Safety and Efficacy of Ruxolitinib in an Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis (MF): An 1144-Patient Update

Abstract BACKGROUND Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated reductions in splenomegaly and disease-related symptoms, as well as improved survival, in patients with MF and has proved superior to placebo and best available therapy in the 2 phase 3 COMFORT studies. JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) is a phase 3b, expanded-access trial for countries with no access to ruxolitinib outside a clinical trial and was designed to assess the safety and efficacy of ruxolitinib in patients with MF. As of 03 June 2014, 2027 patients have been enrolled in 25 countries, with a planned enrollment of 2500 patients. METHODS Eligible patients had MF classified as high risk, intermediate (Int)-2 risk, or Int-1 risk, with a palpable spleen (≥ 5 cm from the costal margin). Patients received starting doses of ruxolitinib 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 ruxolitinib. 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 patients have completed 24 months of treatment or ended treatment due to commercial availability. RESULTS This analysis includes results for 1144 enrolled patients (primary MF, 58.8%; n = 673) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2014). At baseline, median age was 68 y (range, 18-89 y); 46.7% were female; median palpable spleen length was 13 cm below the costal margin; median hemoglobin was 105 g/L (range, 44-200 g/L) and 40.3% of patients had hemoglobin levels ˂ 100 g/L; median platelet level was 256 × 109/L (75-1910 × 109/L); mean FACT-Lym TS was 41.9. Most patients (69%) remained on treatment (35.5%) or completed treatment per protocol (33.5%; transition to commercial drug). Primary reasons for discontinuation included adverse events (AEs; 13.8%), disease progression (7.1%), and death (3.8%). Median exposure was 11.1 months; the median average daily dose was 37.2 mg for patients starting at 20 mg bid (64%; n = 728) and 23.4 mg for patients starting at 15 mg bid (33%; n = 374). The majority of patients (75.7%) had dose increases/decreases and 23.9% had a dose interruption. The most common hematologic grade ≥ 3 AEs were anemia (33.0%), thrombocytopenia (12.5%), and neutropenia (3.9%), which led to discontinuation in 2.6%, 3.2%, and 0.3% of patients, respectively. Mean hemoglobin levels declined from baseline (108 g/L) to a nadir of 85 g/L at 8 to 12 weeks and increased to near-baseline levels after week 12; mean platelet levels decreased from baseline (318 × 109/L) to a nadir of 139 × 109/L and remained stable over time. The most common nonhematologic AEs (≥ 10%) were diarrhea (14.5%), pyrexia (13.3%), fatigue (12.9%), and asthenia (12.5%) and were primarily grade 1/2; grade ≥ 3 AEs were low overall (< 2%), except pneumonia (3.6%), which led to discontinuation in 6 patients (0.5%). Serious AEs were reported for 32.3% of patients. Rates of infections were low; all-grade infections ≥ 5% included nasopharyngitis (6.3%), urinary tract infection (6.0%), and pneumonia (5.3%). Tuberculosis was reported for 3 patients (0.3%; no grade 3/4); no hepatitis B was reported. At weeks 24 and 48, 55% (431/782) and 61% (301/497) of patients achieved a ≥ 50% reduction from baseline in palpable spleen length, respectively; 23% (181/782) and 18% (88/497) had 25% to 50% reductions. Most patients (69%; 733/1062) experienced a ≥ 50% reduction in spleen length from baseline at any time (Figure). Clinically significant improvements on the FACT-Lym TS were seen as early as week 4 and were maintained at week 48 (mean change from baseline: week 4, 11.0; week 48, 9.4; the range for the minimally important difference is 6.5 to 11.2 points). CONCLUSIONS The JUMP study includes the largest cohort of MF patients treated with ruxolitinib reported to date. Consistent with previous reports, the most common AEs were anemia and thrombocytopenia; however, they rarely led to discontinuation. As observed previously, the majority of patients experienced reductions in spleen length and clinically meaningful improvements in symptoms were observed with ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the phase 3 COMFORT studies. Figure 1 Figure 1. Disclosures le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Schafhausen:Novartis: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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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 ◽

10.1182/blood.v126.23.2799.2799 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2799-2799 ◽

Cited By ~ 4

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.

