MM-005: A Phase 1 Trial Of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone (PVD) In Relapsed and/Or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1969-1969 ◽  
Author(s):  
Paul G. Richardson ◽  
Craig C. Hofmeister ◽  
David Siegel ◽  
Sagar Lonial ◽  
Jacob P. Laubach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Low Dose ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
The Us ◽  
Equity Ownership ◽  
Grade 3

Abstract Background The combination of the immunomodulatory drug lenalidomide (LEN) with the proteasome inhibitor bortezomib (BORT) and dexamethasone (DEX) has demonstrated substantial preclinical and clinical activity in patients with MM (Richardson PG, et al. Blood. 2010; Kumar S, et al. Blood. 2012). Pomalidomide (POM), a distinct immunomodulatory agent, has been approved by the US FDA for patients with RRMM with ≥ 2 prior therapies, including LEN and BORT, and progressive disease (PD) on or within 60 days of completion of the last line of treatment (Tx). POM with low-dose DEX (LoDEX) has demonstrated efficacy in patients with RRMM treated with prior LEN and BORT (San Miguel, EHA 2013; Leleu X, et al. Blood. 2013; Richardson PG, et al. Blood 2013; Lacy MQ, et al. Blood. 2011). MM-005 was designed to identify the optimal dose of POM-BORT-DEX (PVD) combination Tx for a phase 3 trial comparing PVD vs BORT + LoDEX (VD) in patients with RRMM (MM-007). Methods Eligible patients had RRMM with 1-4 prior lines of Tx including ≥ 2 consecutive cycles of LEN and a proteasome inhibitor. Patients must have been refractory to LEN (PD during or within 60 days of LEN Tx) but not refractory to BORT (at 1.3 mg/m2 twice weekly). The maximum tolerated dose (MTD) was determined using a 3 + 3 design in 5 cohorts. Each cohort received 21-day cycles of POM (1-4 mg/day on days 1-14); intravenous BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11); and LoDEX (20 mg/day on days 1-2, 4-5, 8-9, and 11-12; patients aged > 75 years received 10 mg/day on days 1-2, 4-5, 8-9, 11-12). The study protocol was revised to include a 6-patient cohort receiving subcutaneous BORT. Thromboprophylaxis was given to all patients as either aspirin or low-molecular-weight heparin. Once established, an expansion cohort was enrolled at the MTD. Tx was continued until PD or unacceptable toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1. MTD was the primary endpoint; secondary endpoints included safety, overall response rate (ORR; ≥ partial response), duration of response, and time to response (TTR). Results A total of 28 patients across all Tx cohorts is planned. As of April 2013, 22 patients have been enrolled, 21 patients were evaluable for baseline characteristics and safety, and 20 patients were evaluable for response. The median age was 57 years (range, 36-75 years). The median number of prior Tx lines was 2 (range, 1-4). All patients were refractory to LEN and had received prior BORT. 67% of patients had progressed on LEN as their last prior Tx and an additional 2 patients never responded to LEN. At the time of analysis, 14 of 22 (64%) patients remain on study. The primary reason for discontinuation was PD (27%). No DLTs have been observed during cycle 1 at any dose level; thus, the MTD/maximum planned PVD dose is POM 4 mg (days 1-14); intravenous BORT 1.3 mg/m2 (days 1, 4, 8, and 11 for cycles 1-8; days 1 and 8 for cycles 9+); and LoDEX 20 mg/day (days 1-2, 4-5, 8-9, and 11-12 for cycles 1-8; days 1-2, 8-9 for cycles 9+). The most common grade 3/4 adverse events (AEs) were neutropenia (29%) and thrombocytopenia (19%). With thromboprophylaxis, no deep vein thrombosis was observed. Despite 62% of patients having a history of peripheral neuropathy (PN) at baseline, only 29% developed grade 1 and 14% developed grade 2 PN; no grade 3/4 PN was observed. Only 1 patient has discontinued due to AE (Tx-unrelated metastatic pancreatic cancer). Thus far, the ORR is 75% (15 of 20 evaluable), 30% achieving very good partial response (VGPR) or better (including 1 patient in stringent complete response). Responses were rapid (median TTR of 1 cycle [range 1-3]). Many responses are ongoing and may