scholarly journals Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3063-3063 ◽  
Author(s):  
Michael J. Mauro ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil P. Shah ◽  
Dale L. Bixby ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 1 Trial ◽  
Equity Ownership

Abstract Background: Ponatinib, an oral tyrosine kinase inhibitor with potent activity against native and mutant BCR-ABL1, is approved for patients with refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated, or for patients with the T315I mutation. The efficacy and safety of ponatinib in patients with resistant/refractory hematologic malignancies were evaluated in a phase 1 trial (NCT00660920). Here, we report 4-year follow-up data from chronic-phase (CP)-CML patients; final data (approximately 5-year follow-up) will be presented. Methods: In this open-label, dose-escalation, phase 1 trial, 81 patients with resistant/refractory hematologic malignancies (CP-CML, 43 patients; accelerated-phase CML, 9 patients; blast-phase CML, 8 patients; Ph+ ALL, 5 patients) were enrolled. Patients were treated with ponatinib at a starting dose of 2 mg/d - 60 mg/d; intra-patient dose escalation was permitted. In Oct 2013, dose reduction instructions were provided in response to an observed accumulation of arterial occlusive events (AOEs) with longer follow-up across the ponatinib clinical program. For data presented herein, the data cutoff date is 2 Feb 2015, with median follow-up of 53.1 months (range, 1.7 - 69.9 months) for CP-CML patients. Results: Among CP-CML patients, at baseline, median age was 55 years and median time since diagnosis was 6.6 years; BCR-ABL1 kinase domain mutations were reported in 63% of patients, with T315I confirmed at a central laboratory in 28% of patients. Patients were heavily pretreated, with 37% having received 2 prior TKIs and 60% having received ≥3 prior TKIs. Of 43 CP-CML patients, 22 (51%) remained on ponatinib treatment at data cutoff. Adverse events (AEs; 26%) and disease progression (9%) were the most common reasons for discontinuation of treatment. Cumulative response rates were: major cytogenetic response (MCyR), 72%; complete cytogenetic response (CCyR), 65%; major molecular response (MMR; assessed at a central laboratory), 56%; molecular response 4 (MR4), 42%; MR4.5, 28%. Responses were durable (Table), with median durations of response not reached for MCyR, CCyR, and MMR. Among patients who received ponatinib at starting doses of ≤30 mg/d (n = 15), MCyR was achieved by 67%, CCyR by 53%, and MMR by 47%; ponatinib dose was ≤30 mg/d in all but one of these patients at the time of response. Of 19 patients who were ongoing and in MCyR as of Oct 2013, 13 had their dose reduced; all 13 dose-reduced patients maintained MCyR at data cutoff. Of the 22 ongoing patients at the time of the present analysis, 18 (82%) had CCyR and 17 (77%) had MMR or better (MMR, 6 patients; MR4, 1 patient; MR4.5, 9 patients; MR5, 1 patient) as their response at the data cutoff; 14/22 (64%) ongoing patients were receiving 15 mg/d as their current dose as of the data cutoff. Rash (65%), fatigue (63%), abdominal pain (58%), headache (58%) and arthralgia (53%) were the most common treatment-emergent AEs. The incidence of AOEs (any/serious) was 40%/30% (by subcategory: cardiovascular, 30%/21%; cerebrovascular, 9%/7%; peripheral vascular, 14%/9%). Conclusions: With median follow-up of over 4 years in this phase 1 study, ponatinib continues to provide clinical benefit to heavily pre-treated CP-CML patients, approximately half of whom continue to receive ponatinib, with a majority in deep response that has been long-lasting; final study data will be presented. The most common treatment-emergent AEs were consistent with the AE profile across the clinical program. Potential for long-term benefit, demonstrated herein, versus risk should be considered when using ponatinib in this patient population. Study sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Mauro: BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Shah:ARIAD: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Plexxikon: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Santillana:ARIAD: Employment, Equity Ownership. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; Pfizer: Consultancy; Bayer: Research Funding; BMS: Research Funding; Blueprint Medicines: Consultancy; MolecularMD: Consultancy, Equity Ownership; ARIAD: Consultancy, Research Funding; Onyx: Consultancy. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Talpaz:Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.

Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 602-602 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil Shah ◽  
Dale Bixby ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutation Status ◽  
Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 452-452 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp D. LeCoutre ◽  
Ricardo Pasquini ◽  
Saengsuree Jootar ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Safety Data ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase According to Reasons for Switching from Imatinib to Nilotinib: Subgroup Analysis from ENESTop

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 792-792 ◽  
Author(s):  
Timothy P. Hughes ◽  
Carla Maria Boquimpani ◽  
Naoto Takahashi ◽  
Noam Benyamini ◽  
Nelma Cristina D Clementino ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Loss Of Response ◽  
Equity Ownership ◽  
Treatment Free Remission

Abstract Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: 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; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.

scholarly journals Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1650-1650 ◽  
Author(s):  
B. Douglas Smith ◽  
Tim H Brümmendorf ◽  
Gail J. Roboz ◽  
Carlo Gambacorti-Passerini ◽  
Aude Charbonnier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Equity Ownership

Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Maintenance of Health-Related Quality of Life in the Phase 4 BYOND Study of Bosutinib for Pretreated Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4157-4157
Author(s):  
Tim H Brümmendorf ◽  
Carlo Gambacorti-Passerini ◽  
Camille Abboud ◽  
Justin M. Watts ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Well Being ◽  
Employment Equity ◽  
Advisory Committees ◽  
Starting Dose ◽  
Previously Treated ◽  
Equity Ownership

Background: Bosutinib is approved at a starting dose of 500 mg once daily (QD) in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who are resistant or intolerant to prior treatment and at a starting dose of 400 mg QD in newly diagnosed patients with chronic phase (CP) CML. Approval of bosutinib after prior therapy was based on a phase 1/2 study in patients previously treated with imatinib ± dasatinib and/or nilotinib. After long-term follow-up (≥4 years), durable responses and maintenance of health-related quality of life (HRQoL) were seen in patients after prior imatinib (CP CML second-line [CP2L] cohort [n=284]) or prior imatinib + dasatinib and/or nilotinib (CP CML third/fourth-line [CP3L/CP4L] cohort [n=115/4]). As a post-authorization commitment to the European Medicines Agency, the BYOND study is providing additional safety and efficacy data for bosutinib in patients with CML after failure of prior tyrosine kinase inhibitor (TKI) treatment. Cumulative confirmed major cytogenetic response rate by 1 year (primary endpoint; not powered) in evaluable patients with CP CML was 75.8% after 1 or 2 prior TKIs (n=99) and 62.2% after 3 prior TKIs (n=45). Cumulative complete cytogenetic response rate anytime on treatment was 86.0%, 83.9%, and 73.3% in the CP2L, CP3L, and CP4L cohorts, respectively. Patients had high rates of molecular responses across all lines of treatment. Evaluation of HRQoL through patient-reported outcome (PRO) measures is an exploratory objective of BYOND. Methods: BYOND (NCT02228382) is an ongoing, phase 4, single-arm, open-label study of bosutinib at a starting dose of 500 mg QD in patients with CML and resistance/intolerance to prior treatment. At baseline and during treatment, patients were asked to complete the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu v4) instrument, a 44-item, valid assessment of HRQoL in patients with leukemia. Each item was scored on a scale from 0 to 4, with higher scores indicating better HRQoL. Changes in HRQoL that are clinically meaningful to a patient have been defined as the minimal important difference (MID) for most FACT-Leu domains. We report PRO results at Month 12 of bosutinib treatment in the CP CML cohorts; for comparison, we present PRO data at Month 12 from the CP CML cohorts of the phase 1/2 study of bosutinib in previously treated patients. Results: At baseline, most FACT-Leu scores were similar (<5% difference) in the CP2L and CP3L cohorts of the BYOND study (Table); social and functional well-being scores were lower and the emotional well-being score was higher in the CP2L cohort. Baseline FACT-Leu scores were lower in the CP4L cohort, with >5% differences seen for physical and emotional well-being compared with the CP2L cohort, and for physical, social, and functional well-being, FACT-General (FACT-G) total, FACT-Leu total, and trial outcome index (TOI) FACT-Leu compared with the CP3L cohort. At Month 12, no mean change in a FACT-Leu domain score met the MID (Figure), indicating preservation of baseline HRQoL across all cohorts. Mean changes in FACT-Leu scores from baseline to Month 12 were similar in the CP2L cohorts of the BYOND study and the phase 1/2 study. HRQoL trends were also generally similar in the CP3L cohort of BYOND and the CP3L/4L cohort of the phase 1/2 study, in which 97% of patients received third-line bosutinib. Conclusions: HRQoL was maintained from baseline in patients with CP CML following 12 months of bosutinib treatment in the BYOND study. HRQoL changes at Month 12 were comparable to those observed in previously treated patients in the initial phase 1/2 study of bosutinib, wherein long-term efficacy and HRQoL stability were subsequently reported. In addition, FACT-G scores in the BYOND study were consistent with those previously reported for general populations as well as patients with various cancers. Maintenance of HRQoL is important for patients with CP CML who potentially will receive lifelong TKI treatment, and the PRO results from BYOND suggest bosutinib is a well-tolerated treatment option, thus providing further support for its use in patients with CP CML resistant/intolerant to prior TKIs. Relationships between molecular response and HRQoL in the BYOND study are being explored. Disclosures Brümmendorf: University Hospital of the RWTH Aachen: Employment; Merck: Consultancy; Ariad: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Watts:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Russell-Smith:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. Reisman:Pfizer Inc: Employment, Equity Ownership. Giles:Actuate Therapeutics Inc: Employment; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Novartis: Consultancy. Hochhaus:MSD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding.

