Expanding Nilotinib Access In Clinical Trials Research Articles

Expanding Nilotinib Access in Clinical Trials (ENACT), an open-label multicenter study of oral nilotinib in adult patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase or blast crisis

Nilotinib has shown favorable safety in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic (CML-CP) or accelerated phase (CML-AP) who failed prior imatinib, and superior efficacy over imatinib in newly diagnosed Ph+ patients with CML-CP. Reported here are the efficacy and safety data for patients in CML-AP (n = 181) or blast crisis (CML-BC) (n = 190; myeloid BC, 133; lymphoid BC, 50; unknown, seven) enrolled in an expanded access phase IIIb study. Non-hematologic adverse events were mostly mild to moderate. Drug-related myelosuppression was generally manageable with dose reductions or interruptions and infrequently led to discontinuation of nilotinib. Drug-related grade 3/4 elevations in serum bilirubin and lipase were infrequent. While an analysis of efficacy was not the primary objective of this study, significant hematologic and cytogenetic responses were observed. These results support the safety and efficacy of nilotinib in patients with advanced CML in AP and BC.

Expanding Nilotinib Access in Clinical Trials (ENACT)

AbstractBACKGROUND:Nilotinib is a selective, potent BCR‐ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome‐positive chronic myeloid leukemia patients in chronic phase (CML‐CP) or accelerated phase who failed prior imatinib.METHODS:This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML‐CP (N = 1422).RESULTS:In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression‐free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re‐escalation, 87% successfully achieved re‐escalation to the full dose.CONCLUSIONS:This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society.

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.

Abstract 3286Poster 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.

Nilotinib Responses and Tolerability Confirmed in North American Patients with Chronic Myeloid Leukemia (CML) From ENACT (Expanding Nilotinib Access in Clinical Trials).

Abstract 3295 Poster Board III-1 Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib. The open label, multicenter ENACT study was initiated as a global expanded access program to obtain additional safety information in CML pts in a clinical practice setting outside of a registration study. This report focuses on a subset of patients enrolled in North America. Methods: Adult patients with imatinib resistant or -;intolerant Ph+ CML-CP, AP or BC were admitted to the study. The definition of imatinib resistance and intolerance were the same as the pivotal phase II registration study and pts could have been previously treated with other TKIs in addition to imatinib. Patients with impaired cardiac function, concurrent severe medical conditions or taking prohibited medications were excluded. Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction to 400 mg once daily due to toxicity were allowed to have a dose re-escalation to 400 mg BID after resolution of the adverse events (AEs), lack of response, or persistent disease at the investigator's discretion. Results: A total of 207 North American pts were enrolled in the ENACT study between 01/2006 and 10/2008, including 172 CP pts (83%), 15 AP pts (7%) and 20 BC pts (10%). The median age of all pts was 54 years; 53% were imatinib-resistant, 45% were imatinib-intolerant, and 1.4% were resistant/intolerant. The most common prior anti-neoplastic therapy (other than imatinib) was hydroxyurea (73% of CP pts, 87% of AP pts, and 90% of BC pts), followed by dasatinib (32% of CP pts, 40% of AP pts, and 30% of BC). At study completion, 100 pts (48%) were continuing on nilotinib and 107 pts (52 %) discontinued treatment; 29 (17%) CP pts, 7 (47%) AP pts, and 14 (70%) BC pts discontinued due to disease progression. There were a total of 7 (3.4%) deaths during the study. Patient disposition is summarized in Table 1. Median (range) duration of nilotinib exposure was 227 (1-807) days for CP pts, 78 (15-426) days for AP pts, and 73 (8-571) days for BC pts; median average dose intensity was 766, 785 and 766 mg/day, respectively. Thirty-five CP pts (20%), 3 AP pts (20%) and 6 BC pts (30%) had their dose reduced due to AE, while 75 CP pts (44%), 5 AP pts (33%), and 8 BC pts (40%) had their dose interrupted due to AE. Median duration of dose interruption due to AE was short (8 days for CP and BC pts and 3 days for AP pts). The most common grade 3/4 hematologic AEs suspected of being drug related were thrombocytopenia (12% of CP pts, 20% of AP pts, and 15% of BC pts) followed by neutropenia (9% of CP pts, 27% of AP pts, and 15% of BC pts). The most frequent non hematologic all grades AEs or lab abnormalities included rash, headache, nausea, fatigue and hyperbilirubinaemia, and all were slightly higher in North American patients compared with the overall ENACT population. No patients discontinued treatment due to pleural effusion and there was no incidence of QTcF prolongation &gt; 500 msec. Overall, major cytogenetic responses (MCyR) rates were 49% in CP, 27% in AP and 20% in BC pts, while complete cytogenetic responses (CCyR) rates were 36% in CP, 7% in AP and 20% in BC pts. Conclusions: ENACT is the largest dataset from a single CML study of the available TKIs that further demonstrates that nilotinib is generally well tolerated in pretreated patients in all phases of CML. The safety profile in this study is similar to that observed the pivotal phase II registration study, as are the cytogenetic response rates, with a maintenance of high dose intensity. This data supports the use of nilotinib at 400 mg BID as the recommended dose in these CML populations. Disclosures: Powell: Novartis Pharmaceuticals: Research Funding. Khoury:BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Rizzieri:Novartis Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Turner:Novartis Pharmaceuticals: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; wyeth: Research Funding.

