Efficacy and Safety Of Ponatinib Following Failure Of Dasatinib In Patients (pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML) In The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1498-1498 ◽  
Author(s):  
Andreas Hochhaus ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D le Coutre ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Group I ◽  
Grade 3 ◽  
Group D

Abstract Background The efficacy and safety of subsequent TKIs in pts who have experienced failure of dasatinib is not fully known. Ponatinib, a pan-BCR-ABL inhibitor, was evaluated in a phase 2, international, open-label clinical trial (PACE). This post-hoc analysis explored the efficacy and safety of ponatinib following failure of dasatinib in CP-CML pts in the PACE trial. Methods The PACE trial enrolled 449 pts, including 270 with CP-CML. Pts had to be resistant or intolerant to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. The primary endpoint in CP-CML was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for pts remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 107 CP-CML pts following failure of dasatinib as the most recent prior therapy, irrespective of other TKI therapy, is presented (Group D). Eighteen pts who experienced failure of dasatinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group D: 52 pts whose only TKI therapy was imatinib followed by dasatinib (Group I-D), and 46 pts whose only TKI therapy was imatinib, then nilotinib, and then dasatinib (Group I-N-D). An analysis of cross-intolerance was also conducted in 69 pts with prior dasatinib treatment at any time who discontinued dasatinib due to intolerance. Results Baseline characteristics are shown in the table. Group I-D tended to be younger, with less time since diagnosis versus Group I-N-D. At the time of analysis, 60%, 65%, and 54% of pts in Groups D, I-D, and I-N-D remained on study. The most common reasons for discontinuation were adverse events (AEs; 16%, 15%, 17%) and progressive disease (9%, 6%, 11%) in Groups D, I-D, and I-N-D. Efficacy end points are shown in the table. In Group D, MCyR was seen in pts with the following dasatinib-resistant mutations at baseline: V299L, 3/4 (75%); T315I, 17/23 (74%); F317L, 3/10 (30%). The most common treatment-related AEs were thrombocytopenia (44%, 37%, 57%), rash (39%, 39%, 39%), and dry skin (39%, 29%, 52%) in Groups D, I-D, and I-N-D. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 3% of pts in Group D (treatment-related: 3%, 1%, 0%). Seventy-three of 217 pts receiving prior dasatinib at any time discontinued dasatinib due to intolerance. Of these 73 pts, 27 experienced the same AE(s) with ponatinib that led to dasatinib intolerance; 12 pts had grade 3/4 thrombocytopenia, 6 pts had other grade 3/4 AEs (3 with neutropenia, 1 each with pleural effusion, dyspnea, pulmonary hypertension), 8 pts had grade 1/2 AEs. Six of these 27 pts discontinued ponatinib due to the same AE that led to dasatinib intolerance. Thrombocytopenia was the primary AE involved in cross-intolerance (4 pts); congestive cardiac failure (grade 5) and pleural effusion each occurred once. Conclusions Ponatinib has substantial activity in pts with CP-CML following failure of dasatinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between dasatinib and ponatinib was infrequent. Disclosures: Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis,IL-Yang: Consultancy; BMS, Novartis, Pfizer,ARIAD,IL-Yang: Research Funding; BMS, Novartis,Pfizer,IL-Yang: Honoraria; BMS, Novartis,Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad and Teva: Consultancy; Novartis & Bristol Myers Squibb: Research Funding; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis, BMS, Teva: Speakers Bureau; Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:RIAD, Novartis, BMS, Pfizer: Research Funding.

Efficacy and Safety Of Ponatinib Following Failure Of Nilotinib In Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML) In The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2738-2738 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D. le Coutre ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Anticancer Therapy ◽  
Advisory Board ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Group I ◽  
Grade 3

