scholarly journals Improved Safety with the Use of Subcutaneous Bortezomib in Combination with Panobinostat and Dexamethasone: Preliminary Data from a Panobinostat Global Expanded Treatment Protocol

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5692-5692
Author(s):  
Andreas Guenther ◽  
Lars-Olof Mügge ◽  
Mathias Haenel ◽  
Fredrik H. Schjesvold ◽  
Daniel Lechner ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Adjustment ◽  
Treatment Protocol ◽  
Open Label ◽  
Older Population ◽  
Phase 3 ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its epigenetic effects as well as its effect on the aggresome. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN+BTZ+Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to approval in Europe of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory agent. The purpose of this expanded treatment protocol (ETP) is to further evaluate safety and to provide panobinostat prior to commercial availability to patients with relapsed/refractory MM who have received ≥ 2 prior lines of therapy but for whom satisfactory treatment alternatives are not available. Methods: Panobinostat-ETP is a multicenter, open-label, ETP study of PAN+BTZ+Dex in adult patients with MM relapsed and/or refractory to ≥ 2 prior lines of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN 20 mg (days 1, 3, 5, 8, 10, and 12) plus intravenous or subcutaneous BTZ 1.3 mg/m2 (days 1, 4, 8, and 11) for eight 21-day cycles. Patients with ≥ stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex 20 mg was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed prior to TP2 as a dose reduction strategy. Results: A total of 49 patients with a median age of 67 years (range, 45-85 years) were enrolled in the study. Patients were heavily pretreated; 73.5% received ≥ 3 prior lines of therapy. Most patients (n = 43 [87.8%]) received subcutaneous BTZ, while 3 (6.1%) received intravenous BTZ, and another 3 (6.1%) received both. The median duration of treatment with PAN+BTZ+Dex was 67 days (range, 12-305 days). The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (51.0%), anemia (12.2%), and neutropenia (10.2%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were diarrhea (14.3%), fatigue (8.2%), infection (6.1%), and nausea (6.1%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (51.0%), constipation (16.3%), and nausea (16.3%). Interestingly, in the patients receiving subcutaneous BTZ, the rates of grade 3/4 diarrhea (11.6%), thrombocytopenia (48.8%), anemia (14.0%), and neutropenia (11.6%) were lower than those seen with intravenous BTZ administration in the phase 3 PANORAMA 1 trial (25%, 57%, 16.8%, and 24.1%, respectively). Two patients died while on treatment; one due to disease progression and the other due to infection. Common serious AEs included diarrhea (12.2%) and thrombocytopenia, atrial fibrillation, infection, pneumonia, and syncope (all 6.1%); serious AEs of atrial fibrillation and syncope were higher than in PANORAMA 1 (1.0% and 1.3%, respectively). AEs led to PAN, BTZ, and Dex dose adjustment in 36.7%, 42.9%, and 16.3% of patients, respectively; the most common AE leading to dose adjustment or temporary interruption was thrombocytopenia (all-grade, 30.6%; grade 3/4, 28.6%). Efficacy data will be reported after sufficient follow-up. Conclusions: Overall, the safety results from panobinostat-ETP, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1, with only a slight increase in atrial fibrillation, potentially because of the older population. In the subgroup of patients receiving subcutaneous BTZ, rates of diarrhea and hematologic toxicities, AEs of interest with PAN+BTZ+Dex therapy, appear to be reduced compared with PANORAMA 1 data with intravenous BTZ administration; however, because of the small size of this study, these results should be interpreted with caution. Further clinical experience with the use of subcutaneous BTZ in this combination will help to determine the potential impact of the route of BTZ administration on tolerability. Disclosures Guenther: Takeda: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol Myers-Suibb: Honoraria. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lechner:Novartis: Honoraria. Gisslinger:Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria. Greil:Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen: Consultancy, Honoraria; Bristol Myer-Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Munder:Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria. Kiani:Novartis: Consultancy, Honoraria, Speakers Bureau. Campello-Iddison:Novartis: Employment, Equity Ownership. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.