Molecular Response, Efficacy and Safety Analysis of 168 Adult French Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Abstract 3293Poster Board III-1 Introduction:Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of Ph+ CML patients (pts) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study, which is a Phase IIIb, open label, multicenter study, was initiated to obtain additional efficacy and safety information in pts with imatinib-resistant or -intolerant CML in CML-CP, CML-AP, or blast crisis (BC) in a clinical practice setting outside of a registration program. Methods:Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Cytogenetic and hematological responses were provided by investigator assessment and monitored according to the current European Leukemia Network (ELN) recommendations. Safety assessments included monitoring for all adverse events (AEs), serious AEs and cardiac procedures. A centralized approach to molecular testing in France facilitated matching of the PCR results to ENACT pts who were monitored for molecular response as a standard of care. BCR-ABL/ABL ratio (in %) were reported on the international scale (IS), French physicians followed the current ELN recommendations and monitored pts by PCR at baseline and every 3 months thereafter. Major molecular response (MMR) was defined as IS ≤ 0.1%. In addition, pts with ≤ 0.003% IS are reported. Confirmed loss of MMR was defined as IS > 0.1% on two consecutive PCR tests in pts previously in MMR Results:A total of 168 French CML-CP pts enrolled in the ENACT study between Jan. 2006 and Oct. 2008 with molecular response data available for 77% of pts. The median age of pts was 57 years, 56% were imatinib-resistant and 43% were imatinib-intolerant as determined by physician assessment. At study completion, 108 (64%) pts were continuing on nilotinib. The main reasons for treatment discontinuation were unsatisfactory therapeutic effect and AEs (16% for both). Median (range) duration of nilotinib exposure was 363 (4–765) days; median (range) average dose intensity was 793 (222–913) mg/day. Dose interruptions and reductions lasting longer than 5 days occurred in 36.9% and 11.9% of pts, respectively, with AEs being the main reason. The majority of nilotinib-related grade 3/4 AEs were hematologic, with thrombocytopenia (22.6%) and neutropenia (14.9%) being the most common. Non-hematologic AEs were mostly grade 1/2, not study drug-related and included fatigue, headache and rash. No incidence of grade 3/4 QT prolongation (QTcF > 500 msec) was observed and no pts experienced study drug-related grade 3/4 pancreatitis or pleural effusion on study. Overall major cytogenetic response (MCyR) and complete hematologic response (CHR) rates were both 54%, which are higher than those observed in the overall ENACT CML-CP cohort at 45% and 43%, respectively. Among the pts with molecular response data, 10 (7.8%) came to the study with MMR, one had a confirmed loss of MMR but subsequently regained MMR. The proportion of pts with post-baseline MMR (regardless of baseline response) was 42% (55 pts); 38% of pts achieved an MMR on study. The proportion of pts with a post-baseline ratio ≤ 0.003% IS was 16% (21 pts). The achieved molecular responses were durable with only 4 pts with confirmed loss of MMR, while another 3 pts met the criteria for loss of response but subsequently regained MMR. Of the 61 pts with CCyR and molecular data available, 72% also achieved MMR (see Table).Molecular Response in CML-CP Patients in FranceN = 168 n (%)Evaluable Pts130(77.4)Major Molecular Response (MMR) RatesOverall MMR rate55(42.3)Cumulative MMR rate3 months15(11.5)6 months34(26.2)9 months43(33.1)12 months46(35.4)+12 months55(42.3)Median Time to MMR for responders (months)6(range)(3–33)≤ 0.003% IS RatesOverall ≤0.003% IS rate21(16.2)Cumulative ≤0.003% IS rate3 months3(2.3)6 months7(5.4)9 months8(6.2)12 months15(11.5)+12 months21(16.2)Median Time to ≤ 0.003% IS for responders (months)12(range)(3–18)Pts with CCyR and post-baseline molecular data:61(100.0)CCyR and MMR44(72.1)CCyR and ≤ 0.003% IS16(26.2) Conclusions:This analysis of the French CML-CP subset of a large expanded access study further demonstrates that nilotinib is well tolerated and effective in heavily pretreated pts with CML-CP. A majority of pts (72%) with CCyR also had MMR. This data supports the use of nilotinib at 400 mg bid as the recommended dose in French pts. Disclosures:Nicolini:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Bordessoule:Novartis Pharmaceuticals: Honoraria. Belanger:Novartis Pharmaceuticals: Employment. Lamy:Novartis Pharmaceuticals: Honoraria. Gardembas-Pain:Novartis Pharmaceuticals: Honoraria. Maloisel:Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Calgene: Research Funding. Rea:Novartis Pharmaceuticals: Honoraria. Johnson-Ansah:Novartis: Consultancy. Lenain:Novartis Pharmaceuticals: Honoraria. Szczudlo:Novartis: Employment. Wang:Novartis Pharmaceuticals: Employment. Duh:Novartis Pharmaceuticals: Research Funding.