Abstract Background Information is generally lacking regarding the efficacy and safety of subsequent TKIs after failure of nilotinib. This post-hoc analysis explored the efficacy and safety of ponatinib, a potent oral pan-BCR-ABL inhibitor, following failure of nilotinib in CP-CML patients in the phase 2 PACE trial. Methods The PACE trial enrolled 449 patients, including 270 with CP-CML. Patients had to be resistant or intolerant to dasatinib or nilotinib, or have the T315I mutation at baseline. The primary end point in CP-CML was MCyR at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for patients remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 106 CP-CML patients following failure of nilotinib as the most recent prior anticancer therapy, irrespective of other TKI therapy, is presented (Group N). Eleven patients who experienced failure of nilotinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group N: 33 patients whose only TKI therapy was imatinib followed by nilotinib (Group I-N), and 68 patients whose only TKI therapy was imatinib, then dasatinib, and then nilotinib (Group I-D-N). An analysis of cross-intolerance was also conducted in 43 patients with prior nilotinib treatment at any time who discontinued nilotinib due to intolerance. Results Baseline characteristics are shown in the table. Group I-N tended to be younger, with less time since diagnosis versus Group I-D-N. At the time of analysis, 59%, 64%, and 56% of patients in Groups N, I-N, and I-D-N remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%, 12%, 13%) and progressive disease (9%, 6%, 9%) in Groups N, I-N, and I-D-N. Efficacy endpoints are shown in the table. In Group N, MCyR was observed in patients with the following nilotinib-resistant mutations at baseline: Y253H, 1/2 (50%); E255K, 5/6 (83%); T315I, 12/22 (55%); F359V, 3/7 (43%); F359C, 1/2 (50%); F359I, 2/3 (67%). The most common treatment-related AEs were thrombocytopenia (38%, 33%, 40%), rash (35%, 30%, 37%), and dry skin (35%, 42%, 31%) in Groups N, I-N, and I-D-N. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 4%, and 2% of patients in Group N (treatment-related: 3%, 1%, 2%). Forty-four of 184 patients discontinued prior nilotinib at any time due to intolerance. Of these 44 patients, 24 experienced the same AE(s) with ponatinib that led to nilotinib intolerance; 12 patients had grade 3/4 thrombocytopenia, 6 patients had other grade 3 AEs (2 with dyspnea, 1 each with atrial fibrillation, musculoskeletal pain, abdominal pain, pain in extremity), 6 patients had grade 1/2 AEs. 7 of the 24 patients discontinued ponatinib due to the same AE that led to nilotinib intolerance. Thrombocytopenia (5 patients) was the primary AE involved in cross-intolerance; atrial fibrillation and pain in extremity each occurred once. Conclusions Ponatinib has substantial activity in patients with CP-CML following failure of nilotinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between nilotinib and ponatinib was infrequent. Disclosures: Kantarjian: ARIAD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; IL-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; ARIAD: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:ARIAD: Consultancy; Novartis: Consultancy; BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:Pfizer: Honoraria; ARIAD: Honoraria; Teva: Honoraria; Novartis: Honoraria; BMS: Honoraria. Baccarani:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Teva: Honoraria, Speakers Bureau. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; BMS: Honoraria. ARIAD: Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner: ARIAD: Employment. Haluska: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS: Consultancy, Research Funding; ARIAD: advisory board, advisory board Other, Consultancy; Novartis: advisory board, advisory board Other, Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; ARIAD: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; MSD: Research Funding. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Ponatinib In Heavily Pretreated Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML): Management Of Adverse Events (AEs)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1496-1496 ◽  
Author(s):  
Philipp D. Le Coutre ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Ronald Paquette ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Peripheral Vascular ◽  
Vascular Events ◽  
Advisory Committees ◽  
Dose Modification ◽  
Advisory Boards ◽  
Initial Onset ◽  
Grade 3

Abstract Background Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) with activity against native and mutant BCR-ABL. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial. Objectives To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial. Methods A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos. Results Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had ≥2 prior TKIs, 60% ≥3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%). The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below (Figure). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia. The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash. Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification. Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification. Conclusions Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received ≥2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. ClinicalTrials.gov ID: NCT01207440 aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100 Disclosures: Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Paquette:Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Ariad, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Yanase:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:ARIAD: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

