A Phase II Study of Nilotinib A Novel Tyrosine Kinase Inhibitor Administered to Imatinib-Resistant or Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Accelerated Phase (AP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2169-2169 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Norbert Gattermann ◽  
Andreas Hochhaus ◽  
Richard Larson ◽  
Teresa Rafferty ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Myelogenous Leukemia ◽  
Tolerability Profile ◽  
Average Dose ◽  
Safety And Efficacy ◽  
Imatinib Resistant

Abstract Nilotinib is a potent, highly selective, aminopyrimidine inhibitor of Bcr-Abl which in vitro is 30-fold more potent than imatinib. It is active against 32/33 imatinib resistant Bcr-Abl mutations. This open-label study was designed to evaluate the safety and efficacy as defined by hematologic/cytogenetic response (HR/CyR) rates of nilotinib at a dose of 400 mg bid in imatinib resistant or intolerant AP patients. Daily doses of nilotinib could be escalated to 600 mg BID for patients who did not adequately respond to treatment, and in the absence of safety concerns. Safety and efficacy data are reported for 64 patients of which 52 (81%) are resistant and 12 (19%) are intolerant to imatinib. More than half (63%) of the patients had CML for ≥ 5 years. The median age was 61 (range 24-79) years and the median time from CML diagnosis and AP diagnosis were 74 (range 2 to 298), and 2 (range 0-106) months, respectively. Of the 64 patients, 17 (27%) had extramedullary disease at baseline. The median duration of nilotinib exposure was 141 (range 2–380) days and the median average dose intensity (mg/days) for all patients, with and without dose escalations, was 797 (range 157 to 1136). Treatment is ongoing for 33 (52%) patients, and 31 (48%) have discontinued (14 for disease progression, 8 for adverse events, 1 each for an abnormal laboratory value, administrative problems, lost to follow up, 4 patients withdrew consent and there were 2 deaths listed as the primary reason for discontinuation). Overall, there were 7 deaths including 4 for disease progression, one related to progressive disease complicated by a cerebral hemorrhage, one cardiac failure and one due to sepsis. Confirmed HR occurred in 28 (44%) patients, of which 11 (17%) were complete, 5 (8%) were marrow responses/no evidence of leukemia, 12 (19%) were return to chronic phase. There were 7 (11%) patients with stable disease/no response, 6 (9%) with disease progression and 21 (33%) patients were not evaluable. Major CyR occurred in 20 (31%) patients, of which 11 (17%) were complete, 9 (14%) were partial, 11 (17%) were minor, and 15 (23%) were minimal. There were 6 patients (9%) that did not respond. The rate of major CyR for the resistant and intolerant patients was 16 (31%) and 3 (25%), respectively. The majority of Grade 3 or 4 adverse events included thrombocytopenia in 21 (33%), neutropenia in 17 (27%), anemia in 10 (16%) patients, decreased hemoglobin in 4 (6%) patients, and increased lipase in 5 (8%). In summary, these data suggest nilotinib is clinically active and has an acceptable safety and tolerability profile when administered to patients with CML-AP. Updated information will be presented at the meeting.

A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Patients with Imatinib Resistant or Intolerant Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis (BC) Who Have Also Failed Dasatinib Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2170-2170
Author(s):  
Francis Giles ◽  
Philipp le Coutre ◽  
Kapil Bhalla ◽  
Gianantonio Rosti ◽  
G.J. Ossenkopplele ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Patient Death ◽  
Open Label ◽  
Imatinib Resistant