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Safety and Efficacy of Ruxolitinib for the Final Enrollment of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis (N = 2233)

Blood ◽

10.1182/blood.v128.22.3107.3107 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3107-3107 ◽

Cited By ~ 1

Author(s):

Lynda Foltz ◽

Giuseppe A. Palumbo ◽

Bruno Martino ◽

Francesca Palandri ◽

Haifa Kathrin Al-Ali ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Final Analysis ◽

Costal Margin ◽

Open Label ◽

Advisory Committees ◽

Safety And Efficacy ◽

Fatigue Score ◽

Expanded Access

Abstract BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has proved superior to placebo and best available therapy in the phase 3 COMFORT studies for patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF). Ruxolitinib-treated pts demonstrated improvements in splenomegaly and MF-related symptoms as well as improved overall survival. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of ruxolitinib in pts with MF and includes those with no access to ruxolitinib outside of a clinical trial. Here, we report updated safety and efficacy findings for the full enrollment of JUMP, which includes 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 ruxolitinib based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to < 100 × 109/L], 15 mg bid [100 to 200 × 109/L], 20 mg bid [> 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores. The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 2233 pts (primary MF, 59.4% [n = 1326]) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2016). At baseline, median age was 67 y (range, 18-89 y); 54.5% were male; median palpable spleen length was 12 cm below the costal margin; median time since diagnosis was 25.8 months. Median hemoglobin (Hb) was 106 g/L, and 38.3% of pts had Hb levels ˂ 100 g/L; median platelet count was 254 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.9 and 33.4, respectively. At data cutoff, 15.8% of pts (353/2233) remained on treatment and 45.1% (1006/2233) completed treatment per protocol (ie, transitioned to commercial ruxolitinib). The primary reasons for treatment discontinuation were adverse events (AEs; 17.7%), disease progression (8.6%), and death (4.1%). Median exposure was 12.4 months; the median average daily dose of ruxolitinib was 23.1 mg for pts starting at 15 mg bid (n = 647 [29.0%]) and 36.5 mg for pts starting at 20 mg bid (n = 1384 [61.9%]). Overall 66.7% of pts had dose modifications and 26.3% had a dose interruption. Grade (G) 3/4 hematologic AEs included anemia (34.1%), thrombocytopenia (16.3%), and neutropenia (4.5%), which led to discontinuation in 1.5%, 2.7%, and 0.1% of pts, respectively. Nonhematologic AEs were primarily G1/2, and the most common (≥ 10%) were pyrexia (15.6%; G3/4, 2.3%), asthenia (14.9%; G3/4, 2.2%), and diarrhea (12.0%; G3/4, 1.1%). Rates of other G3/4 AEs were low (≤ 2%), except pneumonia (4.3%), which led to discontinuation in 10 pts (0.5%). Rates of infections were generally low; all-grade infections in ≥ 5% of pts included pneumonia (6.8%), urinary tract infection (5.6%), and nasopharyngitis (5.0%). Herpes zoster was reported in 4.6% of pts (G3/4, 0.5%), tuberculosis in 0.2% (G3/4, 0.04%) and hepatitis B in 1 pt (G3/4, 0.04%). At wk 24 and 48, 56.6% (874/1545) and 61.6% (658/1069) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 23.3% (360/1545) and 18.9% (202/1069) had 25% to 50% reductions, respectively. Most pts (70.2% [1441/2054]) experienced a ≥ 50% reduction at any time; 23.7% had complete resolution of splenomegaly (Figure). At wk 24 and 48, 97.1% (67/69) and 92.3% (48/52) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (42.4% [596/1406]; 46.6% [675/1447]) and wk 48 (42.9% [404/941]; 45.4% [434/957]). Overall, 221 patients received ESAs to manage anemia (G1, 7.2%; G2, 49.8%; G3, 38.9%; G4, 4.1%), and the majority had improved (32.6%) or resolved (31.7%) anemia (worsened, 16.3%; no change, 19.5%). CONCLUSIONS: This study includes the largest cohort of pts with MF treated with ruxolitinib to date. Consistent with findings from other studies, 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 ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the COMFORT studies. Disclosures Foltz: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Le Coutre:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Vannucchi:Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Bouard:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Khanna:Novartis Healthcare Pvt. Ltd: Employment. Zaritskey:Janssen: Consultancy; Novartis: Consultancy.