KIT Inhibitor Midostaurin Exhibits a High Rate of Clinically Meaningful and Durable Responses in Advanced Systemic Mastocytosis: Report of a Fully Accrued Phase II Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 316-316 ◽  
Author(s):  
Jason Gotlib ◽  
Daniel J. DeAngelo ◽  
Tracy I. George ◽  
Christopher L. Corless ◽  
Andrea Linder ◽  
...  
Keyword(s):  
Mast Cell ◽  
Pleural Effusion ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Efficacy And Safety ◽  
Serum Tryptase ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 316 Background: The pathogenetic and high frequency D816V KIT mutation in aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) exhibits in vitro and clinical resistance to imatinib. Midostaurin (PKC412) is an inhibitor of the KIT tyrosine kinase and can block D816V KIT-transformed cell growth at an IC50 of 30–40nM. Herein we report updated results of our fully accrued investigator-initiated, multicenter, phase II study of oral PKC412 in World Health Organization-defined ASM/MCL patients (pts). Method: PKC412 100 mg bid was administered as continuous 28-day cycles until progression/ intolerable toxicity. Lack of a major response (MR) or partial response (PR) per Valent criteria by the end of 2 cycles resulted in discontinuation from the protocol. Result: Efficacy and safety data for all 26 pts (15 male: 11 female) are presented. The distribution of SM pts with one or more “C” findings included ASM (n=4), SM-CMML (n=14), SM-MDS (n=3), SM-MDS/MPN-U (n=1), and MCL (n=4, two with associated MDS). The median age of pts was 62 years (range 24–79 years), and the median # of prior therapies was 1.5 (range 0–4). Responses have been observed in 18/26 pts (69%), consisting of 10 pts (38%) with a MR (6 incomplete remissions and 4 pure clinical responses), 5 pts (19%) with a good partial response (GPR), and 3 pts with a minor PR . Four pts had stable disease, and 4 pts exhibited progressive disease (PD). In subjects with higher quality responses, responses have been durable, with PKC412 administered for a median of 19.5 cycles (1.5 years) for MR pts and 15 cycles (1.2 years) for MR+PR pts (range 4+ - 58+ cycles). Major responses have included normalization of hypoalbuminemia, improvement of hemoglobin and platelet counts, and resolution of liver function abnormalities. High quality responses have also included near complete resolution of pleural effusion and ascites (with reduction of paracentesis), and substantial reversion or normalization of weight loss (including one pt discontinuing TPN). Clinically meaningful responses have been accompanied by reduction of palpable and/or 3-D volumetric CT measurement of hepato/splenomegaly, a >50% decrease in the serum tryptase level and/or marrow mast cell (MC) burden, and improvement in mediator symptoms and ECOG performance status. Cutaneous mast cell lesions faded in 2 pts. One patient with MCL has achieved a near complete remission with RBC transfusion independence, normalization of albumin, disappearance of 18 cm palpable splenomegaly (70% volume reduction by imaging), decrease of serum tryptase from 763 to < 20 ng/mL, and decrease of marrow MC burden from 60–70% to 5%. Of particular interest, in 3 pts with SM-CMML (all D816V KIT+), associated marked eosinophilia normalized (e.g. decreased from 50% to 1% in one pt).The most common grade 1–2 non-hematologic toxicities were nausea and/or vomiting, and less frequently diarrhea and fatigue. Asymptomatic and reversible hyperlipasemia occurred in 5 pts (grade 3, n=1). Hematologic toxicity with a suspected relationship to PKC412 has included ≥ grade 3 worsening of pre-existing anemia, and in one pt, recurrent grade 3 thrombocytopenia despite dose reduction to 50 mg bid. Dose reduction was undertaken in 4 additional pts (N/V, n=2; HA, n=1; transient increase in pre-existing pleural effusion, n=1). Dose re-escalation to 100 mg bid was feasible in 3 of these 4 pts. As of August 5, 2010, 8 pts continue PKC412, and treatment has been discontinued in 18 pts. Among the latter, 2 pts had PKC412 discontinued after 4 cycles (grade 3 fatigue, grade 2 N/V, n=1 each), and 7 initial responders have terminated therapy for PD after 8–39 cycles (1 for progression of CMML). Allele-specific PCR detected D816V KIT in 18/26 (69%) pts, and a novel, activating two–amino acid insertion in MPL was identified in a D816V KIT-negative pt. A statistically significant association was observed between positivity for D816V KIT and achieving a MR versus any other type of response (p=0.0095, Fisher's exact test). Pharmacokinetic data and histopathologic correlates of response (e.g. marrow MC burden and serum tryptase levels) will be presented. Conclusion: PKC412 is well tolerated and exhibits clinically relevant and durable responses which compare very favorably to literature reports of interferon-alpha or cladribine in advanced SM. An ongoing international trial aims to further evaluate the efficacy and safety of PKC412 in this pt population. Disclosures: Gotlib: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. George:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dutreix:Novartis: Employment. Gross:Novartis: Employment. Nikolova:Novartis: Employment. Graubert:Novartis: Research Funding.

Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3866-3866 ◽  
Author(s):  
Maria Teresa Petrucci ◽  
Igor W. Blau ◽  
Paolo Corradini ◽  
Meletios A. Dimopoulos ◽  
Johannes Drach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Bortezomib Treatment ◽  
Best Response ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3286-3286 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Bernadeta Ceglarek ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

scholarly journals Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 327-327 ◽  
Author(s):  
Susan O'Brien ◽  
Jeffrey A. Jones ◽  
Steven Coutre ◽  
Anthony R. Mato ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

scholarly journals Efficacy and Safety of Once Weekly Bortezomib In Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3029-3029 ◽  
Author(s):  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Davide Rossi ◽  
Alessandra Romano ◽  
Mariella Genuardi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Severe Thrombocytopenia ◽  
Weekly Schedule ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3 ◽  
The Impact ◽  
Weekly Group ◽  
Dose Reductions

Abstract Abstract 3029 Background. In a recent phase 3 trial, bortezomib–melphalan – prednisone–thalidomide followed by maintenance treatment with bortezomib–thalidomide (VMPT-VT) demonstrated superior efficacy compared with VMP. Peripheral neuropathy (PN) was the most important dose limiting toxicity. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions. This post-hoc analysis assessed the impact of bortezomib dose-modification schedule on clinical outcomes and safety. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction:V 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; M 9 mg/m2 d 1–4, P 60 mg/m2, d 1–4, T 50 mg d 1–42; maintenance: V 1.3 mg/m2 every 14 days and T 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). Patients receiving VMPT-VT and VMP were pooled together and stratified according to the once-weekly or twice-weekly infusion modality; analyses were also conducted for patients receiving VMP only, to eliminate the influence of thalidomide and of maintenance on efficacy and safety. Results. Patients were evaluated in intention-to-treat: 372 patients received once-weekly and 139 twice-weekly bortezomib infusion. Patient characteristics were similar in the two groups, median age was 71 years. The efficacy data did not appear to be affected by the bortezomib schedule. Overall response rates were 85% with once weekly and 86% with twice- weekly schedule (P = .78), including CR rates of 30% and 35% (P = .27).Three-year PFS was 50% in the once-weekly and 47% in the twice-weekly group (P = 1.00), and 3-year OS was 88% and 89%, respectively (P = .54). Similar outcome was seen in the analyses restricted to VMP patients: CR rates were 23% with once-weekly and 27% with twice-weekly schedule (P = .54), 3-years PFS was 46% in once-weekly and 39% (P = .86) in twice-weekly group and 3-years OS was 87% and 89% (P = .47), respectively. The incidence of grade 3/4 hematologic toxicity was similar in the two groups (44% vs 45%, P = .83), but severe thrombocytopenia was slightly less common in the once-weekly patients (19% vs 26%, P = .08).The incidence of non-hematologic grade 3/4 adverse events was significantly reduced in the once-weekly: 35% vs 51% (P = .003). Grade 3/4 gastrointestinal events (6% vs 11%, P = .08), severe systemic events (4% vs 7%, P = .09) and grade 3/4 dermatologic events (2% vs 7%, P = .006) were less frequent in patients receiving once-weekly bortezomib. There was a significantly reduced overall incidence of grade 3/4 PN (8% vs 28%, P < .001) in the once-weekly group. The median time to onset of grade 3/4 sensory PN was 4.3 months in the once-weekly group and 3.2 months in the twice-weekly group (P = .10). The cumulative incidence of sensory PN appeared to plateau after 12 months of therapy in both groups. Rates of discontinuations (5% versus 15%) and dose reductions (15% versus 41%) due to PN were also significantly lower in the once-weekly group (P < .001). These results were reflected in analysis restricted to VMP patients, in which the incidence of grade 3/4 PN (7% vs 29%, P < .001), the discontinuation rate (4% vs 16%, P = 0.002), and the dose reductions rate (15% vs 41% P < 0.001) were significantly lower in once-weekly group. Despite the cumulative planned dose being lower in the once-weekly group (46.8 vs 67.6 mg/m2), the delivered cumulative dose of bortezomib was similar in the two groups (39.4 mg/m2 vs 40.1 mg/m2). No association of PN with age or other baseline characteristics was outlined. The only significant factor influencing the incidence of PN was the reduction of bortezomib infusion from twice- to once-weekly (p<0.001). Low dose thalidomide did not affect grade 3/4 PN rate (p=0.16). Conclusion. These results demonstrate that 1. both once-weekly and twice-weekly schedules in combination with MP ± thalidomide are highly effective in patients ≥ 65 years; 2. once-weekly schedule significantly reduced the incidence of PN and decreased the rate of discontinuation, resulting in similar cumulative bortezomib doses in the two groups; 3. the improvement in the safety profile was not associated with any reduction in the efficacy. Disclosures: Bringhen: Celgene: Honoraria; Janssen Cilag: Honoraria. Leoni:Celgene: Honoraria; Janssen Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Elice:Celgene: Honoraria; Novatis: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo: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.