improve with longer follow-up. Responses were also observed in patients with adverse cytogenetics. Updated and pharmacokinetic data on all 28 patients are planned for presentation at the meeting. Conclusions PVD was generally well tolerated in this population of LEN-refractory and BORT-exposed patients with RRMM, with no DLTs and no discontinuations due to Tx-related AEs to date. PVD had promising activity in this population of LEN-refractory and BORT-exposed RRMM pts with an ORR of 75% and 30% ≥ VGPR. The maximum planned dose of POM 4 mg/day on days 1-14; BORT 1.3 mg/m2 on days 1, 4, 8, and 11; and LoDEX 20 mg on days 1-2, 4-5, 8-9, and 11-12 (21-day cycles) has been incorporated into the ongoing MM-007 randomized, prospective phase 3 trial comparing PVD with VD in patients with RRMM (N = 782). Disclosures: Richardson: Johnson & Johnson: 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. Off Label Use: POM is approved in the US but not in Europe. Hofmeister:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Lonial:Sanofi: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Vesole:Millennium: Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Raje:Millennium: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding. Zaki:Celgene: Employment, Equity Ownership. Hua:Celgene: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Anderson:Acetylon: Equity Ownership; Gilead: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Oncopop: Equity Ownership.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Board ◽  
Prior Exposure ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: 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 Pharma: 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. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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.

Patient Outcomes By Prior Therapies and Depth Of Response: Analysis Of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 686-686
Author(s):  
Jesús F. San Miguel ◽  
Katja Weisel ◽  
Kevin W. Song ◽  
Michel Delforge ◽  
Lionel Karlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Depth Of Response ◽  
The Us ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Protein Reduction

Abstract Background Patient (pt) survival after becoming refractory/intolerant to novel agent treatment (Tx) is short (Kumar 2012). Depth of response has been shown to predict favorable outcomes (Harousseau, 2010). POM is a distinct oral IMiD® immunomodulatory agent with 3 primary activities: direct anti-myeloma activity, stromal cell-support inhibition, and immune modulation (Quach, 2010). POM has been approved by the US FDA for RRMM pts with ≥ 2 prior Tx, including lenalidomide (LEN) and bortezomib (BORT), and progressive disease (PD) on or within 60 days of completion of the last line of Tx. The randomized phase 3 trial MM-003 demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) with an acceptable tolerability profile for POM + LoDEX vs HiDEX in pts with RRMM (San Miguel, EHA 2013). Methods Pts must have been refractory to last prior Tx (PD during Tx or within 60 days) and exhausted BORT and LEN after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1-4, 9-12, and 17-20. HiDEX was chosen as the comparator to isolate the effects of POM as at the time of trial design it was the standard salvage Tx for heavily pretreated pts. Tx continued until PD or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS, time to progression (TTP), overall response rate (ORR; ≥ partial response [PR]), and safety. The current analysis describes pt outcomes by prior Tx history and depth of response. Results 302 pts were randomized to POM + LoDEX and 153 pts to HiDEX. Pt characteristics were well balanced between Tx arms. The median number of prior Tx was 5 (range, 2-17). Most pts (75%) were refractory to both BORT and LEN. POM + LoDEX significantly prolonged PFS vs HiDEX regardless of type or number of prior Tx (Table). OS favored POM + LoDEX for all subgroups analyzed. Importantly, significant OS benefits were observed in pts with ≤ 3 prior Tx and in pts who were refractory to LEN as last prior Tx. The ORR was