Impact of Prior Therapy and Suboptimal Response to Imatinib On the Efficacy and Safety of Nilotinib Among 1,422 Patients with Imatinib-Resistant or —Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): Sub-Analyses of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Abstract 2201 Poster Board II-178 Introduction: Nilotinib, a potent and highly selective BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (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 400 mg twice daily in 1,422 pts with CP who were resistant and/or intolerant to imatinib. It is the largest single source of efficacy and safety information of any available TKI in CML. Study results are presented for all CP pts as well as 2 subpopulations: (1) 2nd-line pts who received imatinib as the only prior CML therapy with no prior exposure to other therapy including interferon (IFN), busulfan and ara-c; and (2) pts with 6- and 12-month suboptimal cytogenetic response (SoR) to prior imatinib therapy. Methods: In addition to all CP pts, ENACT study results are presented for 2 subpopulations, defined as follows. (1) Pts who received nilotinib as 2nd-line therapy received only imatinib (hydroxycarbamide was allowed) prior to nilotinib. Pts with any other therapy, including interferon, busulfan and ara-c were excluded. (2) Pts with 6- or 12-month cytogenetic SoR to imatinib were identified as: a) received imatinib as 1st-line therapy within 12 months of CML diagnosis; b) did not have imatinib resistance; and c) met ELN criteria for cytogenetic SoR (<PCyR at month 6 or <CCyR at month 12.) Results: A total of 1,422 CP pts were enrolled in the ENACT study between Jan. 2006 and Oct. 2008 from 293 study sites worldwide. The median age of pts was 52 years. At study completion, 857 (60%) pts were continuing on nilotinib. Median (range) duration of nilotinib exposure was 266 (1 - 807) days; median average dose intensity was 783 mg/day. The main reasons for treatment discontinuation were inadequate response (16%), AEs (14%) and other (10%). The majority of grade 3/4 AEs suspected of being study drug related were hematologic and the most common hematologic toxicities were thrombocytopenia (22%) and neutropenia (14%). Nonhematologic AEs were mostly grade 1/2. Grade 3/4 nonhematologic AEs were infrequent and included rash ( 5 days was similar between these pts and overall (interruption: 39% and 41%; reduction: both 5%), as was the median dose intensity for nilotinib (788 and 783 mg/day). MCyR and CHR rates were also similar between 2nd-line therapy pts and overall (MCyR: 47% and 45%; CHR: both 43%). (2) 12 pts were identified with cytogenetic SoR to prior imatinib therapy; 11 pts were 6-month cytogenetic SoR, 1 pt was 12-month cytogenetic SoR. The median duration of nilotinib exposure for these pts was higher than overall at 344 days (vs. 266) while their median dose intensity was slightly lower than overall at 741 mg/day (vs. 783). Of pts with cytogenetic SoR to imatinib, 75% (9) achieved MCyR, 50% (6) achieved CCyR and 67% (8) achieved CHR, compared to 45%, 34% and 43% for overall, respectively. MCyR and CCyR rates among pts with hematologic response were 60% and 80%, respectively. Median time to achieving MCyR and CHR among cytogenetic SoR pts was 3.8 and 3.4 months, respectively, faster than in the overall study (MCyR: 6.1 months; CHR: 4.9). Conclusions: This analysis further demonstrates that nilotinib is well tolerated in heavily pretreated pts with CML-CP with the efficacy and safety profile reported in ENACT being similar to that observed in the pivotal phase II registration study. The first sub-analysis of CP pts showed that prior exposure to therapeutic agents including IFN, busulfan and ara-c in addition to imatinib does not affect nilotinib dose intensity or response rates. The second sub-analysis demonstrates that pts with 6- or 12-month cytogenetic SoR experience higher CHR, MCyR and CCyR rates, and faster time to CHR and MCyR than pts who were imatinib failures, suggesting that nilotinib may be a suitable treatment option in pts with cytogenetic SoR on imatinib therapy. Studies are ongoing with nilotinib in suboptimal imatinib responders. Disclosures: Nicolini: Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Kim: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek: Novartis Pharmaceuticals: Honoraria. Turkina: Novartis Pharmaceuticals: Honoraria. Shen: Novartis Pharmaceuticals: Honoraria. Smith: Novartis Pharmaceuticals: Honoraria. Rizzieri: Novartis: Honoraria, Research Funding, Speakers Bureau. Szczudlo: Novartis: Employment. Berton: Novartis Pharmaceuticals: Employment. Wang: Novartis Pharmaceuticals: Employment. Bieri: Novartis Oncology: Research Funding. le Coutre: Novartis : Honoraria, Research Funding; Bristol Myers Squibb: Honoraria.