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Safety and Efficacy of Ruxolitinib Retreatment after Treatment Interruption in Patients Enrolled in an Open-Label, Multicenter, Expanded-Access Study in Myelofibrosis

Blood ◽

10.1182/blood.v124.21.5567.5567 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5567-5567

Author(s):

Vikas Gupta ◽

Renato S Tavares ◽

Martin Griesshammer ◽

Lynda M Foltz ◽

Pia Raanani ◽

...

Keyword(s):

Research Funding ◽

Treatment Interruption ◽

Costal Margin ◽

Open Label ◽

Expanded Access ◽

Jak2 Inhibitor ◽

Length Increase ◽

Study Population ◽

Large Phase ◽

Grade 3

Abstract BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and myelofibrosis (MF)-related symptoms. Additionally, ruxolitinib proved superior to placebo and best available therapy in the phase 3 COMFORT studies and showed improved survival. In some patients (pts) receiving ruxolitinib, adverse events (AEs) may lead to treatment interruption; in such pts, AE management, dose optimization, and efficacy expectations may be balanced. This analysis provides further information about the efficacy and safety of ruxolitinib in pts who have restarted treatment after treatment interruption (cutoff date, 01 January 2014) in the JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) trial, a large, phase 3b, expanded-access program. METHODS: Pts with MF classified as high risk, intermediate-2 risk, or intermediate-1 risk, with a palpable spleen (≥ 5 cm from the costal margin), received starting doses of ruxolitinib based on their 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]). Endpoints included safety and tolerability, as well as changes in spleen length, symptoms, and laboratory values. This analysis included all pts who started study treatment ≥ 1 year before data cutoff and had ≥ 1 dose interruption of ≥ 7 days. RESULTS: This analysis included 207 pts (primary MF, 68.1%; female, 53.1%; median age, 69 years) presenting with baseline medians: spleen length, 13 cm (range, 1.0-35.0 cm); hemoglobin, 99 g/L (50.7% of pts with < 100 g/L); and platelets, 199.5 × 109/L. At data cutoff, most pts (60.9%) remained on treatment (38.2%) or completed treatment per protocol (22.7%); the main reasons for discontinuation included AEs (18.4%), death (6.8%), disease progression (5.3%), and other (8.7%). Overall, the median duration of exposure was 12.5 months: 1.9 months from baseline to interruption and 6.5 months after restart. The mean daily dose was 30.5 mg prior to treatment interruption and 19.4 mg after treatment restart. Dose interruptions lasted 7 to 14 days in 41.1% of pts (15 to 21 days, 26.6%; > 21 days, 32.4%) and were mostly due to AEs (92.3%). Most pts (67.1%) had only 1 dose interruption. At weeks 12, 24, and 48, overall 45%, 53%, and 54% of pts, respectively, achieved a ≥ 50% reduction from baseline in palpable spleen length. In addition, at the same time points, 29%, 23%, and 23% achieved reductions from 25% to 50%. 68.2% (133/195) of pts experienced a ≥ 50% reduction at any time; 77 pts (58%) achieved it before interruption and 56 pts (42%) after restart. From spleen length at restart, 24% of pts achieved a further 50% reduction, 9% experienced a spleen length increase ≥ 50%, and 67% remained stable in between. Clinically meaningful improvements in symptoms (the range for the minimally important difference is 6.5 to 11.2 points), as assessed by the FACT-Lymphoma Total Score, were observed as early as week 4 (mean change from baseline, 9.6), with a trend toward improvement at week 48 (6.1). The most common hematologic grade 3/4 AEs were anemia (43.5%) and thrombocytopenia (41.1%), leading to permanent discontinuations in 9 (4.4%) and 14 pts (6.8%), respectively. Rates of nonhematologic AEs grade ≥ 3 were low (≤ 2%), except for pneumonia (5.8%), abdominal pain (3.4%), urinary tract infection (3.4%), increased γ-glutamyltransferase (2.4%), asthenia (2.4%), and dyspnea (2.9%), but these rarely led to discontinuations (≤ 1%). Despite > 3-times longer exposure after restart, the rates of AEs before ruxolitinib interruption and after treatment restart were similar overall. CONCLUSIONS: In this cohort of pts, ruxolitinib provided reductions in spleen size and symptoms prior to and after treatment interruption. After restart of treatment, pts were able to stay on ruxolitinib at a median dose of ≈ 10 mg bid, and most pts did not require another interruption. Rates of AEs did not increase after treatment restart, with rates of some AEs decreasing; discontinuation rates after restart of treatment are comparable to those observed in the overall study population (Al-Ali et al. EHA 2014). Overall, ruxolitinib is generally safe and well tolerated and provides meaningful reductions in splenomegaly and symptoms in pts who have restarted ruxolitinib after treatment interruption. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