consistently and significantly higher for POM + LoDEX vs HiDEX. The TTP for POM + LoDEX pts was similar in this trial vs that seen with their last prior LEN-based line of Tx (4.8 vs 6.2 months; P =.11). Additionally, LEN as the last prior Tx did not negatively impact PFS, OS, or ORR when compared with the intent-to-treat (ITT) population. In the POM + LoDEX arm, a total of 17 pts (6%) achieved a very good partial response or better, and 78 pts (26%) achieved PR as best response. Baseline characteristics were generally similar regardless of the degree of M-protein reduction. Analyses of the correlation between M-protein reduction and PFS and OS are ongoing and will be presented at the meeting. Conclusions In this heavily pretreated population, POM + LoDEX provided consistent efficacy regardless of number of prior Tx or prior Tx type. Significant OS benefits were observed for pts who received POM + LoDEX earlier in Tx and immediately following the development of LEN-refractory disease. Importantly, LEN as last prior Tx did not impact response, PFS, or OS vs the overall ITT population. POM + LoDEX should be considered a standard Tx option in RRMM pts. Disclosures: San Miguel: Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: POM is approved in the US but not in Europe. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Song:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Delforge:Celgene: Honoraria. Karlin:Celgene: Export board committee Other, Honoraria; Janssen: Honoraria. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Moreau:Celgene: Honoraria, Speakers Bureau. Oriol:Celgene: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Alegre:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Martinez-Lopez:Celgene: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Renner:Celgene: Consultancy, Honoraria, Travel support Other. Bahlis:Celgene: Consultancy, Honoraria, Research Funding. Yu:Celgene: Employment, Equity Ownership. Teasdale:Celgene: Employment, Equity Ownership. Sternas:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Dimopoulos:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Health-Related Quality of Life Among Patients with Relapsed or Refractory Multiple Myeloma Who Received Pomalidomide, Bortezomib, and Low-Dose Dexamethasone Versus Bortezomib and Low-Dose Dexamethasone - Results from the Phase 3 Optimismm Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1960-1960 ◽  
Author(s):  
Katja Weisel ◽  
Meletios A Dimopoulos ◽  
Philippe Moreau ◽  
Munci Yagci ◽  
Alessandra Larocca ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Equity Ownership

Abstract Introduction : A diagnosis of multiple myeloma (MM) has a substantial impact on health-related quality of life (HRQoL) due to associated symptoms, such as bone pain, infection, and fatigue. Furthermore, HRQoL deteriorates with each subsequent line of therapy. The phase 3 OPTIMISMM study (NCT01734928) demonstrated that pomalidomide, bortezomib, and low-dose dexamethasone (PVd) resulted in a significantly longer progression-free survival (PFS) and greater overall response rate (ORR) compared with bortezomib and low-dose dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM), all of whom had received prior treatment with lenalidomide. Given that HRQoL in RRMM is an important consideration, we conducted this analysis to evaluate the effect of PVd versus Vd on HRQoL in patients enrolled in the OPTIMISMM study. Methods : The OPTIMISMM study was a phase 3, multicenter, randomized, open-label study that enrolled adult RRMM patients who had received 1 to 3 prior anti-myeloma regimens including lenalidomide. Patients (N=559) were randomly assigned to receive PVd (n=281) or Vd (n=278) per 21-day treatment cycle until progression or treatment discontinuation. HRQoL was assessed as an exploratory endpoint using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30) questionnaire at Day 1 of each 21-day cycle prior to treatment administration and at the end of treatment. The primary domain of interest was the Global Health Status/QoL domain of the QLQ-C30. Analyses were performed in the HRQoL-evaluable