Abstract Nilotinib is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and active against 32/33 imatinib resistant cell lines with Bcr-Abl mutations. This open-label study was designed to evaluate the efficacy and safety as defined by hematologic and cytogenetic response rates (HR/CyR) of nilotinib administered at a daily dose of 400 mg bid to patients who previously received and either failed or were intolerant to imatinib and dasatinib. A total of 50 patients were enrolled and included CP (n=26), AP (n=10), and BC (n=14) patients. Of the 14 BC patients 10 were myeloid and 4 were lymphoid. Overall 8 (16%) patients had extramedullary disease at baseline. The median age was 57 (range 19–78) years and the median time from first diagnosis of CP, AP, or BC to treatment was 65 (range 8–213) months. The median duration of nilotinib exposure was 226 (range 3–379) days. A total of 28 (56%) patients remain on treatment, 22 (44%) discontinued (6 for adverse events, 11 for disease progression, 3 withdrew consent, and there were 2 deaths related to cerebral hemorrhages). Complete (HR) was reported in 9 of the 20 (45%) CP patients who did not have a CHR at baseline. Of the 26 CP patients, 8 (31%) had a major CyR (2 complete and 6 partial), 2 (8%) patients had minimal responses, and 9 (35%) patients had no response. Disease progression occurred in one CP patient and 6 patients were not evaluable. Confirmed hematologic responses were observed in 2 of 10 (20%) AP patients who had a return to chronic phase (RTC), 7 patients were not evaluable and there was one patient death. Of the 10 AP patients 1 (10%) each had CyR (partial, minor, minimal and no response). Of the 14 BC patients 1 had a CHR (7%), 2 (14%) had a return to chronic phase (RTC), 6 (43%) were not assessable for response, and 5 (36%) had progressive disease. Overall the most frequent Grade 3 or 4 adverse events reported were thrombocytopenia in 12 (24%), neutropenia in 11 (22%), and anemia in 5 (10%) patient. In summary, nilotinib has significant clinical activity and an acceptable safety and tolerability in CML-CP, AP, and BC patients who were resistant or intolerant to imatinib and have also failed dasatinib therapy.

Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 735-735 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Andreas Hochhaus ◽  
Jorge Cortes ◽  
Giovanni Martinelli ◽  
Kapil N. Bhalla ◽  
...  
Keyword(s):  
Median Duration ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Tolerability Profile ◽  
Average Dose ◽  
Imatinib Resistance ◽  
Serum Lipase ◽  
Imatinib Resistant

Abstract Background: Nilotinib is a novel, selective BCR-ABL inhibitor, designed to bind the ATP-binding site of BCR-ABL protein with higher affinity than imatinib. It is more potent than imatinib (IC50 <30 nM) against wild-type BCR-ABL and active against 32/33 imatinib-resistant BCR-ABL mutants. Methods: This open-label study was designed to evaluate the safety and efficacy of nilotinib in patients (pts) with Philadelphia (Ph+) imatinib-resistant or -intolerant CML-CP. Planned nilotinib dose was 400 mg twice daily (BID) with escalation to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR) determined on the conventional intent-to-treat patient population. Cytogenetic response (CyR) was assessed by bone marrow karyotyping; peripheral blood FISH was used if a marrow sample cannot be obtained. Results: This analysis includes data from 320 pts who received at least 6 months of nilotinib therapy (70.6% imatinib-resistant; 29.4% imatinib-intolerant). The median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males. Treatment with nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the treatment [51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE)]. The median duration of nilotinib exposure was 341 (1–624) days and the median average dose intensity was 792.1 mg/d (47.9–1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%). Complete hematological remission (CHR) at baseline was reported in 114 pts. Of the remaining 206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%): 128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27%), neutropenia (30%), anemia (9%), and asymptomatic serum lipase elevation (15%). Conclusion: The present study confirms nilotinib is an effective therapeutic option in CML-CP pts with imatinib-resistance or -intolerance, with an acceptable safety and tolerability profile. With longer follow up, cytogenetic response continues to increase and no change in safety profile has been observed on nilotinib therapy.

A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Imatinib-Resistant and -Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 165-165 ◽  
Author(s):  
Philipp le Coutre ◽  
Kapil Bhalla ◽  
Francis Giles ◽  
Michele Baccarani ◽  
Gert J. Ossenkoppele ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Median Time ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Tolerability Profile ◽  
Average Dose ◽  
Imatinib Resistance ◽  
Serum Lipase ◽  
Imatinib Resistant

