carfilzomib was well tolerated and demonstrated promising efficacy.

  • an open label single arm pilot phase ii study px 171 003 a0 of low dose single agent Carfilzomib in patients with relapsed and refractory multiple myeloma
    Clinical Lymphoma Myeloma & Leukemia, 2012
    Co-Authors: Sundar Jagannath, Suzanne Trudel, Keith A Stewart, Andrzej J Jakubowiak, Nizar J Bahlis, Ravi Vij, Sagar Lonial, Tony Reiman, George Somlo, Lori Kunkel
    Abstract:

    Abstract Background Carfilzomib is a next-generation selective proteasome inhibitor that irreversibly binds its target and has demonstrated single-agent activity in patients with bortezomib-resistant multiple myeloma (MM). PX-171-003-A0, an open-label single-arm multicenter pilot phase II study, enrolled 46 patients with relapsed MM after ≥ 2 previous therapies including bortezomib and an immunomodulator (thalidomide or lenalidomide) and disease refractory to the last treatment regimen preceding study entry. Methods Patients received Carfilzomib 20 mg/m 2 intravenously on days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles. Responses in 42 evaluable patients were assessed per International Myeloma Working Group Uniform Response Criteria, with minimal response assessed per European Group for Blood and Marrow Transplantation (EBMT) criteria. Results The primary endpoint of best ORR was 16.7%, including 7 partial responses. Median duration of response was 7.2 months. Clinical benefit response (CBR) rate was 23.8% with a median duration of response of 13.8 months. The most common treatment-emergent adverse events (AEs) of any grade were anemia (73.9%), fatigue (69.6%), and thrombocytopenia (50.0%). Notably, peripheral neuropathy and neuropathy-related AEs were generally mild and infrequent. Conclusion This pilot study was the first phase II single-agent trial conducted with Carfilzomib. Based on these findings, the study was amended to test a higher Carfilzomib dose in an additional 250 patients (PX-171-003-A1).

  • an open label single arm phase 2 study of single agent Carfilzomib in patients with relapsed and or refractory multiple myeloma who have been previously treated with bortezomib
    British Journal of Haematology, 2012
    Co-Authors: D S Siegel, Lori Kunkel, Sundar Jagannath, Andrzej J Jakubowiak, A K Stewart, Kevin T Mcdonagh, Nizar J Bahlis, Andrew R Belch, Sandra Wear, Alvin F Wong
    Abstract:

    Summary Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, Carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1–3 prior therapies, including at least one bortezomib-based regimen, received Carfilzomib 20 mg/m 2 in a twice-weekly, consecutive-day dosing schedule for 12 monthly cycles. The best overall response rate (ORR) was 171% and the clinical benefit response rate (ORR + minimal response) was 314%. The median duration of response was >106 months and the median time to progression was 46 months. The most common adverse events were fatigue (629%), nausea (600%), and vomiting (429%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent Carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of Carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of Carfilzomib as single agent or in combination with other agents.

  • 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
    Clinical Cancer Research, 2012
    Co-Authors: Melissa Alsina, Suzanne Trudel, Richard R Furman, Peter Rosen, Owen A Oconnor, Raymond L Comenzo, Alvin Wong, Lori Kunkel, Christopher J Molineaux, Andre Goy
    Abstract:

    Purpose: Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of Carfilzomib in patients with relapsed or refractory hematologic malignancies. Experimental design: Carfilzomib (doses ranging from 1.2–27 mg/m 2 ) was administered i.v. on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation ( n = 37) was followed by a dose-expansion phase ( n = 11) that comprised 2 cohorts (Carfilzomib or Carfilzomib + dexamethasone). During dose expansion, Carfilzomib was administered starting with 20 mg/m 2 during the first week (days 1, 2) and then escalated to 27 mg/m 2 thereafter. Results: A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of ≥ grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m 2 , there was evidence of activity among patients with multiple myeloma and with non-Hodgkin lymphoma. Conclusions: Escalated dosing of Carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE. Clin Cancer Res; 18(17); 4830–40. ©2012 AACR .

Roman Hajek - One of the best experts on this subject based on the ideXlab platform.