population, which included randomized patients who completed the QLQ-C30 assessment at baseline and at least one post-baseline visit. Key primary analyses of PVd versus Vd on the global QoL domain of the QLQ-C30 included a longitudinal assessment of change from baseline using a mixed-model repeated measure (MMRM) approach; an assessment of the proportion of patients experiencing clinically meaningful deterioration (i.e., ≥10 points worsening from baseline) at pre-selected post-baseline visits; and an analysis of time to first clinically meaningful deterioration. Results : The HRQoL-evaluable population consisted of 240 patients in the PVd group and 209 in the Vd group; baseline characteristics were well-balanced between the treatment groups. HRQoL compliance rates based on the number of patients expected to complete the QLQ-C30 at each given visit exceeded 80% for most visits among both groups. Mean (SD) baseline scores for the global QoL domain of the QLQ-C30 were similar between groups (61.0 [23.2] in the PVd group and 63.5 [21.3] in the Vd group); these scores were maintained over time for both treatment groups, with no clinically meaningful differences observed between the treatment groups at any cycle (Figure 1). The MMRM analyses showed no clinically meaningful difference in global QoL of patients between the PVd group and the Vd group. There was also no significant difference observed in the proportion of patients who experienced clinically meaningful worsening in the global QoL domain between the treatment groups throughout the pre-selected post-baseline visits. The median time to the first clinically meaningful worsening was also similar between treatment groups: 3.0 months for the PVd group and 3.4 months for the Vd group, respectively (hazard ratio: 1.20; 95% confidence interval: 0.9456, 1.5151; p=0.1351; Figure 2 for when death was considered as an event); similar results were observed when death was censored. Conclusions: The results from this analysis of the OPTIMISMM study showed that the triplet regimen of PVd, which consisted of pomalidomide added to the doublet regimen of Vd, did not compromise HRQoL in lenalidomide-treated patients with RRMM. Overall, there were no clinically meaningful differences in the Global Health Status/QoL domain of the QLQ-C30 between treatment groups. These results are meaningful and provide further evidence of the clinical benefits of the addition of pomalidomide to Vd, which include significant improvements in PFS and ORR. Disclosures Weisel: Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria. Rodriguez Otero:Clínica Universidad de Navarra: Employment; Takeda: Consultancy; Bristol Myers Squibb: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hayden:Celgene: Honoraria; Jassen: Honoraria; Amgen: Honoraria. Krauth:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Guo:Celgene Corporation: Consultancy. Purnomo:Celgene: Employment. Yu:Celgene: Employment, Equity Ownership. Grote:Celgene: Employment. Biyukov:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Phase I Study to Assess the Safety and Tolerability of AZD1152 In Combination with Low Dose Cytosine Arabinoside In Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 656-656 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Mikkael A. Sekeres ◽  
Vincent Ribrag ◽  
Philippe Rousselot ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Cytosine Arabinoside ◽  
Research Funding ◽  
Low Dose ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 656 Background: Aurora B kinase is a key mitosis regulator that is overexpressed in a range of malignancies, including AML. AZD1152 is a potent selective inhibitor of Aurora B kinase. This ascending dose cohort study was designed to assess the safety and tolerability of AZD1152 in combination with low dose cytosine arabinoside (LDAC), the only agent that has currently demonstrated a survival advantage over palliative care in older patients with AML. Methods: Patients aged ≥60 years with newly diagnosed AML unfit for intensive induction chemotherapy were included. Cohorts of 6 patients received escalating doses of a 7-day continuous iv