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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 ◽

10.1182/blood.v114.22.301.301 ◽

2009 ◽

Vol 114 (22) ◽

pp. 301-301 ◽

Cited By ~ 4

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.

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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 ◽

10.1182/blood.v122.21.4071.4071 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4071-4071 ◽

Cited By ~ 7

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.

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Safety and Efficacy of Ruxolitinib in Patients with Low Platelets Enrolled in a Phase 3b Expanded-Access Study in Myelofibrosis (MF)

Blood ◽

10.1182/blood.v124.21.1859.1859 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1859-1859 ◽

Cited By ~ 2

Author(s):

Martin Griesshammer ◽

Alessandro M. Vannucchi ◽

Philipp le Coutre ◽

Renato S Tavares ◽

Haifa Kathrin Al-Ali ◽

...

Keyword(s):

Adverse Events ◽

Interim Analysis ◽

Research Funding ◽

Costal Margin ◽

Efficacy Data ◽

Safety And Efficacy ◽

Expanded Access ◽

Daily Dose ◽

Median Daily Dose ◽

Grade 3

Abstract BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and MF-related symptoms and improved survival compared with placebo and best available therapy in the 2 large phase 3 COMFORT studies. Those studies required baseline platelet (PLT) counts ≥ 100 × 109/L, limiting safety and efficacy data in patients (pts) with lower PLTs; however, thrombocytopenia is frequent in MF. Ongoing phase 2 clinical trials in pts with low PLTs have shown ruxolitinib to be generally well tolerated and to provide efficacy benefits for these pts. To gather additional safety and efficacy data in pts with low PLTs, recruitment for JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients), a phase 3b expanded-access trial for countries with no access to ruxolitinib outside a clinical trial, was extended to pts with baseline PLT counts ≥ 50 × 109/L. Here, we present safety and efficacy data from a planned interim analysis of ruxolitinib in pts with baseline PLT count ≥ 50 to < 100 × 109/L. METHODS: Eligible pts had high-, intermediate-2, or intermediate-1-risk MF, with a palpable spleen (≥ 5 cm from the costal margin) and baseline PLT counts ≥ 50 × 109/L. The starting doses of ruxolitinib was 5 mg bid for pts with baseline PLTs ≥ 50 to < 100 × 109/L. The primary endpoint was assessment of safety and tolerability of ruxolitinib based on the frequency, duration, and severity of adverse events (AEs). An interim analysis of the safety and efficacy of ruxolitinib in pts with PLTs ≥ 50 to < 100 × 109/L at baseline (low-PLT group) was planned for when the first 50 low-PLT pts had completed 6 mo of therapy; this analysis includes results from the first 6 mo of treatment. The final analysis will be performed after all pts have completed 24 mo of treatment or ended treatment due to commercial availability. RESULTS: At data cutoff (01 January 2014), 50 pts with low PLTs had been treated for 6 mo and are included in this analysis. Pt characteristics were median age, 68.5 years; median palpable spleen length, 15.5 cm below the costal margin; and female, 50.0%. Median (range) baseline hemoglobin (Hb) was 98 g/L (57-149 g/L) and PLT count was 87 × 109/L (68 to 98 × 109/L). Most pts (76.0%) remained on or completed treatment as per protocol at the time of data cutoff. The primary reasons for discontinuation