Patterns and Management of Selected Adverse Events of Adult Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Abstract 1115Poster Board I-137 IntroductionNilotinib, 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) or 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. Data from ENACT are used to characterize the patterns and management of adverse events (AEs) in nilotinib pts with imatinib-resistant or -intolerant CML-CP or -AP. MethodsPts received nilotinib 400 mg twice daily. Safety assessments included monitoring for all AEs and cardiac procedures. The first occurrence of the following AEs were selected on the basis of the following criteria: 1) the most frequently reported hematologic or biochemical laboratory abnormalities; or 2) identified by participating investigators as AEs of interest that may lead to study drug discontinuation: thrombocytopenia, neutropenia, hyperglycaemia, elevated lipase, elevated amylase, hyperbilirubinaemia, elevated alanine transaminase (ALT), and elevated aspartate transaminase (AST). There were no differences observed between the pattern of management between AEs suspected and regardless of study drug relationship as well as all grades vs. grade 3/4. For this reason this analysis covers management of grade 3/4 AEs suspected of study-drug relationship including duration and subsequent management. The following actions taken were reported by the treating physicians: study drug dose adjusted or temporarily interrupted, non-drug therapy given, no action taken, study drug permanently discontinued, concomitant medication taken or hospitalization/ prolonged hospitalization. More than one action was allowed to be selected. ResultsThe AEs experienced by 1,603 pts (1,422 CP and 181 AP) were generally identified during nilotinib treatment and lasted for short durations. The number of the grade 3 and 4 AEs in CP and AP, median time from start of treatment and median duration are reported in Table. For all included AEs, the overall most common action taken for the first occurrence was dose adjustment or temporary interruption with the exception of hyperglycaemia which was most often managed by treatment with concomitant medications (8/11 of hyperglycaemia AEs in CP and 1/2 in AP). In the majority of the biochemical abnormalities other than hyperglycaemia there was no additional action taken. 49/308 (16%) events of thrombocytopenia in CP pts (9 in AP) were managed by non-drug therapy. 31/204 (15%) events of neutropenia in CP pts were managed by concomitant medication (6/33 events in AP). Permanent discontinuation of study drug was infrequently observed (number of pts in CP; AP): thrombocytopenia (25; 7), neutropenia (15; 2), hyperglycaemia (1; 0), elevated lipase (3; 0), elevated amylase (0; no pts), hyperbilirubinaemia (2; 0), elevated ALT (3; 0), and elevated AST (1; 0). ConclusionsBased on a large cohort of 1,603 nilotinib pts with CML-CP and CML-AP, nilotinib is well-tolerated. Most study drug-related grade 3/4 AEs could be managed by temporary treatment interruption or dose adjustment, such that permanent discontinuation of study drug due to AEs was infrequent. The only events requiring concomitant medication administration or non-drug therapy were thrombocytopenia, neutropenia, hyperglycaemia and hyperbilirubinaemia. The AE profile observed was predictable and similar to that seen in registration trial.CML-CP (N=1,422)Number of AEsDays from start of treatmentDuration of AEN%MedianMedianThrombocytopena30821.7%4216Neutropenia20414.3%4914Elevated lipase936.5%79Hyperbilirubinaemia594.1%188Elevated ALT302.1%1910Elevated AST120.8%4514Elevated amylase120.8%147Hyperglycaemia110.8%721CML-AP (N=181)Number of AEsDays from start of treatmentDuration of AEN%MedianMedianThrombocytopena5832.0%2714Neutropenia3318.2%2810Hyperbilirubinaemia95.0%712Elevated lipase63.3%716Hyperglycaemia21.1%1912Elevated ALT10.6%14812Elevated AST10.6%8341Elevated amylase00.0%−− Disclosuresle Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Ceglarek:Novartis Pharmaceuticals: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. 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. Dial: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.