scholarly journals Current Results of Lentiglobin Gene Therapy in Patients with Severe Sickle Cell Disease Treated Under a Refined Protocol in the Phase 1 Hgb-206 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1026-1026 ◽  
Author(s):  
John F. Tisdale ◽  
Julie Kanter ◽  
Markus Y. Mapara ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership ◽  
Grade 3

Abstract Background β-globin gene transfer has the potential for substantial clinical benefit in patients with sickle cell disease (SCD). LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin gene therapy is being evaluated in the ongoing Phase 1 HGB-206 study (NCT02140554). Results in the initial 7 patients treated with LentiGlobin DP from steady state bone marrow harvested (BMH) HSCs using original DP manufacturing process (Group A) demonstrated stable HbAT87Q production in all patients, but at levels below the anticipated target. The protocol was thus amended to include pre-harvest RBC transfusions, optimize myeloablation by targeting higher busulfan levels, and use a refined DP manufacturing process (Group B); additionally, HSC collection by plerixafor mobilization/apheresis was instituted (Group C). Data from patients in Group C, treated under the modified protocol with DPs manufactured from plerixafor-mobilized HSCs using the refined process, are reported here. Results in patients in Groups A and B are reported separately. Methods Patients with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Patients in Group C received ≥2 months of transfusions to reach Hb of 10 - 12 g/dL and <30% HbS before HSC collection. Patients received 240 μg/kg of plerixafor 4 - 6 hours before HSCs were collected by apheresis and CD34+ cells were transduced with the BB305 LVV at a central facility. Following myeloablative conditioning with busulfan, the DP was infused, and patients were monitored for adverse events (AEs), engraftment, peripheral blood (PB) vector copy number (VCN), HbAT87Q expression, and HbS levels. Summary statistics are presented as median (min - max). Results As of 15 May 2018, 11 Group C patients (age 25 [18 - 35] years) had undergone mobilization/apheresis, 9 patients had DP manufactured (median 1 cycle of mobilization [1 - 3]) and 6 patients had been treated. Cell dose, DP VCN and % transduced cells in the 6 treated patients were: 7.1 (3 - 8) x 106 CD34+ cells/kg, 4.0 (2.8 - 5.6) copies/diploid genome (c/dg) and 81 (78 - 88) % transduced cells. The median follow-up was 3.0 (1.2 - 6.0) months. Patients achieved neutrophil engraftment at a median of 19 (18 - 20) days. Platelet engraftment was achieved at a median of 28 (12 - 64) days in 4 patients; platelet engraftment was pending in 2 patients. Two of 11 patients experienced 4 grade ≥3 AEs associated with plerixafor mobilization/HSC collection: 1 had vaso-occlusive pain and hypomagnesaemia, and the other had vaso-occlusive pain and non-cardiac chest pain. The toxicity profile from DP infusion to last follow-up in the 6 treated patients was consistent with myeloablative conditioning. Febrile neutropenia (n=5) and stomatitis (n=4) were the most common non-hematologic grade ≥3 AEs. Serious AEs were reported in 3 patients post-DP infusion: splenic hematoma, non-cardiac chest pain and mucosal inflammation. To date, there have been no DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. In the 6 treated patients, PB VCN at last visit ranged from 1.4 - 2.9 c/dg. In the 3 patients with 3 months follow-up, total Hb levels were 11.7 g/dL, 9.8 g/dL and 9.2 g/dL, and HbAT87Q levels were 4.7 g/dL, 3.2 g/dL and 3.5 g/dL. One additional patient with 6 months follow-up was off transfusions and had total Hb of 14.2 g/dL, of which 62% (8.8 g/dL) was vector-derived HbAT87Q and 36% (5.1 g/dL) was HbS. All 4 patients had HbAT87Q (median 39%) levels higher than or equal to HbS (median 31%) at the 3-month visit. Summary HGB-206 protocol changes and refined DP manufacturing have improved the LentiGlobin DP characteristics resulting in significantly improved outcomes. In addition, the HbAT87Q expression is comparable to, or exceeds, HbS levels as early as 3 months post DP infusion. These data support the feasibility of plerixafor-mediated CD34+ cell collection in patients with severe SCD and the efficacy of gene therapy. The safety profile of LentiGlobin gene therapy remains consistent with single-agent busulfan conditioning. Additional data and longer follow-up will determine the clinical effect of increased HbAT87Q/HbS ratios. Disclosures Kanter: Global Blood Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees. Mapara:Incyte: Consultancy. Kwiatkowski:Novartis: Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:Amgen: Research Funding; Celgene: Research Funding; Baxalta/Shire: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding; Biomarin: Research Funding; La Jolla Pharmaceutical: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