included adverse events (AEs; n = 9) and disease progression (n = 2). The median daily dose was 11.8 mg/day (range, 5.9-40.0 mg/day). Of evaluable pts at week 24, 38.2% (13/34 pts) achieved a ≥ 50% reduction from baseline in palpable spleen length; 38.2% had reductions of ≥ 25% to < 50%. Overall, 44.7% of pts achieved a ≥ 50% reduction from baseline in spleen length at any time. Clinically meaningful improvements in symptoms, as assessed using the FACT-Lymphoma Total Score (the range for the minimally important difference is 6.5 to 11.2 points), were seen as early as week 4 (mean change from baseline, 8.2) and were durable through week 12 (9.6). The most common hematologic grade ≥ 3 AEs were anemia (28.0%) and thrombocytopenia (30%; 4% grade 4); 3 pts discontinued due to thrombocytopenia and 1 due to anemia. Four pts had grade 1/2 hemorrhages (1 conjunctival, 1 gastric, and 2 epistaxis) and 2 pts had grade 3/4 (1 intestinal and 1 esophageal varices). PLT counts decreased slightly from baseline (mean change at nadir, −5.9 × 109/L); 3 pts required PLT transfusions. The mean change from baseline to nadir in Hb was −13.4 g/L. Rates of nonhematologic grade ≥ 3 AEs were low overall (1 pt each), with the exception of pyrexia (6.0%), septic shock (4.0%), and arthralgia (4.0%); 44.0% of pts had ≥ 1 dose modification and 28.0% had ≥ 1 dose interruption. CONCLUSIONS: In this cohort of pts with low PLTs, ruxolitinib demonstrated an AE profile consistent with that previously reported in pts with normal PLTs. As compared to a previous analysis of pts with median baseline PLT counts of 248 × 109/L from this same study (Al-Ali et al. EHA 2014), pts in this low-PLT cohort experienced similar improvements in symptoms (mean change from baseline at week 12, 9.6 vs 11.8) but lower achievement of a ≥ 50% reduction from baseline in spleen length within the first 24 weeks of treatment (44.7% vs 69%), likely due to the lower median daily dose (11.8 mg/day vs 36.8 and 24.0 mg/day for pts with starting doses of 20 and 15 mg bid, respectively). Taken together, these data suggest that low-dose ruxolitinib is generally safe and efficacious in pts with PLTs ≥ 50 to < 100 × 109/L. Disclosures Griesshammer: Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Shire: Honoraria; Amgen: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. le Coutre:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Foltz:Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy. Bouard:Novartis: Employment. Perez Ronco:Novartis: Employment. Ghosh:Novartis: Employment.

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

Blood ◽

10.1182/blood.v128.22.5692.5692 ◽

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.

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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 ◽

10.1182/blood.v120.21.lba-6.lba-6 ◽

2012 ◽

Vol 120 (21) ◽

pp. LBA-6-LBA-6 ◽

Cited By ~ 5

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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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 ◽

10.1182/blood.v128.22.470.470 ◽

2016 ◽

Vol 128 (22) ◽

pp. 470-470 ◽

Cited By ~ 20

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.

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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 ◽

10.1182/blood-2020-139174 ◽

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.

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