Lower Healthcare Resource Utilization Associated with Managing Nilotinib Related Adverse Events in Chronic Myeloid Leukemia (CML) Patients – Evidence From a Clinical Practice Setting Study.

Abstract 4285 BackgroundOnly few studies have characterized the healthcare burden associated with managing adverse events (AEs) in the second-line treatment of CML. Information on incidence of AEs and resource utilization in managing these events would be valuable treatment related attributes. Nilotinib is a potent and selective BCR-ABL kinase inhibitor that is approved for the treatment of Ph+ CML patients in Chronic Phase (CP) and Accelerated Phase (AP), who were intolerant or have failed previous imatinib treatment. Dasatinib is another approved second-line agent in the treatment of imatinib resistant or intolerant CML. Nilotinib and dasatinib have shown differences in their safety profiles in clinical trials. ObjectivesThis study compared the safety profile of nilotinib, observed in a large study of CML patients in a clinical practice setting from participating North American sites to product information of nilotinib and dasatinib, and also compare potential cost differences between the two settings. MethodsAdult patients with imatinib resistant or intolerant Ph+ CML in CP, AP, and blast crisis (BC) were recruited to participate in this phase IIIb, open label, multi-center ENACT (Expanding Nilotinib Access in Clinical Trials) study. Data obtained from the participating North America sites is presented here. Patients who previously failed dasatinib treatment were also allowed to participate. The primary objective of the ENACT study was to obtain additional safety information with nilotinib treatment in a clinical practice setting. Patients received nilotinib 400 mg twice daily (BID). Patients were not permitted to dose escalate. A comprehensive set of hematological and non-hematological adverse event information was obtained in the study. Follow-up treatment in managing the AE, either as dose reduction, dose interruption, or other treatment is also recorded. Incidence of adverse events reported in this study was compared to nilotinib and dasatinib product information. Healthcare resource utilization was estimated from a US health plan perspective by constructing six-month marginal cost increase in patients who received follow-up care for the management of adverse event. Cost data were obtained from MedStat market scan database that contained over 5,000 CML patients. Multivariate regression models and sensitivity analyses were conducted to derive the marginal cost estimates. ResultsA total of 207 patients (172 CP pts, 15 AP pts, and 20 BC pts) were enrolled in the study from several sites in North America between Jan 2006 – Oct 2008. The median age was 54 years. At study completion, 48% were continuing on study treatment, 25% discontinued treatment due to unsatisfactory therapeutic effect, 14% discontinued due to AEs, and 13% discontinued due to other reasons. Percentage of patients with grade 3/4 hematological AEs suspected of being study drug related in CP, AP were: thrombocytopenia (12%, 20%), neutropenia (9%, 27%) and anemia (1.2%, 13%). The most frequent non hematologic AEs (all grades) included rash, headache, nausea, and fatigue. Study patients requiring additional therapy for the reported hematological adverse events was less than 50% in most cases. Dose reductions and dose interruptions of greater than 5 days to manage AEs occurred in 2.3% and 32% patients, respectively, with median duration of dose interruption of 12 days in CP patients and 7 days in AP patients. Total medical costs associated with managing the adverse events, estimated from MedStat cost data, for both hematological and non-hematological AEs observed in this analysis based on patients receiving additional treatment were $6,314 for CML patients in CP and AP, over a six-month treatment period. Medical costs associated with managing hematological adverse events made up the majority of these costs. The estimated costs from this study were significantly lower compared to the estimated burden of the AEs in the product information for nilotinib or dasatinib ($9,730 and $12,372, respectively). ConclusionsNilotinib related adverse event costs observed in this large clinical practice setting study compare favorably to the estimated costs from product information from nilotinib and dasatinib. The analysis is comprehensive in estimating the healthcare costs by characterizing the incidence of the AEs, and managing of the AEs through dose reductions, dose interruption or follow-up care. Disclosures:Guerin:Novartis: Consultancy, I am working for Analysis Group Inc and Analysis Group Inc received funds from Novartis to conduct the analysis. Bollu:Novartis Oncology: Employment. Williams:Novartis Pharmaceuticals: Employment.