Nilotinib Demonstrates Superior Efficacy Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: Results From the International Randomized Phase III ENESTnd Trial

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. LBA-1-LBA-1 ◽  
Author(s):  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
Philipp D. le Coutre ◽  
Josy Reiffers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Standard Of Care ◽  
Tolerability Profile ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract LBA-1 Background: Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL, the only proven molecular target for CML therapy. ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) is a phase 3, randomized, open-label, multicenter study comparing the efficacy and safety of 300 or 400 mg bid nilotinib with 400 mg qd imatinib in patients (pts) with newly diagnosed Ph+ CML in chronic phase (CML-CP). Methods: 846 pts with newly diagnosed Ph+ CML-CP, diagnosed within 6 mos, and stratified by Sokal risk score, were randomized 1:1:1 to nilotinib 300 mg bid (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg qd (n=283) arms. The primary endpoint was rate of major molecular response (MMR) at 12 months (mos). All pts had a minimum of 12 mos of treatment or discontinued early; median follow-up was 14 mos. MMR was defined as a value of ≤ 0.1% of BCR-ABL/ABL ratio on the International Scale. Molecular response was assessed by RQ-PCR at baseline, monthly for 3 mos and every 3 mos thereafter. Samples were analyzed at a central PCR laboratory. The major secondary endpoint was rate of complete cytogenetic response (CCyR) by 12 mos based on bone marrow cytogenetics. Results: Baseline demographics, disease characteristics, and Sokal scores were well balanced among the 3 arms; pts with high-risk Sokal scores were 28% in all arms. Median dose intensities of nilotinib delivered were 592 mg/day for 300 mg bid and 779 mg/day for 400 mg bid; imatinib dose intensity was 400 mg/day. Overall, 84%, 82%, and 79% of pts remained on the study for 300 mg bid nilotinib, 400 mg bid nilotinib, and 400 mg qd imatinib, respectively. Rates of MMR at 12 mos (Table) were superior for nilotinib 300 mg bid compared with imatinib 400 mg qd (44% vs. 22%,P < .0001) and also for nilotinib 400 mg bid compared with imatinib 400 mg qd (43% vs. 22%,P < .0001). Median time to MMR among pts who achieved MMR was faster for nilotinib 300 mg bid (5.7 mos) and nilotinib 400 mg bid (5.8 mos) compared with imatinib 400 mg qd (8.3 mos). Rates of CCyR by 12 mos were significantly higher for both nilotinib at either 300 mg bid compared with imatinib 400 mg qd (80% vs. 65%,P < .0001) and for nilotinib 400 mg bid compared with imatinib 400 mg qd (78% vs. 65%,P = .0005). Overall, progression to advanced disease was lower for nilotinib 300 mg bid (2 pts) and nilotinib 400 mg bid (1 pt) compared with imatinib 400 mg qd (11 pts). Overall, both drugs were well-tolerated. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for nilotinib 300 mg bid, 11% for nilotinib 400 mg bid, and 9% for imatinib 400 mg qd. Pts were monitored for QT prolongation and LVEF. No patients in any treatment arm showed a QTcF interval > 500 msec. There was no decrease from baseline in mean LVEF anytime during treatment in any arm. The study is ongoing. Conclusions: Nilotinib at both 300 mg bid and 400 mg bid induced significantly higher and faster rates of MMR and CCyR compared with imatinib 400 mg qd, the current standard of care in pts with newly diagnosed CML. Nilotinib was effective across all Sokal scores. After only one year of treatment, both nilotinib arms resulted in a meaningful clinical benefit compared to imatinib, with reduction of transformation to AP/BC. Nilotinib exhibited a favorable safety and tolerability profile. The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML. Disclosures: Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Off Label Use: Nilotinib is not currently approved for first-line treatment of CML. The presentation will report the results from a randomized study of imatinib versus nilotinib in patients with newly diagnosed Ph+ CML-CP. Kim:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Schering: Membership on an entity’s Board of Directors or advisory committees. Clark:Novartis: Honoraria, Research Funding, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Gallagher:Novartis: Employment, Equity Ownership. Hoenekopp:Novartis: Employment. Dong:Novartis: Employment, Equity Ownership. Haque:Novartis: Employment. Larson:Novartis:

The Incidence of BCR-ABL Mutations and Their Impact on Outcome in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Nilotinib or Imatinib in ENESTnd: 36-Month Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2755-2755
Author(s):  
Timothy P. Hughes ◽  
Dong-Wook Kim ◽  
Gabriel Etienne ◽  
Carmino De Souza ◽  
Mineo Kurokawa ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
T315i Mutation ◽  
Equity Ownership

Abstract Abstract 2755 Background: In ENESTnd, nilotinib demonstrated superior efficacy vs imatinib in newly diagnosed patients (pts) with CML-CP, including a significantly reduced rate of progression to AP/BC on treatment. Here, we examined the occurrence of emergent mutations on treatment and their impact on response. Data on the incidence of mutations and impact on efficacy with a minimum follow-up of 36-months (mo) for all pts will be presented. Methods: Pts with CML-CP were randomized to receive nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283). Mutation testing was performed by direct sequencing of the kinase domain (amino acids 230 to 490; sensitivity, 10%-20%) in a central lab at: baseline, 5-fold increase in BCR-ABL levels, lack of MMR at 12 mo, loss of MMR, or treatment discontinuation. Results: With a minimum follow-up of 24 mo, twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10, nilotinib 300 mg BID; n = 8, nilotinib 400 mg BID), with the majority of mutations emerging in pts with high and intermediate Sokal scores (Table). Of pts with mutations emerging on imatinib, the majority (65%) had nilotinib-sensitive, imatinib-resistant mutations; whereas nilotinib was effective in preventing the emergence of clones with nilotinib-sensitive mutations. The incidence of T315I mutations was similar for the nilotinib (n = 3, nilotinib 300 mg BID; n = 2, nilotinib 400 mg BID) and imatinib (n = 3) arms and most of these T315I mutations (6/8) were detected within the first 12 mo of therapy. All but 1 pt with the T315I mutation had a high Sokal risk; the other pt had an intermediate Sokal risk. Overall, across the 3 treatment arms, the incidence of any mutation was 14% in pts who had BCR-ABLIS > 10% at 6 mo vs 4% in pts with BCR-ABLIS ≤ 10% at 6 mo. The majority of pts with emerging mutations had suboptimal response (SoR) or treatment failure (TF) on treatment; all pts with the T315I mutation had SoR or TF. Of the pts with mutations, 1/10 pts on nilotinib 300 mg BID, 2/8 pts on nilotinib 400 mg BID, and 7/20 pts on imatinib, progressed to AP/BC on treatment. BCR-ABL mutations did not account for all cases of progression to AP/BC, loss of CCyR, and loss of MMR on treatment (Table). Of the pts who achieved an MMR on treatment, 0/203 (0%), 2/192 (1%) and 3/131 (2%) had a mutation and lost MMR with nilotinib 300 mg BID, nilotinib 400 mg BID or imatinib, respectively. Conclusions: Nilotinib may be more effective in preventing the development of emerging mutations vs imatinib. More pts with new mutations progressed to AP/BC on imatinib than on nilotinib. These data suggest that deeper molecular responses with nilotinib protect from the development of emerging mutations and progression to AP/BC vs imatinib. Disclosures: Hughes: 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; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurokawa:Novartis Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalaycio:Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Saglio:Bristol Myers Squipp: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Shou:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Rosti:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Roche: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.

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

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

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

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

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

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

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