  • isatuximab Carfilzomib and dexamethasone in relapsed multiple myeloma ikema a multicentre open label randomised phase 3 trial
    The Lancet, 2021
    Co-Authors: Philippe Moreau, Kwee Yong, Roman Hajek, Ivan Spicka, Thierry Facon, Meletiosathanasios Dimopoulos, Joseph Mikhael, Marcelo Capra, Ross I Baker, Kihyun Kim
    Abstract:

    Summary Background Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and Carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus Carfilzomib–dexamethasone versus Carfilzomib–dexamethasone in patients with relapsed multiple myeloma. Methods This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus Carfilzomib–dexamethasone (isatuximab group) or Carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous Carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. Findings Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. Interpretation The addition of isatuximab to Carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. Funding Sanofi. Video Abstract Video abstractYouTube link: https://youtu.be/5kXtQQlzRh4

  • analysis of Carfilzomib cardiovascular safety profile across relapsed and or refractory multiple myeloma clinical trials
    Blood Advances, 2018
    Co-Authors: Ajai Chari, Philippe Moreau, Keith A Stewart, Stuart D Russell, Joerg Herrmann, Jose Banchs, Roman Hajek, John D Groarke, Alexander R Lyon, George N Batty
    Abstract:

    Carfilzomib is a selective proteasome inhibitor approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). It has significantly improved outcomes, including overall survival (OS), and shown superiority vs standard treatment with lenalidomide plus dexamethasone and bortezomib plus dexamethasone. The incidence rate of cardiovascular (CV) events with Carfilzomib treatment has varied across trials. This analysis evaluated phase 1-3 trials with >2000 RRMM patients exposed to Carfilzomib to describe the incidence of CV adverse events (AEs). In addition, the individual CV safety data of >1000 patients enrolled in the Carfilzomib arm of phase 3 studies were compared with the control arms to assess the benefit-risk profile of Carfilzomib. Pooling data across Carfilzomib trials, the CV AEs (grade ≥3) noted included hypertension (5.9%), dyspnea (4.5%), and cardiac failure (4.4%). Although patients receiving Carfilzomib had a numeric increase in the rates of any-grade and grade ≥3 cardiac failure, dyspnea, and hypertension, the frequency of discontinuation or death due to these cardiac events was low and comparable between the Carfilzomib and control arms. Serial echocardiography in a blinded cardiac substudy showed no objective evidence of cardiac dysfunction in the Carfilzomib and control arms. Moreover, Carfilzomib had no significant effect on cardiac repolarization. Our results, including the OS benefit, showed that the benefit of Carfilzomib treatment in terms of reducing progression or death outweighed the risk for developing cardiac failure or hypertension in most patients. Appropriate Carfilzomib administration and risk factor management are recommended for elderly patients and patients with underlying risk factors.

  • Carfilzomib lenalidomide and dexamethasone in patients with relapsed multiple myeloma categorised by age secondary analysis from the phase 3 aspire study
    British Journal of Haematology, 2017
    Co-Authors: Meletios A Dimopoulos, Keith A Stewart, Roman Hajek, Tamas Masszi, Ivan Spicka, Albert Oriol, Laura Rosinol, David A Siegel, Georgi Mihaylov, Vesselina Goranovamarinova
    Abstract:

    Summary A primary analysis of the ASPIRE study found that the addition of Carfilzomib to lenalidomide and dexamethasone (Carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the Carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the Carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the Carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (Carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (Carfilzomib group) and 66·1% (control group). Within the Carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. Trial Registration: clinicaltrials.gov identifier: NCT01080391.