Expanding Nilotinib Access in Clinical Trials (ENACT) study in adult patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP), or blast crisis (BC): Updated safety analysis

7059 Background: Nilotinib, is a potent and highly selective oral inhibitor of BCR-ABL, approved in both the US and Europe for the treatment of patients (pts) with Ph+ CML-CP and -AP who are resistant or intolerant to prior therapy including imatinib. Methods: The ENACT study, which is ongoing, was initiated to provide expanded access to nilotinib and to obtain additional safety information in pts with imatinib-resistant or -intolerant CML-CP, -AP, or -BC. Pts received 400 mg nilotinib twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction to 400 mg once daily due to toxicity were allowed to have a dose re-escalation to 400 mg BID after resolution of the adverse events (AEs) to grade 1, lack of response, or persistent disease at the investigator's discretion. Results: Results are available for the first 1056 of the more than 1400 currently enrolled pts (CP, n = 818; AP, n = 120; BC, n = 118). Median age of pts was 53 years, and 69% were imatinib-resistant. AE data are available for 974 pts. At data cutoff (June 30, 2007), 710 pts (67%) were continuing on nilotinib. Median duration of nilotinib exposure was 124 days for CP, 90 days for AP, and 54 days for BC. The main reasons for discontinuation were inadequate responses (13%) and AEs (11%). The majority of AEs were hematologic, with the most common grade 3/4 hematologic lab abnormalities being thrombocytopenia (22%) and neutropenia (13%). Non-hematologic AEs were mostly mild to moderate and included headache, rash, and nausea. Deaths were reported for 28 (3%) pts, and occurred more frequently among those with BC (n = 15). A low incidence of QT prolongation (QTcF > 500 msec, n = 2, 0.2%) was observed overall. Conclusions: This updated analysis of a large expanded access study further demonstrates that nilotinib is generally well tolerated in heavily pretreated pts in all phases of CML and shows no change in the safety profile of nilotinib in Ph+ CML. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis

Pharmacokinetic analysis of nilotinib in Chinese chronic myelogenous leukemia (CML) patients (pts) with imatinib-resistant or-intolerant disease in blast crisis (BC), accelerated phase (AP) or chronic phase (CP)