infusion of AZD1152, at doses of 800 mg up to the monotherapy maximum tolerated dose (MTD) of 1200 mg, in combination with LDAC 20 mg sc injection twice daily for 10 days. AZD1152 and LDAC were administered in 28-day cycles. If 1 or fewer dose-limiting toxicities (DLTs) were observed in a cohort, AZD1152 dose was escalated. A DLT was an adverse event (AE) or laboratory abnormality considered related to AZD1152, which was a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non-hematological toxicity (despite adequate supportive care). If 2 or more of 6 patients had a DLT, the dose was reduced or enrollment was stopped into that cohort. The MTD was defined as the dose at which 0 or 1 of 6 patients experienced a DLT. Following determination, the MTD cohort was expanded to 12 patients. Objective response was evaluated by the investigators using AML International Working Group clinical response criteria. AEs and serious AEs (SAEs) were evaluated according to CTCAE version 3. Blood samples were taken pre-dose and at selected times post dose for 3 cycles to determine levels of AZD1152, its active metabolite AZD1152 hQPA and LDAC. Results: At the data cut-off on 02/08/10 (data validation ongoing), 22 patients had been treated with the combination of LDAC plus AZD1152 (n=6 800 mg; n=13 1000 mg; n=3 1200 mg). Mean age (range) across the 3 cohorts was 71.1 (61–82) years, 14 (64%) were male, 21 were Caucasian and 1 was African American. The mean age of the 800 mg cohort was older (75.2 years) compared with the 1000 mg and 1200 mg cohorts (70.3 and 67.3 years, respectively). At baseline, 8 (36%) patients had de novo AML, and 7 (32%), 2 (9%) and 1 (5%) had AML secondary to myelodysplastic syndrome, myeloproliferative disorder and chemotherapy, respectively. All 22 patients had newly diagnosed AML. All patients received at least 1 cycle of treatment, 10 received ≥2 cycles and 1 received 5 cycles. One patient received an AZD1152 dose reduction (1000 mg to 800 mg) for their second cycle due to a high creatinine level, which was present at pre-dosing. Two patients in the 1200 mg group had DLT episodes of CTCAE grade 3 mucositis. The MTD of AZD1152 in combination with LDAC was defined as 1000 mg. All patients had at least 1 AE, the most common were myelosuppression (febrile neutropenia, anemia and thrombocytopenia in 50%, 36% and 27% of patients, respectively), stomatitis/mucosal inflammation, nausea, diarrhea and infection (each in 45% of patients). The most common grade 3/4 CTCAEs were febrile neutropenia, infection, thrombocytopenia and anemia. There were 3 (13.6%) deaths, 1 in each cohort; 2 were due to SAEs of febrile neutropenia (multiple-organ failure) and hypoxia (fungal pulmonary infection) and 1 was due to an unknown cause. Nine of 21 patients (43%) were reported by the investigators to have had a clinical response (CR + CRi) (Table). Conclusion: The MTD of AZD1152 in combination with LDAC in older patients with newly diagnosed AML was 1000 mg. AZD1152 at a dose of 1000 mg combined with LDAC had an acceptable tolerability profile. Two patients had DLTs of mucositis at the monotherapy MTD of 1200 mg. AEs of febrile neutropenia, thrombocytopenia and anemia were slightly higher than those in patients treated with either agent alone, although many patients experienced these AEs at study entry. The investigator-reported clinical response rate (CR + CRi) was 43%. The development of AZD1152 is continuing with a Phase II study in older patients with AML considered unfit for intensive chemotherapy. Disclosures: Kantarjian: AstraZeneca: Research Funding. Off Label Use: Low-dose cytosine arabinoside is an approved agent for the treatment of patients with AML; this study evaluated low-dose cytosine arabinoside in combination with AZD1152, an investigational agent that inhibits Aurora Kinase B . Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Ribrag:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Celgene: Research Funding; LFB: Research Funding. Owen: AstraZeneca: Employment, Equity Ownership. Stockman:AstraZeneca: Employment, Equity Ownership. Oliver:AstraZeneca: Employment, Equity Ownership.