scholarly journals Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4457-4457 ◽  
Author(s):  
Franck Morschhauser ◽  
Ian Flinn ◽  
Ranjana H Advani ◽  
Catherine S. Diefenbach ◽  
Kathryn Kolibaba ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Grade 5 ◽  
Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 933-933 ◽  
Author(s):  
Nathan Fowler ◽  
Brad S Kahl ◽  
Peter Rosen ◽  
Jeffrey Matous ◽  
Amanda Cashen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Clin Oncol ◽  
Board Of Directors ◽  
Research Funding ◽  
High Risk Population ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

Efficacy and Safety of Three Bortezomib-Based Combinations in Elderly, Newly Diagnosed Multiple Myeloma Patients: Results From All Randomized Patients in the Community-Based, Phase 3b UPFRONT Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 478-478 ◽  
Author(s):  
Ruben Niesvizky ◽  
Ian W. Flinn ◽  
Robert Rifkin ◽  
Nashat Gabrail ◽  
Veena Charu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Community Based ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 478 Background: The US community-based, phase 3b randomized, open-label, multicenter UPFRONT trial compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible multiple myeloma (MM) patients. This is the first phase 3 study of VcD and VcTD in this patient population. Methods: Patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc as before; T 100 mg/day, days 1–21; D as before); VcMP: Vc as before; M 9 mg/m2 and P 60 mg/m2, days 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc 1.6 mg/m2, days 1, 8, 15, 22. Patients in the VcTD arm received concomitant prophylaxis with aspirin, full-dose warfarin, or low-molecular weight heparin unless medically contraindicated. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR)/near CR (nCR) and very good partial response (VGPR) rates, overall survival (OS), and safety. Best confirmed responses were assessed by investigators per modified International Myeloma Working Group (IMWG) criteria. Adverse events (AEs) were graded by NCI-CTCAE v3.0. PFS and OS were estimated by Kaplan–Meier methodology. For the first time, we report results from the entire cohort of 502 randomized patients (VcD, n=168; VcTD, n=167; VcMP, n=167), who completed up to a maximum of 13 cycles of treatment. Results: Patients in the VcD, VcTD, and VcMP arms had a median age of 74.5, 73.0, and 72.0 years, respectively, and 71%, 62%, and 72% had ISS stage II/III disease. Patients received a median of 8 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles; 50%, 38%, and 42% of patients, respectively, received Vc maintenance. Response and safety data are summarized in the table. All three Vc-based induction regimens exhibited substantial activity, with ORR of 73% (VcD), 80% (VcTD), and 69% (VcMP) during the treatment period. After a median follow-up of 21.8 months, no significant difference in PFS was observed between the treatment arms; median PFS was 13.8 months (VcD), 14.7 months (VcTD), and 17.3 months (VcMP), respectively (Figure). 1-year OS estimates were 87.4% (VcD), 86.1% (VcTD), and 88.9% (VcMP). Rates of grade ≥3 AEs, serious AEs (SAEs), and discontinuations due to AEs during the treatment period were highest for the VcTD arm. The most common grade ≥3 AEs across all three arms during the treatment period were neuropathy peripheral (23%), fatigue (10%), and diarrhea (9%). Grade ≥3 pneumonia was reported in 10% (VcD), 6% (VcTD), and 6% (VcMP) of patients. AEs of deep vein thrombosis/pulmonary embolism were reported in 8% (VcD), 7% (VcTD), and 2% (VcMP) of patients. Compared with rates during induction, Vc maintenance produced little additional toxicity; across all three treatment arms, only 5% of patients experienced grade ≥3 peripheral neuropathy during cycles 9–13. One second primary malignancy (lung neoplasm) was reported in the VcMP arm. Conclusions: VcD, VcTD, and VcMP induction followed by weekly Vc maintenance produced similar activity in elderly, newly diagnosed, transplant-ineligible MM patients. Patients in the VcD doublet arm appear to have similar long-term outcomes to patients in the VcTD and VcMP triplet arms. Disclosures: Niesvizky: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charu:GSK: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership; Pfizer: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment.

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