Obinutuzumab or Rituximab Plus CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma: Final Results from an Open-Label, Randomized Phase 3 Study (GOYA)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 470-470 ◽  
Author(s):  
Umberto Vitolo ◽  
Marek Trněný ◽  
David Belada ◽  
Angelo M Carella ◽  
Neil Chua ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Secondary Endpoints ◽  
Grade 3

Abstract Background: Rituximab (R) plus CHOP (R-CHOP) is standard-of-care treatment for previously untreated diffuse large B-cell lymphoma (DLBCL). Approximately 35-40% of patients (pts) will relapse following R-CHOP, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered, type II anti-CD20 monoclonal antibody with greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R. In the Phase 2 GATHER study (NCT01414855), G plus CHOP (G-CHOP) demonstrated manageable toxicity and promising efficacy in pts with advanced untreated DLBCL. GOYA (NCT01287741) is an open-label, multicenter, randomized Phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. GOYA was sponsored by Roche with scientific support from the Fondazione Italiana Linfomi. Methods: Eligible pts were aged ≥18 years and had adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status (PS) of ≤2 and an International Prognostic Index (IPI) score of ≥2 (high, high-intermediate or low-intermediate risk). Low-risk pts with an IPI score of 1 (but not due to age alone) or with an IPI score of 0 with bulky disease (one lesion ≥7.5cm) were also eligible. Pts were randomized 1:1 to receive 8 (21-day) cycles of G (1000mg i.v. on Days [D] 1, 8, and 15, Cycle [C] 1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP (number of cycles preplanned in advance for all pts at each site). Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS); for the target hazard ratio (HR) of 0.75, the 3-year PFS was expected to improve from 60% to 68%. Secondary endpoints included: PFS assessed by Independent Review Committee (IRC); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (assessed by INV or IRC according to modified Cheson 2007 criteria); and safety. Results: 1418 pts were randomized to study treatment: 706 to G-CHOP and 712 to R-CHOP. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms: mean age, 62.0 years in both arms; ECOG PS ≥2, 12% vs. 14%; IPI score ≥3, 47% vs. 43%; Ann Arbor stage III-IV, 76% in both arms. Cell-of-origin distribution, as assessed by gene-expression profiling (NanoString), was similar in both treatment groups (GCB: 58% [271/471] G-CHOP, 58% [269/462] R-CHOP; ABC: 27% [125/471] G-CHOP, 26% [118/462] R-CHOP; Unclassified: 15.9% [75/471] G-CHOP, 16.2% [75/462] R-CHOP). For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3-year PFS, 69% vs. 66%; stratified HR, 0.92; 95% confidence interval [CI], 0.76, 1.12; p=0.3868; Table). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms (Table). In a prespecified subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for pts with GCB DLBCL (3-year PFS, 79% vs. 70%). No new safety signals were identified. Grade ≥3 adverse events (AEs; 74% vs. 65%) and serious AEs (43% vs. 38%) were more common in the G-CHOP than in the R-CHOP arm. Grade ≥3 AEs of particular interest that were numerically more common with G-CHOP than R-CHOP included neutropenia (57% vs. 48%), infusion-related reactions (45% vs. 32%), infections (54% vs. 44%), and thrombocytopenia (8% vs. 3%). AEs resulting in withdrawal from treatment (12% [84/704] G-CHOP; 9% [60/703] R-CHOP) and AEs with fatal outcome (6% [41/704] G-CHOP; 4% [30/703] R-CHOP) were slightly more common with G-CHOP. The most common AEs leading to death were pneumonia (5 G-CHOP; 6 R-CHOP) and sepsis/septic shock (7 G-CHOP; 3 R-CHOP). Conclusions: The primary endpoint of this study was not met: G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. No unexpected safety signals were identified. Further investigation of outcomes in subgroups is planned. Disclosures Vitolo: Gilead: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Trněný:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Belada:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chua:Roche: Consultancy, Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Consultancy. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Kim:Celltrion, Inc.: Consultancy, Honoraria. Pinto:Millennium: Research Funding; Takeda: Honoraria; Helssin: Honoraria; Roche: Honoraria; Celgene: Honoraria; Servier: Honoraria; Janssen: Honoraria. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Oestergaard:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Catalani:Roche: Employment. Nielsen:Hoffmann-La Roche: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

scholarly journals An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients with Previously Treated Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3027-3027
Author(s):  
Vincent L Hansen ◽  
Morton Coleman ◽  
Stephanie Elkins ◽  
Jeffrey P. Letzer ◽  
Moshe Yair Levy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stable Disease ◽  
Safety Data ◽  
Treatment Protocol ◽  
Treatment Phase ◽  
Progression Free Survival ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its effects on epigenetics and protein metabolism. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN-BTZ-Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to US Food and Drug Administration approval of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens including BTZ and an immunomodulatory agent. The "PANobinostat EXpansion treatment protocol" (PANEX) study was developed to provide access to PAN and gather additional safety data on the PAN-BTZ-Dex combination until PAN became commercially available. Methods: PANEX is a multicenter, open-label, expanded treatment protocol study of PAN-BTZ-Dex in adult patients with MM relapsed and/or refractory to ≥ 1 prior line of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN (20 mg; days 1, 3, 5, 8, 10, and 12) plus intravenous (IV) or subcutaneous (SC) BTZ (1.3 mg/m2; days 1, 4, 8, and 11) for eight 21-day cycles. Patients with at least stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex (20 mg) was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed before TP2 as a dose reduction strategy. Response assessments were completed per modified European Group for Blood and Marrow Transplantation criteria. Results: A total of 39 patients, with a median age of 70 years (range, 44-88 years), were enrolled in the study. Patients were heavily pretreated, with a median of 3 prior lines of therapy (range, 1-12; 21% ≥ 7 prior therapies), with nearly half of the patients (48.7%) having progressed on their most recent therapy. Most patients received SC BTZ (87.2% [n = 34] vs 12.8% [n = 5] IV BTZ), with a median treatment duration of 9.4 weeks (range, 2-34). A total of 21 patients achieved a partial response, leading to an overall response rate of 53.8%; an additional 17.9% achieved a minimal response, for a clinical benefit rate (≥ minimal response) of 71.8%, with 25.6% having stable disease. Notably, no patients in the current trial had a best response of progressive disease. The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (53.8%), anemia (17.9%), and neutropenia (17.9%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were dehydration (28.2%), fatigue (28.2%), diarrhea (17.9%), asthenia (10.3%), and pneumonia (10.3%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (48.7%), nausea (25.6%), and vomiting (12.8%), and nearly all cases of dehydration were associated with these gastrointestinal events. Interestingly, in the patients receiving SC BTZ (n = 34), the rate of grade 3/4 diarrhea was 11.8%, approximately half the rate seen with IV BTZ administration in the phase 3 PANORAMA 1 trial (25%). Common serious AEs included dehydration (15.4%), diarrhea (12.8%), and pneumonia (10.3%). AEs led to PAN, BTZ, and Dex dose reductions in 59.0%, 59.0%, and 46.2% of patients, respectively. Conclusions: Overall, the results from PANEX, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1. In the subgroup of patients receiving SC BTZ, the rate of diarrhea, an AE of interest with PAN-BTZ-Dex therapy, appeared to be reduced when compared with PANORAMA 1 data with IV BTZ administration. Further clinical experience with the use of SC BTZ in this combination will help to determine the potential impact of route of BTZ administration on tolerability. Disclosures Elkins: Pharmacyclics/Janssen: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Letzer:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Levy:Takeda: Consultancy. Seneviratne:Novartis: Honoraria, Speakers Bureau. Rine:Novartis: Employment. White:Novartis: Employment. Kuriakose:Novartis: Employment, Equity Ownership.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 301-301 ◽  
Author(s):  
Paul Richardson ◽  
David Siegel ◽  
Rachid Baz ◽  
Susan L. Kelley ◽  
Nikhil C. Munshi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Dose Dependent Increase

Abstract Abstract 301 Background: Pomalidomide (POM) is an IMiD® derived from thalidomide with a modified chemical structure with improved potency in vitro and potential efficacy and safety benefits in vivo. Two phase (Ph) 1b, single-center, ascending dose, open-label studies in pts with relapsed/refractory multiple myeloma (MM; Schey et al, 2004, Streetly et al, 2008) identified maximum tolerated dose (MTD) as 2mg QD or 5mg on alternate days (28 of each 28-day cycle). High response rates of POM alone in heavily pretreated pts were encouraging. To evaluate the MTD, safety and efficacy of POM alone or with Dexamathasone (dex) on a 21/28 day schedule, a Ph 1/2, multicenter, randomized, open-label, 3×3 dose-escalation study was initiated in pts with relapsed/refractory MM after at least 2 prior regimens, including bortezomib and lenalidomide. Methods: The study has a Ph 1 POM MTD (n=32) portion, followed by Ph 2 open-label randomized POM+ dex vs POM alone (192 pts planned). Eligible pts had documented relapsed/refractory MM. All pts received low-dose prophylactic aspirin QD and monitored for venous thromboembolic events (VTE). In Ph 1, POM was given QD on Days 1–21 of 28-day cycle: 4 dose levels of POM (2, 3, 4, 5mg) were studied with option to add dex at 40 mg/wk after 4 cycles for lack of response or progressive disease (PD). Pts enrolled in Ph 1 and discontinued either for intolerance or PD could not be enrolled in Ph 2. Toxicities and responses were assessed using CTCAE v3 and modified European Group for Blood and Marrow Transplantation (EBMT) criteria. Results: Results from Ph 1 of the study are reported with 32 pts enrolled to date. Fifteen pts discontinued therapy and 17 pts are ongoing for both safety and efficacy analyses. Mean age is 66.6 yrs (range 38–84), with median number of prior regimens 7 (range 2–18). MTD has not yet been reached. There were 4 dose reductions due to POM (5mg [2-neutropenia, 1-rash]; 3mg [1-neutropenia]) after 108 completed cycles. Neutropenia and thrombocytopenia were the most common grade 3/4 toxicities, with no dose-dependent increase apparent so far: 12 serious adverse events (SAEs) occurred in 10 pts; drug related events included POM (VTE, syncope, 3rd degree AV block, asthenia, diarrhea, neutropenia, anemia, rash); dex (lung infection with neutropenia); POM + dex (sepsis with pharyngeal abscess). AEs such as somnolence (1) VTE (1) neuropathy (2), and constipation (4) were uncommon. There were 3 deaths on study not attributed to POM; 2 pts died of rapid PD, 1 pt died of gastrointestinal perforation due to amyloidosis. Responses were seen at each dose level (Table 1). In 20/21 (95%) evaluable pts, clinical activity (SD or better) was reported. During treatment with POM alone, overall response rate (ORR; 1 CR, 2 PR, 5 MR) was 38% (8/21), mean duration of response (DOR) was 11.1 (range 4–32) wks, mean time to progression (TTP) was 8.3 (range 2–36) wks. Median completed cycles of POM +/− dex overall was 4 (range 1–12), with 13/21 evaluable pts (62%) having dex added to their regimens at various different cycles (median cycle 3, range 2–9) for PD or lack of response. During treatment with POM+dex, ORR (2 PR, 3 MR) was 38%, mean DOR of 14.2 (range 4–32) wks, and mean TTP of 20 (range 4–52) wks. In addition, there were 9 stable diseases (SD) on POM alone with mean DOR of 7.1 (range 4–16) wks, and 6 SD on POM + dex with mean DOR of 10.7 (range 8–16) wks. In 5/13 pts (38%), responses improved after dex was added (2 PR, 2 MR, 1 SD). Conclusions: These preliminary results indicate that POM alone or in combination with dex is associated with 38% MR or better, while SD was achieved in 43% (POM alone) and 46% (POM + dex), amongst heavily pretreated pts with relapsed/refractory MM. The incidence of SAEs and discontinuations decreased with increased dose of POM with no dose-dependent increase in grade 3/4 hematological toxicities. The MTD has not been reached to date. Overall, these data indicate that POM has an acceptable safety profile and is a clinically active therapeutic option for advanced refractory MM, warranting further investigation in this patient population. Disclosures: Richardson: Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an anti-proliferative and immunomodulatory agent that is in clinical development for relapsed/refractory MM. Siegel:Celgene: Speakers Bureau; Millenium Pharmaceuticals: Speakers Bureau. Baz:Celgene: Research Funding. Munshi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Sullivan:Merck: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Merrion: Membership on an entity's Board of Directors or advisory committees. Doss:Celgene: Speakers Bureau. Larkins:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment. Donaldson:Celgene: Employment. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Baseline Characteristics and Symptom Burden in RESPONSE: A Randomized, Open-Label, Phase 3 Study of Ruxolitinib In Polycythemia Vera Patients Resistant to or Intolerant of Hydroxyurea

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4071-4071 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Jean-Jacques Kiladjian ◽  
Martin Griesshammer ◽  
Tamás Masszi ◽  
Simon Durrant ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Symptom Burden ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Jak2 Inhibitor ◽  
Open Label Phase ◽  
Night Sweats ◽  
Equity Ownership

Abstract Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is characterized by elevated hematocrit requiring phlebotomy, splenomegaly, a variety of symptoms and increased thrombotic risk. Ruxolitinib, a JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses in a phase 2 study of patients (pts) with PV who were resistant to or intolerant of hydroxyurea (HU). Pts experienced phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) counts, platelet (PLT) counts, and disease-related symptoms. Here, we describe the baseline (BL) characteristics and symptom burden of pts in a phase 3 study of ruxolitinib in pts with PV who are resistant to or intolerant of HU. Methods RESPONSE is a randomized (1:1), open-label, phase 3 study (NCT01243944) comparing the efficacy and safety of ruxolitinib with best available therapy (BAT) in pts with PV who are resistant to or intolerant of HU (modified European LeukemiaNet criteria), have splenomegaly, and require phlebotomy for inadequate hematocrit (Hct) control. Fourteen disease-related symptoms were assessed on a scale of 0 (absent) to 10 (worst imaginable) using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Blinded data are presented here. Results BL demographic data are available for the 222 enrolled pts (Table). Apart from HU, other common prior medications for PV included interferons (15%), PLT aggregation inhibitors (10%), alkylating agents (3.6%), alkyl sulfonates (3.2%), pyrimidine analogues (1.8%), and nitrosoureas (1.4%). The majority of pts (54.5%) had 1 phlebotomy within 12 weeks prior to screening; 23.9% had 2 and 17.1% had 3 or more phlebotomies. RESPONSE BL demographics are generally similar in terms of age (60 years vs 57-67); sex (66% male vs 58%-68%); Hct (44% vs 45%-48%); and platelets (419 x 109/L vs 320-429 x 109/L) to other PV studies including trials of givinostat (Finazzi BJH 2013) and AOP2014 (Gisslinger ASH 2012) and the ECLAP-PV (Marchioli JCO 2005) and CYTO-PV studies (Marchioli NEJM 2012). At the time of writing, BL symptom data from the MPN-SAF were available for 164 pts (Table). Pts in this study reported a similar symptom burden as PV pts from a large study of pts with MPNs (Emanuel JCO 2012; N = 1425; PV, n = 538), including similar mean scores for early satiety, abdominal discomfort, concentration problems, night sweats, itching, and tiredness/fatigue. In addition, prior therapy may have adversely affected BL symptom burden, as many of these symptoms (concentration problems, night sweats, fatigue) have been shown to be worsened by the use of conventional therapy to strictly control Hct (< 45%) and cardiovascular risk (Emanuel EHA 2013). BL MPN-SAF symptom data for all 222 pts will be presented. In addition, correlations between BL EORTC QLQ-C30 and MPN-SAF scores will be presented. Summary/Conclusions Demographic and BL symptom data from the RESPONSE study demonstrated that pts with HU refractory or intolerant PV have a significant disease burden that includes a variety of symptoms. These findings are consistent with those of Emanuel (JCO 2012), which showed that pts with PV have a significant symptom burden and a reduced quality of life. Pts with PV in the RESPONSE study are representative of those who have been studied in other clinical trials for the treatment of PV. Disclosures: Vannucchi: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF and by the European Commission and Health Canada for the treatment of disease-related splenomegaly or symptoms in adult patients with MF. Here, we describe the baseline (BL) characteristics and symptom burden of patients in a phase 3 study of ruxolitinib in patients with PV who are resistant to or intolerant of HU. Kiladjian:Novartis: Honoraria; Shire: Honoraria. Durrant:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pane:Novartis: Consultancy, Honoraria; Shire: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; SBio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. He:Incyte: Employment. Leopold:Incyte: Employment, Stock options Other. Li:Novartis: Employment, Equity Ownership. Pirron:Novartis: Employment, Equity Ownership. Lawniczek:Novartis: Employment. Verstovsek:Incyte: Research Funding.