  • a randomized phase iii study of Carfilzomib vs low dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma focus
    Leukemia, 2017
    Co-Authors: Roman Hajek, Kwee Yong, Tamas Masszi, Albert Oriol, Laura Rosinol, M T Petrucci, Antonio Palumbo, Arnon Nagler, Jiri Minarik, Luděk Pour
    Abstract:

    This randomized, phase III, open-label, multicenter study compared Carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive Carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to Carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with Carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with Carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with Carfilzomib vs control. Median OS for single-agent Carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

  • Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma endeavor a randomised phase 3 open label multicentre study
    Lancet Oncology, 2016
    Co-Authors: Meletios A Dimopoulos, Philippe Moreau, Roman Hajek, Albert Oriol, Antonio Palumbo, Heinz Ludwig, Douglas E Joshua, Ludek Pour, Thierry Facon, Hartmut Goldschmidt
    Abstract:

    Summary Background Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of Carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive Carfilzomib with dexamethasone (Carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with Carfilzomib (20 mg/m 2 on days 1 and 2 of cycle 1; 56 mg/m 2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m 2 ; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the Carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3–16·1) in the Carfilzomib group and 11·1 months (8·2–14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6–not estimable) in the Carfilzomib group versus 9·4 months (8·4–10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44–0·65]; p vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation For patients with relapsed or refractory multiple myeloma, Carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Heinz Ludwig - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Carfilzomib based regimens in frail patients with relapsed and or refractory multiple myeloma
    Blood Advances, 2020
    Co-Authors: Thierry Facon, David S Siegel, Ruben Niesvizky, Heinz Ludwig, Sara Bringhen, Cara A Rosenbaum, Katja Weisel, Mariavictoria Mateos, Shaji Kumar, Kenneth Wang
    Abstract:

    Frailty is most prevalent among elderly multiple myeloma (MM) patients, and frail patients have a higher risk of poor outcomes due to reduced performance status or comorbidities. This post hoc analysis assessed efficacy and safety of Carfilzomib combinations in frail patients with relapsed and/or refractory MM from the phase 3 ASPIRE (Carfilzomib [27 mg/m2]-lenalidomide-dexamethasone [KRd27] vs lenalidomide-dexamethasone [Rd]), ENDEAVOR (Carfilzomib [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), and ARROW (once-weekly Carfilzomib [70 mg/m2]-dexamethasone [Kd70] vs Carfilzomib [27 mg/m2]-dexamethasone [Kd27]) studies. A frailty algorithm incorporating age, Charlson comorbidity index, and performance status classified patients as fit, intermediate, or frail. Results are presented for frail patients (ASPIRE, n = 196; ENDEAVOR, n = 330; ARROW, n = 141). In ASPIRE, median progression-free survival (PFS) (hazard ratio; 95% confidence interval) was 24.1 (KRd27) vs 15.9 months (Rd) (0.78; 0.54-1.12); median overall survival (OS) was 36.4 vs 26.2 months (0.79; 0.57-1.08). In ENDEAVOR, median PFS was 18.7 (Kd56) vs 6.6 months (Vd) (0.50; 0.36-0.68); median OS was 33.6 vs 21.8 months (0.75; 0.56-1.00). In ARROW, median PFS was 10.3 (once-weekly Kd70) vs 6.6 months (twice-weekly Kd27) (0.76; 0.49-1.16). In all 3 studies, rates of grade ≥3 treatment-emergent adverse events were consistent with those observed in the primary studies. The ASPIRE, ENDEAVOR, and ARROW primary analyses demonstrated favorable benefit-risk profiles with Carfilzomib-containing regimens compared with controls. Across clinically relevant subgroups, including those by frailty status, consistent efficacy and safety were observed with KRd27, Kd56, and weekly Kd70, and treatment with these regimens should not be restricted by frailty status.

  • health related quality of life of Carfilzomib and daratumumab based therapies in patients with relapsed refractory multiple myeloma based on german benefit assessment data
    Quality of Life Research, 2020
    Co-Authors: Katja Weisel, Heinz Ludwig, Achim Rieth, Andrea Lebioda, Hartmut Goldschmidt
    Abstract:

    Carfilzomib and daratumumab are licensed in relapsed/refractory multiple myeloma (RRMM), but no head-to-head trials have been conducted. We used data from dossiers prepared for the German Federal Joint Committee based on two phase III randomized trials of Carfilzomib-based therapies (ASPIRE, ENDEAVOR) and two of daratumumab-based therapies (POLLUX, CASTOR) to conduct a descriptive assessment of health-related quality of life (HRQoL). HRQoL was assessed using the European Organisation for Research and Treatment of Cancer 30-item HRQoL Questionnaire, with hazard ratios calculated for Carfilzomib- and daratumumab-based therapy versus comparators for time to HRQoL deterioration of ≥ 10 points. Analyses were also conducted on data from the EORTC 20-item myeloma-specific questionnaire, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, and the visual analog scale of the EuroQoL 5-dimension, 5-level questionnaire, where results for these instruments were available. As the designs and patient population of the four trials were similar but not identical, the analysis included only indirect, descriptive comparisons. Compared with lenalidomide/dexamethasone, median time to deterioration in global health status/QoL was longer for Carfilzomib-based therapy versus control, but similar for daratumumab-based therapy and control. Compared with bortezomib/dexamethasone, time to deterioration was significantly longer for Carfilzomib-based therapy versus control for global health status/QoL and numerous functional and symptom subscales. HRQoL measurement is feasible in large RRMM populations. Descriptive assessment of HRQoL data suggests potential benefits for Carfilzomib-based over daratumumab-based therapy.

  • Carfilzomib or bortezomib in relapsed or refractory multiple myeloma endeavor an interim overall survival analysis of an open label randomised phase 3 trial
    Lancet Oncology, 2017
    Co-Authors: Meletios A Dimopoulos, Albert Oriol, Ruben Niesvizky, Heinz Ludwig, Robert Z Orlowski, Hartmut Goldschmidt, Douglas E Joshua, Wee Joo Chng, Thierry Facon
    Abstract:

    Summary Background The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with Carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups. Methods ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive Carfilzomib and dexamethasone (Carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m 2 on days 1 and 2 of cycle 1; 56 mg/m 2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m 2 ) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the Carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients. Findings Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the Carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5–not evaluable) in the Carfilzomib group versus 40·0 months (32·6–42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648–0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the Carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the Carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the Carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the Carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two ( Interpretation Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, Carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease. Funding Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary.

  • Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma endeavor a randomised phase 3 open label multicentre study
    Lancet Oncology, 2016
    Co-Authors: Meletios A Dimopoulos, Philippe Moreau, Roman Hajek, Albert Oriol, Antonio Palumbo, Heinz Ludwig, Douglas E Joshua, Ludek Pour, Thierry Facon, Hartmut Goldschmidt
    Abstract:

    Summary Background Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of Carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive Carfilzomib with dexamethasone (Carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with Carfilzomib (20 mg/m 2 on days 1 and 2 of cycle 1; 56 mg/m 2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m 2 ; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the Carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3–16·1) in the Carfilzomib group and 11·1 months (8·2–14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6–not estimable) in the Carfilzomib group versus 9·4 months (8·4–10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44–0·65]; p vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation For patients with relapsed or refractory multiple myeloma, Carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

  • design and rationale of focus px 171 011 a randomized open label phase 3 study of Carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma r r mm
    BMC Cancer, 2012
    Co-Authors: Roman Hajek, Richard Bryce, Barbara Klencke, Heinz Ludwig
    Abstract:

    Background: Carfilzomib is a next-generation proteasome inhibitor with single-agent activity in patients with relapsed and refractory multiple myeloma (R/R MM). In PX-171-003-A1, a single-arm phase 2 study of Carfilzomib monotherapy in heavily pretreated patients, the overall response rate was 23.7%, 37% of patients achieved ≥minimal response and median overall survival (OS) was 15.6 months. Based on this study, Carfilzomib was recently approved by the US Food and Drug Administration for the treatment of R/R MM. Herein we describe the trial design and rationale for a phase 3 randomized study, FOCUS (Carfilzomib for AdvanCed Refractory MUltiple Myeloma European Study), being conducted to compare OS after treatment with single-agent Carfilzomib to best supportive care (BSC) regimen in R/R MM. Methods: Patients must have received ≥3 prior regimens, must be responsive to at least 1 line of therapy, and be refractory to their most recent therapy. Eligible patients are randomized 1:1 to receive either Carfilzomib (28day cycles at 20 mg/m 2 IV on Days 1–2 of Cycle 1, escalating to 27 mg/m 2 IV on Days 8, 9, 15, and 16 and continuing at 27 mg/m 2 through Cycle 9 and Days 1, 2, 15, and 16 ≥Cycle 10) or an active BSC regimen