scholarly journals Selinexor in Combination with Bortezomib and Dexamethasone (SdB) Demonstrates Significant Activity in Patients with Refractory Multiple Myeloma (MM) Including Proteasome-Inhibitor Refractory Patients: Results of the Phase I Stomp Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 977-977 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Rami Kotb ◽  
Michael Sebag ◽  
Heather J. Sutherland ◽  
Richard LeBlanc ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Low Dose ◽  
Refractory Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Best Response ◽  
Equity Ownership

Abstract Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (dex) has demonstrated potent anti-cancer activity in patients with heavily pretreated MM. While the development of proteasome inhibitors (PIs) has transformed the treatment of MM, acquired resistance to PIs limit their efficacy. Preclinical studies have shown that selinexor, when combined with bortezomib, can restore sensitivity of bortezomib-resistant MM to this drug, inducing tumor growth inhibition and increasing survival in MM models in mice. In this clinical trial (NCT02343042), we investigated the safety, tolerability and efficacy of the combination of selinexor, bortezomib and low dose dex (SdB) in patients (pts) with refractory MM. Methods - This phase 1b/2 dose escalation study using a standard 3+3 design, was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for SdB. The study included pts with refractory MM, after ≥ 1 prior therapy. Pts with prior PI relapsed and/or refractory disease were included, provided the patient's MM was not refractory to bortezomib as last therapy. Selinexor was independently dosed escalated in once-weekly (QW, starting at 80 mg; N=7, 100 mg N=6 pts) or twice-weekly (BIW, starting at 60 mg; N=3, 80 mg N=6 pts) regimens. Bortezomib (1.3 mg/m2 sc) was administered either once-weekly or twice-weekly and dex was given orally 40 mg QW or 20 mg BIW. Results - As of July 25th, 2016, enrollment in the dose escalation cohorts has been completed with 22 pts (12 male /10 female). The median age is 65 years (range, 46 - 74), with a median of 4 (range, 1 - 12) prior treatment regimens. One dose limiting toxicity (Grade 4 thrombocytopenia without bleeding) in the 80 mg BIW cohort was observed but the MTD has not been reached. Common related grade 1/2 adverse events (AEs) include: fatigue 41%, nausea 41%, anorexia 36%, and weight loss 18%. Grade 3/4 AEs include: thrombocytopenia 41%, anemia 18%, and neutropenia 18%. One case of grade 1 peripheral neuropathy in the 80 mg BIW cohort was reported. All pts were evaluable for response. The ORR (≥partial response, PR) was 77% with ≥VGPR 27% (1 pt in CR and 5 pts in VGPR) and 11 PRs. There were 3 minor responses (14%), 1 stable disease, 1 progressive disease (5% each). Seven of the 12 pts with PI-refractory MM responded (ORR 58%). A summary of response by PI treatment history is shown in Table 1. Ten patients have remained on study >4 months, including 7 patients still on trial (longest >9 months). Based on tolerability and anti-MM activity, RP2D of SdB is selinexor 100 mg, bortezomib 1.3 mg/m2 and dex 40 mg, all given once weekly. At the RP2D, all six pts achieved ≥PR (ORR 100%). Conclusions - Selinexor in combination with bortezomib and dex is well tolerated and highly active in refractory MM. Toxicities are manageable and similar to selinexor or bortezomib monotherapy. Peripheral neuropathy is uncommon, consistent with the use of weekly bortezomib sc and the lack of neuropathy with selinexor. Overall, the SdB regimens induced an ORR of 77% with ≥VGPR of 27%. In patients with PI-refractory MM, the ORR was 58%, indicating that the addition of selinexor restores sensitivity to bortezomib. These results confirm the preclinical data supporting synergistic effects of selinexor when combined with PIs. This promising, once-weekly treatment regimen may provide deeper and more durable responses in pts with relapsed / refractory MM, including those with PI-refractory disease. Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Disclosures Bahlis: Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria. Sebag:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Sutherland:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Amgen: Honoraria; J+J: Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Kouroukis:Amgen: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Takeda: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Lentzsch:BMS: Consultancy; Celgene: Consultancy, Honoraria. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 814-814 ◽  