Abstract Nilotinib is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. This open-label study was designed to evaluate the safety and efficacy, as defined by hematologic/cytogenetic response rates (HR/CyR) of nilotinib administered at a daily dose of 400 mg bid to imatinib resistant or intolerant CML-CP patients. Daily doses of nilotinib could be escalated to 600 mg BID for patients who did not adequately respond to treatment, and in the absence of safety concerns. Data are available for 132 patients including 91 (69%) with imatinib resistance and 41 (31%) imatinib intolerant. Of the 132 patients, 45 (34%) had a CHR at baseline and 87 (66%) did not. Overall 77 (58%) patients had additional chromosomal abnormalities at baseline, and 16 (12%) had extramedullary involvement. Median age was 58 (range 26–85) years and the median time from first diagnosis to treatment was 57 (range 5–275) months. There were 72 males and 60 females. Nearly half (49%) of the patients had CML for ≥ 5 years and the median overall duration of prior imatinib was 978 days (range 9 to 3468). Treatment with nilotinib is ongoing for 82 of the 132 (62%) patients. A total of 50 (38%) patients have discontinued treatment (26 for adverse events, 15 for disease progression, 7 for other/administrative reasons, and there were two patient deaths (one myocardial infarction in a patient with previous infarctions noted on autopsy, and one with progressive disease). The median duration of nilotinib exposure was 226 (range 3–379) days. The median average dose intensity (mg/days) for all patients, with and without dose escalations, was 800 (range 134 to 1106). CHR was reported in 60 of 87 (69%) patients without a baseline CHR. The median time to CHR was 1.4 months (range 0.3 to 13). Major CyR was observed in 55 (42%), of which 33 (25%) were complete, 22 (17%) partial, 10 (8%) minor, 15 (11%) minimal, 21 (16%) had no cytogenetic response and 4 (3%) had disease progression. The median time to MCyR was 2.6 months (range 0.9 to 8.4). Overall the most frequent Grade 3 or 4 adverse events included thrombocytopenia 34 (26%), neutropenia in 24 (18%), elevated serum lipase in 10 (8%) and anemia in 9 (7%). In summary, nilotinib has demonstrated significant clinical activity as defined by 69% CHR and 42% MCR rates, and an acceptable safety and tolerability profile in patients with imatinib resistant or intolerant CML-CP. Updated information will be presented at the meeting.

A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7026-7026 ◽  
Author(s):  
P. le Coutre ◽  
N. Gattermann ◽  
A. Hochhaus ◽  
R. Larson ◽  
A. Weitzman ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Median Duration ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Average Dose ◽  
Imatinib Resistance ◽  
Safety And Efficacy ◽  
Imatinib Resistant ◽  
Grade 3

7026 Background: CML-AP is often associated with imatinib-resistance and the occurrence of BCR-ABL mutations. This phase II open-label study was designed to evaluate the safety and efficacy of Nilotinib, a potent novel tyrosine kinase inhibitor, in imatinib-resistant or - intolerant CML-AP pts. Methods: Imatinib-resistance and -intolerance were defined using standard criteria, and all resistant pts failed imatinib >/= 600mg/day. Primary endpoint was a confirmed hematologic response (HR) determined by conventional ITT analysis. Nilotinib was started at 400mg BID and escalated to 600mg BID for inadequate responses. Results: Safety and efficacy are reported for first 64 consecutively enrolled pts completing >/= 8 mos treatment. 52 (81%) were imatinib-resistant; 12 (19%) -intolerant. Median duration of CML was 74 mos; median duration of prior imatinib use was 28 mos. Median duration of nilotinib exposure was 208 days; median average dose intensity (mg/days) was 787. Median cumulative duration of dose interruption was 23 days. Treatment is ongoing for 27 (42%) pts; 37 (58%) have discontinued (9 for AEs; 17 for disease progression). HR occurred in 38 (59%) pts, of which 15 (23%) were complete, 8 (13%) were marrow responses, and 15 (23%) returned to chronic phase. MCyR occurred in 23 (36%) pts; 14 (22%) were complete and 9 (14%) were partial. 6 (9%) pts did not respond; 5 (8%) pts had disease progression. Median time to HR was 1.0 (1–3) mos and to MCyR was 2.0 (1–8) mos. Estimated 1-yr survival rate was 69% and median duration of HR has not been reached. The most common Grade 3/4 AEs included neutropenia (45%), thrombocytopenia (40%), asymptomatic lipase elevations (17%), and anemia (16%) pts. No pts experienced Grade 3/4 peripheral edema, or pleural/pericardial effusions; 2 pts had pulmonary edema. Conclusion: In pts with CML-AP, nilotinib is an effective therapeutic option in CML-AP pts with imatinib-resistance or -intolerance and is generally well tolerated with acceptable rates of myelosuppression and minimal non- hematologic toxicities. No significant financial relationships to disclose.