scholarly journals Safety and Efficacy of Ruxolitinib in an 1869-Patient Cohort of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2799-2799 ◽  
Author(s):  
Renato Tavares ◽  
Giuseppe A. Palumbo ◽  
Philipp Le Coutre ◽  
Francesca Palandri ◽  
Haifa Kathrin Al-Ali ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Costal Margin ◽  
Phase 3 ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Expanded Access ◽  
Grade 3

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that demonstrated improvements in splenomegaly and disease-related symptoms, as well as improved survival, in patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF), and has proved superior to placebo and best available therapy in the phase 3 COMFORT studies. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of RUX in pts with MF and includes patients with no access to RUX outside a clinical trial. As of Dec 2014, final enrollment was 2233 pts in 26 countries. METHODS: Eligible pts had Int-2- or high-risk MF with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of RUX based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to < 100 × 109/L], 15 mg bid [100 to 200 × 109/L], or 20 mg bid [> 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of RUX. Additional analyses included changes in palpable spleen length and symptom scores as measured by the FACT-Lymphoma total score (FACT-Lym TS). The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 1869 pts (primary MF, 59.1%; n = 1105) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2015). At baseline, median age was 67 y (range, 18-89 y); 54.1% were male; median palpable spleen length was 12 cm below the costal margin; 87 pts did not have splenomegaly. Median hemoglobin (Hb) was 106 g/L, and 38.9% of pts had Hb levels ˂ 100 g/L; median platelet count was 257 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.7 and 33.2, respectively. At data cutoff, 37.0% of pts remained on treatment; 26.1% had completed treatment per protocol. Primary reasons for discontinuation included adverse events (AEs; 17.4%), disease progression (8.2%), and death (3.4%). Median exposure was 13.6 months; the median average daily dose was 36.7 mg for pts starting at 20 mg bid (n = 1168; 62.5%) and 23.2 mg for pts starting at 15 mg bid (n = 559; 29.9%). The majority of pts (66.0%) had dose modifications, and 26.2% had a dose interruption. Grade 3/4 hematologic AEs included anemia (34.0%), thrombocytopenia (14.9%), and neutropenia (3.9%), which led to discontinuation in 2.2%, 3.3%, and 0.2% of pts, respectively. The most common nonhematologic AEs (≥ 10%) were pyrexia (14.5%), asthenia (13.8%), diarrhea (12.4%), and fatigue (10.3%), and were primarily grade 1/2; grade 3/4 AEs were low overall (≤ 2%), except pneumonia (3.9%), which led to discontinuation in 9 pts (0.5%). Rates of infections were low; all-grade infections ≥ 5% included pneumonia (6.2%), urinary tract infection (5.7%), and nasopharyngitis (5.3%). Tuberculosis was reported in 5 pts (0.3%; grade 3/4, 0.1%); hepatitis B was reported in 1 pt (0.1%; grade 3/4, 0.1%). At wk 24 and 48, 57.2% (742/1297) and 62.0% (588/949) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 22.9% (297/1297) and 19.0% (180/949) had 25% to 50% reductions, respectively. Most pts (70.5%; 1208/1713) experienced a ≥ 50% reduction at any time; 23.3% (399/1713) had complete resolution of splenomegaly (Figure). At wk 24 and 48, 96.6% (57/59) and 91.5% (43/47) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen; 1.7% (1/59) and 4.3% (2/47) had a spleen that was 0-5 cm, and 1.7% (1/59) and 4.3% (2/47) had a spleen ≥ 5 cm. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (43.0% [525/1220]; 47.1% [593/1258]) and wk 48 (43.2% [368/852]; 45.7% [396/867]). Similar responses were seen in pts without a palpable spleen (FACT-Lym TS: wk 24, 44.0% [22/50]; wk 48, 36.1% [13/36]; FACIT-Fatigue: wk 24, 49.1% [27/55]; wk 48, 35.1% [13/37]). CONCLUSIONS: To date, JUMP includes the largest cohort of pts with MF treated with RUX. Consistent with previous findings, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with RUX treatment. Clinically meaningful improvements in symptoms were also seen in pts with no palpable spleen, a pt group not included in the COMFORT studies. Overall, the safety and efficacy profile of RUX in JUMP is consistent with that in the phase 3 COMFORT studies. Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board. Le Coutre:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ullrich:Novartis: Honoraria. Brittain:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foltz:Promedior: Research Funding; Gilead: Research Funding; Novartis: Honoraria, Research Funding. Raanani:Bristol-Myers Squibb: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Gupta:Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghosh:Novartis Pharmaceuticals Corporation: Employment. Tannir:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Vannucchi:Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 409-409 ◽  
Author(s):  
Valeria Santini ◽  