Author(s):  
Paul G. Richardson ◽  
Melissa Alsina ◽  
Donna M. Weber ◽  
Steven E. Coutre ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Treatment Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Overall Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: 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; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3026-3026 ◽  
Author(s):  
Jesús F. San-Miguel ◽  
Vania T.M. Hungria ◽  
Sung-Soo Yoon ◽  
Meral Beksac ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Final Analysis ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Study Therapy

Abstract Introduction: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including epigenetics and protein metabolism. In the phase 3 clinical trial PANORAMA 1, panobinostat in combination with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression-free survival of approximately 4 months compared with that with placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex). Further analyses of patient outcomes by prior treatment demonstrated that the magnitude of PFS benefit was greatest among patients who received at least 2 prior regimens, including bortezomib and an immunomodulatory drug (IMiD; PAN-BTZ-Dex [n = 73]: 12.5 months [95% CI, 7.3-14.0 months]; Pbo-BTZ-Dex [n = 74]: 4.7 months (95% CI, 3.7-6.1 mo; HR 0.47 [95% CI, 0.32-0.72]). These data supported the regulatory approvals of PAN-BTZ-Dex for the treatment of patients with multiple myeloma who received at least 2 prior regimens, including bortezomib and an IMiD. Here we present the final analysis of overall survival (OS) for the entire patient population and among patients who received at least 2 prior regimens, including bortezomib and an IMiD. Methods: The study design for the PANORAMA 1 trial was described previously (San-Miguel. Lancet Oncol. 2014;15:1195-206). The key secondary endpoint was OS. As of June 29, 2015, the 415 events required to conduct the final analysis of OS had been observed. Kaplan-Meier estimation was utilized for OS analyses for the entire population (N = 768), the pre-specified subgroup of patients who received prior bortezomib and IMiD (n = 193), and patients who received at least 2 prior regimens including bortezomib and an IMiD (n = 147). Results: The median OS of patients who received PAN-BTZ-Dex in the overall population was 40.3 months (95% CI, 35.0-44.8 months) vs 35.8 months (95% CI, 29.0-40.6 months) for the Pbo-BTZ-Dex arm with HR 0.94 [95% CI, 0.78-1.14], P = .5435 (Fig 1A). The percentage of patients in each arm who received post-study therapy was 37.7% in the PAN-BTZ-Dex arm and 48.8% in the Pbo-BTZ-Dex arm. The median OS of patients who received at least 2 prior lines, including bortezomib and an IMiD, was 25.5 months (95% CI, 19.6-34.3 months) in the PAN-BTZ-Dex arm vs 19.5 months (95% CI, 14.1-32.5 months) in the Pbo-BTZ-Dex arm (Fig. 1B). The proportion of patients in this subgroup who received post-study therapy was 35.6% in the PAN-BTZ-Dex arm and 66.2% in the Pbo-BTZ-Dex arm. Conclusion: For the overall PANORAMA 1 study population, patients in the PAN-BTZ-Dex arm demonstrated an increase in median OS of 4.5 months vs patients in the Pbo-BTZ-Dex arm, but this result was not statistically significant (P = .5435). Median OS was also slightly longer for the PAN-BTZ-Dex arm among the more heavily pretreated subgroup of patients who received at least 2 prior regimens, including bortezomib and an IMiD. A higher percentage of patients on the Pbo-BTZ-Dex arm received post-study therapy vs the PAN-BTZ-Dex arm, which may have confounded the OS results. In summary, PAN-BTZ-Dex demonstrates statistically significant increases in PFS vs Pbo-BTZ-Dex in patients with relapsed or relapsed and refractory MM; however, this did not translate to a statistically significant increase in OS. Future trials will plan to focus on further optimization of dose and schedule of panobinostat and bortezomib to improve outcome, as well as novel combinations with other agents, including IMiDs and next-generation proteasome inhibitors. Figure 2. Figure 2. Disclosures Beksac: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau. Dimopoulos:Janssen: Honoraria; Janssen-Cilag: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Jedrzejczak:Onconova: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Richardson:Bristol-Myers Squibb: 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; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

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