18020 Background: Nilotinib, a potent and highly selective inhibitor of BCR-ABL, has been approved in both the US and EU for the treatment of patients with CML-CP and -AP resistant or intolerant to prior therapy including imatinib. It has previously been suggested that Asian patients may require different dosing regimens for TKIs than that normally recommended in Caucasian patients. We report here a pharmacokinetic (PK) analysis of nilotinib in 21 Chinese imatinib resistant or intolerant CML pts. Methods: The Expanding Nilotinib Access in Clinical Trials (ENACT) is an ongoing global study initiated to provide expanded access to nilotinib and to obtain additional safety information in pts with imatinib-resistant or -intolerant CML-CP, -AP, or blast crisis (-BC). In this study, nilotinib was administered at 400 mg twice daily (BID). Pharmacokinetic parameters of nilotinib, including area under the concentration-time curve (AUC), maximum concentration (Cmax), time to reach Cmax (Tmax), trough concentration (Cmin), and ratio of accumulation (RA), were obtained on days 1 and 15. Results: 21 Chinese CML patients were included in this analysis. 76% were male; mean age was 40 y (range, 19–67 y); mean body weight was 68.3 kg (range, 48–90 kg). Cmax of nilotinib occurred between 1–12.05 h after drug administration. Mean Cmax of the first dose of nilotinib was 638 ng/mL and occurred a median of 3h after first administration. After repeat dose of 400mg BID for 15 days, mean Cmax was 2161 ng/mL and a Cmin of 1743 ng/mL was reached. Mean AUC was 5076.32 ng·hr/mL on day 1 and 17751.30 ng·hr/mL on day 15. Thus, the steady-state serum level of nilotinib was more than 3 times the level measured after the first dose. The steady-state mean Cmax and AUC values observed in this study were comparable to those observed in previous studies with CML patients from other ethnic groups (Cmax=2260 ng/mL and AUC=18000 ng·hr/mL). The adverse event profile in this cohort was similar to that reported for the pivotal phase I/II registration study. Conclusions: The recommended nilotinib dosing of 400 mg BID is appropriate and well tolerated for Chinese patients with CML. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis

Expanding Nilotinib Access in Clinical Trials (ENACT) Study in Adult Patients (Pts) with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Blast Crisis (BC), Accelerated Phase (AP), or Chronic Phase (CP): Preliminary Safety Analysis.

Background: Nilotinib is a novel, oral ATP-competitive inhibitor of BCR-ABL; it is significantly more potent (>30-fold) and selective than imatinib. ENACT is an ongoing multicenter, open-label, expanded-access study for pts with imatinib-resistant/intolerant CML in all phases. The primary objective is to evaluate the safety of nilotinib in these pts.Methods: Pts with imatinib-resistant or -intolerant CML-CP, -AP, or -BC, who received prior therapies including imatinib and dasatinib were eligible to receive nilotinib 400mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction due to toxicity were allowed to have a dose re-escalation to 400mg BID after resolution of the adverse events (AE) to ≤Grade 1, lack of response, or persistent disease at the investigator's discretion.Results: To date, 1152 pts have been enrolled. Results for the first 587 pts enrolled between January 2006 and January 2007 are presented, 582 received nilotinib and are included for safety analysis (BC n=73, AP n=62, CP n=447): median time since CML diagnosis 52.8 (2.5–468.6) mos; 68.4% were imatinib-resistant and 31.4% were imatinib-intolerant; median duration of nilotinib exposure was 77 days (overall), 84 days for CP, 71 days for AP, and 48 days for BC. At data cutoff (January 31, 2007), 425(73%) pts were continuing on nilotinib, 10% for ≥6 mos. The main reason for discontinuation was unsatisfactory therapeutic effect (11% overall), which as expected was most frequent in BC pts (n=23, 32%). Discontinuations due to AEs occurred in 7% of pts but did not differ significantly among the CML phases: BC 9 (12%); AP 5 (8%); CP 29 (7%). Of the safety population (N=582), 536 (92%) had AEs reported in the database. The incidence and severity of hematologic AEs were higher in BC or AP. Nonhematologic AEs were overall mostly mild to moderate and included headache, rash, nausea, pyrexia, elevated lipase, vomiting, hyperbilirubinemia and myalgia. Among the 536 pts with AEs reported, 15 (2.8%) deaths occurred, most frequently in pts with BC (n=9, 12.5%), rather than AP (n=3, 5.1%) or CP (n=3, 0.7%). The most frequent causes of death in BC were intracranial hemorrhage (n=4), infectious complications (n=2), CML (n=2), or respiratory failure (n=1). Among pts in AP or CP, deaths were attributed to disease progression (n=2), infectious complications (n=2), CML (n=1), or respiratory failure (n=1).Conclusion: Preliminary analysis of this large expanded-access study further demonstrates that nilotinib is safe and well-tolerated in heavily pretreated pts with CML. Importantly, the occurrence of nonhematological AEs for CP, AP and BC pts enrolled in the study appear similar. Overall, both hematologic and nonhematologic AEs have been mild to moderate, and preliminary results from this safety study are consistent with previous published clinical experience with nilotinib phase I/II pivotal studies.