Antonio Almeida ◽  
Aristoteles Giagounidis ◽  
Stephanie Gröpper ◽  
Anna Jonasova ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Safety of Treatment (Tx) with Pomalidomide (POM) and Low-Dose Dexamethasone (LoDEX) in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI), Including Those on Dialysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 374-374 ◽  
Author(s):  
Karthik Ramasamy ◽  
Meletios A. Dimopoulos ◽  
Niels W.C.J. van de Donk ◽  
Barbara Gamberi ◽  
Frank Bridoux ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Comparable Efficacy ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3 ◽  
Dose Modifications ◽  
Support Research

Abstract Background: RI occurs in ≈ 20%-30% of newly diagnosed MM pts and is associated with poor prognosis (Knudsen et al. Eur J Haematol. 2000; Kyle et al. Mayo Clin Proc. 2003). Data from 2 pivotal trials (MM-002, MM-003) suggested comparable efficacy and tolerability of POM + LoDEX in pts with or without moderate RI (Siegel ASH 2012; Weisel ASCO 2013). However, these trials excluded pts with severe RI. MM-013 (NCT02045017) is a European multicenter, open-label phase 2 study designed to assess the efficacy, safety, and pharmacokinetics of POM + LoDEX in RRMM pts with moderate or severe RI, including those on dialysis. Methods: The trial is enrolling RRMM pts (N = 80) across 3 cohorts: cohort A (moderate RI, estimated glomerular filtration rate [eGFR] ≥ 30 to < 45 mL/min/1.73 m2, n = 33), cohort B (severe RI without dialysis, eGFR < 30 mL/min/1.73 m2, n = 33), and cohort C (severe RI requiring dialysis, n = 14). Pts must have MM-related RI and have received ≥ 1 prior Tx (including lenalidomide). POM 4 mg is administered on days 1-21 of a 28-day cycle and LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22 until progressive disease (PD) or unacceptable toxicity. At the time of submission of this abstract, 17 pts terminated Tx; this abstract focuses on tolerability in these pts. Results: This trial is still recruiting; at the time of data cutoff for this abstract, 39 pts were enrolled. Data are included for 17 pts who discontinued Tx. Of all 39 pts, 12 were assigned to cohort A, 18 to cohort B, and 9 to cohort C. The median age of the total population was 72 yrs (range, 52-86 yrs), with 67.7% being male. The median number of prior lines of therapy was 4.0 (3.5 in cohort A, 5.0 in cohort B, and 3.0 in cohort C). This distribution was similar in the 17 pts who discontinued Tx so far (4, 7, and 6 in cohorts A, B, and C, respectively), with a median age of 72 yrs and 58.8% being male. Reasons for discontinuation of Tx were PD (7 pts), adverse events (AEs; 3 pts), death (5 pts: 2 pts due to PD, 2 pts due to infections, 1 pt due to hyperkalemia), and other reasons (2 pts: 1 pt aged 86 yrs with general health problems, 1 pt with increasing RI). Median Tx duration in these pts was 6.9 weeks in cohort A, 12.6 weeks in cohort B, and 12.9 weeks in cohort C. The dosage of POM was reduced to 3 mg in 3 pts (1 patient in each cohort), in all cases due to an AE (thrombocytopenia in 2 pts, pneumonia in 1 pt). However, no further Tx reductions occurred. The most frequent toxicity of any grade in the pts who discontinued was hematologic (82.4% [14 pts]), notably neutropenia in 58.8% (50% in cohort A, 42.9% in cohort B, 83.3% in cohort C), anemia in 52.9% (50% in cohort A, 28.6% in cohort B, 83.3% in cohort C), and thrombocytopenia in 52.9% (75% in cohort A, 14.3% in cohort B, 83.3% in cohort C). Grade 3/4 neutropenia occurred in 47.1%; grade 3/4 thrombocytopenia occurred in 35.3%. Notably, febrile neutropenia was reported in only 1 pt in cohort A. Granulocyte colony-stimulating factor was used in 52.9% of pts. Non-hematologic AEs were less frequent. Infections occurred in 7 pts (41.2%), all of which were pulmonary infections, with the exception of 1 case of nasopharyngitis. Asthenia (23.5%) and fatigue (23.5%) occurred predominantly in cohort C. No thromboembolic events or secondary primary malignancies have been reported to date. Conclusions: These data suggest that the combination of POM and LoDEX can be safely administered in pts with RI. A starting dose of POM 4 mg can be used throughout all stages of RI, and the side effects seen in this population have been previously reported with POM use (ie, mainly hematologic events and infections). Rates of neutropenia and thrombocytopenia are similar to reports in a non-RI population. Dose modifications should be considered in pts who develop neutropenia and thrombocytopenia; in pts showing signs of infections, dose interruptions may be considered. Disclosures Off Label Use: Pomalidomide in MM patients with renal insufficiency.. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Amgen: Honoraria. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Gamberi:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kueenburg:Celgene Corporation: Consultancy, Honoraria. Rosettani:Celgene Corporation: Employment. Collins:Celgene Corporation: Employment. Lersch:Celgene Corporation: Employment. Bacon:Celgene Corporation: Employment, Equity Ownership. Weisel:Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support. Sonneveld:Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 202-202 ◽  
Author(s):  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
Philippe Moreau ◽  
Andrzej Jakubowiak ◽  
Marc S Raab ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Phase 2 ◽  
Phase 3 ◽  
Advisory Committees ◽  
Infusion Reactions ◽  
Grade 3

Abstract Abstract 202 Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of MM cells, with lower expression on natural killer (NK) cells and little to no expression on normal tissues. The mechanism of action of Elo is primarily NK cell-mediated antibody-dependent cellular cytotoxicity against MM cells. In the Phase 1 portion of this 1703 study, Elo escalated from 5 to 20 mg/kg intravenously (IV) plus Ld resulted in an 82% objective response rate (ORR) in pts with R/R MM (Lonial, J Clin Oncol 2012). Historically, lenalidomide plus high dose dexamethasone provided a 61% ORR and a median 11.1 months (mos) progression free survival (PFS) in a similar pt population (Dimopoulos, Weber, N Engl J Med 2007). At the time of previous presentation (Moreau, ASCO 2012), median PFS in the Phase 2 portion the 1703 study of Elo + Ld was not reached (NR) with 10 mg/kg after a median follow-up of 17.2 mo and was 18.6 mo with 20 mg/kg. Methods: Pts with R/R MM previously treated with 1–3 prior therapies were randomized to Elo 10 or 20 mg/kg IV (days 1, 8, 15, 22 every 28 days in cycles 1–2 and days 1, 15 in cycles ≥3) plus lenalidomide 25 mg (PO) (days 1–21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on Elo dosing days. All pts received a premedication regimen of methylprednisolone or dexamethasone, diphenhydramine, ranitidine, and acetaminophen prior to elo dosing to minimize infusion reactions. Treatment continued until disease progression, unacceptable toxicity, or death. Pts were monitored for PFS until 60 days post-treatment follow-up. The primary objective was efficacy (ORR ≥partial response) according to the International Myeloma Working Group criteria. Results: 73 pts were treated (10 mg/kg, n=36; 20 mg/kg, n=37). Median age was 63 (range, 39–82) years, 55% received ≥2 prior therapies, 60% prior bortezomib, and 62% prior thalidomide. Median (range) duration of treatment was 20.5 (3.0–31.0) and 16.0 (1.0–32.0) cycles with 10 and 20 mg/kg, respectively. At the data cutoff (July 10 2012), 27 pts (10 mg/kg, n=15; 20 mg/kg, n=12) were ongoing and 46 pts discontinued (disease progression, n=26; adverse events, n=11; investigator/pt decision, n=9). ORR was 84% overall; 92% with 10 mg/kg (chosen as the Phase 3 dose) and 76% with 20 mg/kg (see Table). Overall median time to objective response was 1 month (range, 0.7–19.2). After a median follow-up of 18.1 mos, median PFS in the 10 mg/kg cohort was 26.9 mos (95% confidence interval [CI]: 14.9–NR); however, 15 pts are still ongoing with a median follow-up of 23.9 mos, and the PFS data will likely mature further with longer follow up. Median PFS in the 20 mg/kg cohort was 18.6 mos (95% CI: 12.9–NR). In subgroup analyses combining 10 and 20 mg/kg cohorts, ORRs for pts with 1 (n=33) or ≥2 prior therapies (n=40) were 91% and 78%, respectively, and overall median PFS were 25.0 (95% CI: 15.7–NR) and 21.3 mos (95% CI: 14.0–NR), respectively. Pts with prior thalidomide (n=45) had an ORR of 82% and median PFS of 26.9 mos (95% CI: 14.9–NR). Fifty-six (78%) pts experienced ≥1 treatment emergent grade ≥3 event. Most common were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%), anemia (12%), leukopenia (10%), hyperglycemia (10%), pneumonia (7%), diarrhea (7%), fatigue (7%), and hypokalemia (6%). Two deaths occurred on study (multiple adverse events [n=1; pneumonia, multiple organ failure and sepsis]; disease progression [n=1]). Investigator-designated (any grade) infusion reactions were reported in 12% of pts; 1 pt had a grade 3 event (rash). There were 4 cases of second primary malignancies (prostate; bladder; myelodysplastic syndrome; nasal squamous cell); all were deemed unrelated to Elo. Conclusions: In pts with R/R MM, Elo + Ld was generally well tolerated. Elo at 10mg/kg (the phase 3 dose) + Ld resulted in a high ORR and an encouraging median PFS of 26.9 mos after 18.1 mos of median follow-up. Phase 3 trials of Elo 10 mg/kg ± Ld are ongoing in newly diagnosed MM (ELOQUENT-1; CA204-006; NCT01335399) and R/R MM (ELOQUENT-2; CA204-004; NCT01239797). Disclosures: Richardson: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Elotuzumab is not currently approved for any indication. Jagannath:Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Facon:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:Celgene: Honoraria, Research Funding. Reece:Johnson & Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Deng:Abbott Biotherapeutics Corp: Employment. Kroog:BMS: Employment. Singhal:Abbott Biotherapeutics: Employment, Equity Ownership. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy.

Pomalidomide in Combination with Low-Dose Dexamethasone: Demonstrates a Significant Progression Free Survival and Overall Survival Advantage, in Relapsed/Refractory MM: A Phase 3, Multicenter, Randomized, Open-Label Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. LBA-6-LBA-6 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Martha Q Lacy ◽  
Philippe Moreau ◽  
Katja C Weisel ◽  
Kevin W. Song ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Open Label ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract LBA-6 Background: Multiple myeloma (MM) patients who have become refractory to bortezomib (BORT) and refractory or otherwise ineligible for thalidomide or lenalidomide (LEN) have a poor prognosis, with a median overall survival (OS) of 9 months (Kumar. Leukemia. 2012). There is no standard treatment available for these patients. Pomalidomide (POM) is a novel immunomodulatory drug that has shown activity in LEN- and BORT-refractory patients (Vij. ASCO 2012). MM-003 is an open-label, multicenter, phase 3 trial designed to compare the efficacy and safety of POM + low-dose dexamethasone (LoDEX) vs high-dose dexamethasone (HiDEX) in a population of patients who are refractory to both LEN and BORT. Here we present the final progression-free survival (PFS) and interim OS analysis of MM-003. Methods: Eligible patients with primary refractory or relapsed and refractory disease were enrolled. All patients with documented disease progression during treatment or within 60 days of completing their last myeloma therapy (including ≥ 2 consecutive cycles of LEN and BORT either alone or in combination), were randomized 2:1 to receive either POM + LoDEX (arm A) or HiDEX alone (arm B). Patients progressing on HiDEX had the opportunity to receive POM in the companion trial, MM-003C. Patients in arm A received POM 4 mg on days 1–21 and DEX 40 mg (20 mg for patients > 75 years of age) on days 1, 8, 15, and 22 in a 28-day cycle. Patients in arm B received DEX 40 mg (20 mg for patients > 75 years of age) on days 1–4, 9–12, and 17–20 in a 28-day cycle. Treatment was continued until progressive disease or unacceptable toxicity. Patients were stratified by age (≤ 75 vs > 75 years), disease population (refractory vs refractory and relapsed vs refractory and intolerant [intolerant to BORT only]), and number of prior therapies (2 vs > 2). The primary endpoint was PFS; secondary endpoints included safety, OS, overall response rate (ORR; ≥ partial response) by IMWG and EBMT criteria, duration of response, time to progression, and quality of life. OS was to be tested only if PFS would be statistically significant; therefore, alpha was controlled at 0.05 2-sided for both PFS and OS. Results: The Data and Safety Monitoring Board (DSMB) reviewed the protocol-specified final analysis results. 455 patients were randomized from March 2011 to Sept 2012. 302 patients received POM + LoDEX, and 153 patients received HiDEX. At the time of analysis, 45% of patients in arm A and 25% of patients in arm B remained on study. The median number of prior therapies was 5 (range, 1–17). 72% of patients were refractory to both LEN and BORT. At the PFS final analysis, with a median follow-up of 18 weeks, PFS was significantly longer with POM + LoDEX vs HiDEX alone (median 15.7 vs 8.0 weeks; 267 total events; hazard ratio [HR], 0.45; P <.001). OS interim analysis was performed as planned; OS also was significantly longer with POM + LoDEX vs HiDEX alone (median not reached vs 34 weeks; 134 events; HR, 0.53; P<.001), crossing the prespecified O’brien-Fleming superiority boundary. This includes 45 pts who received POM after progressing on HiDEX. Median duration of treatment was 12.4 weeks in arm A and 8 weeks in arm B. Following DSMB review of the data, immediate crossover of arm B patients to arm A was recommended. Overall, 25% of patients in arm A and 38% in arm B died, with progressive disease and infections as the primary reasons. Frequent grade 3/4 hematologic toxicities included neutropenia (42% in arm A vs 15% in arm B), thrombocytopenia (21% vs 24%), and febrile neutropenia (7% vs 0%). Other toxicities (grade 3/4) were predominantly infections (24% vs 23%), hemorrhage (3% vs 5%), glucose intolerance (3% vs 7%), neuropathy (1% vs 1%), and venous thromboembolism (1% vs 0%). The primary reason for discontinuation was progressive disease: 35% arm A and 49% arm B. Complete results will be presented at the meeting. Conclusions: POM + LoDEX significantly increased PFS and OS compared with HiDEX in patients who are refractory to LEN and BORT, a population with limited treatment options. The OS superiority boundary was crossed. Based on these data, POM + LoDEX should become the new standard of care in patients who have exhausted the novel agents, LEN and BORT. Disclosures: Dimopoulos: Celgene: Honoraria. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Lacy:Celgene: Research Funding. Moreau:Celgene: Honoraria, Speakers Bureau. Weisel:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Song:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria; OrthoBiotech: Consultancy, Honoraria, Speakers Bureau. Karlin:Celgene: Consultancy. Goldschmidt:Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Yu:Celgene: Employment. Sternas:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. San Miguel:Onyx: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees.

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