A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7040-7040 ◽  
Author(s):  
R. Larson ◽  
O. Ottman ◽  
H. Kantarjian ◽  
P. le Coutre ◽  
M. Baccarani ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Complete Response ◽  
Myelogenous Leukemia ◽  
Safety And Efficacy ◽  
Imatinib Resistant

7040 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. In a phase I trial, nilotinib demonstrated efficacy and favorable tolerability in these pts. These results expand upon the phase I experience Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult imatinib-resistant or - intolerant BC pts or pts with relapsed/refractory Ph+ALL. Primary endpoint was investigator assessment of best hematologic response for BC and complete response for Ph+ALL pts. Nilotinib was started at 400mg BID with escalation to 600mg BID if no adequate response. Results: Safety and efficacy data are reported for 120 BC (27 lymphoid, 87 myeloid, 6 unknown) and 41 Ph+ALL pts (37 active disease, 4 residual disease, 38 relapsed, 3 refractory). 60% of pts had >35% Ph+ metaphases for BC and 31% for Ph+ALL. Median ages was 54 yrs for BC and 46 yrs for Ph+ALL pts. Chromosomal abnormalities other than Ph+ were noted in 64 (53%) BC and 12 (29%) Ph+ALL pts. Extramedullary involvement was present in 44 (37%) BC and 3 (7%) Ph+ALL pts. Treatment is ongoing for 21 (18%) BC and 4 (10%) Ph+ALL pts. Majority of discontinuations were due to disease progression [61 (51%) in BC; 26 (63%) in Ph+ALL). Median treatment duration was 53 (1–441) and 72 (3–363) days for BC and Ph+ALL, respectively. Median dose intensity was 800mg/day for both pt groups. CHR was reported in 25 (21%) pts, marrow responses in 7 (6%) pts, and return to chronic phase in 10 (8%) pts. Complete response was reported in 10 (24%) Ph+ALL; of which, 1 patient had minimal residual disease. The most common Grade 3/4 AEs were thrombocytopenia (41%), neutropenia (28%), pneumonia (11%), and anemia (27%) in BC and thrombocytopenia (24%) in Ph+ALL pts. During study period death occurred in 9 (8%) BC and 3 (7%) Ph+ALL pts. No Ph+ALL pt developed CNS disease while on therapy. Conclusions: Nilotinib has significant clinical activity and is well tolerated in imatinib-resistant or -intolerant BC and relapsed/refractory Ph+ALL pts. Nilotinib represents an important new treatment option for these pts in which there remains a high unmet medical need. No significant financial relationships to disclose.

Nilotinib Therapy after Dasatinib Failure in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis (BC).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1029-1029 ◽  
Author(s):  
Francis J. Giles ◽  
Philipp le Coutre ◽  
Kapil N. Bhalla ◽  
Gert Ossenkoppele ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Clinical Activity ◽  
Open Label ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Background: Nilotinib and dasatinib are the next generation of tyrosine kinase inhibitors (TKIs) which have been developed for use in the treatment of imatinib-resistant/intolerant CML. Few therapeutic options are available for patients (pts) with CML who fail to benefit from or to tolerate first, imatinib, and then, a second generation TKI such as dasatinib and nilotinib. This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in such pts who either failed or were intolerant to imatinib and dasatinib. Methods: Nilotinib was administered at a dose of 400 mg twice daily (BID) to pts with CML-CP, -AP, and -BC who previously received and either failed or were intolerant to imatinib and dasatinib. Pts who had inadequate hematologic and/or cytogenetic responses at 28 days or who had disease progression could be escalated to 600 mg BID in the absence of safety concerns. Results: A total of 67 evaluable pts are reported with CML-CP (27), -AP (15), and -BC (25 total; 15 myeloid, 8 lymphoid). Overall, 25% of pts had extramedullary disease at baseline (14 spleen, 6 liver). For all pts, median time from first diagnosis was 20 (<1–266) months. The median duration of nilotinib exposure was 85 (2–542) days with median dose intensity of 800 (211–1093) mg/day. A total of 22 (33%) pts with dasatinib failure remained on nilotinib and 45 (67%) discontinued (8 for adverse events, 27 for disease progression). Of 17 pts with CML-CP who did not have a complete hematologic response (CHR) at baseline, 11 (65%) achieved a CHR at 4-month follow-up. Of all 22 pts with CML-CP at 4-month follow-up, 7 (32%) had a major cytogenetic response (3 complete, 4 partial). Disease progression occurred in only 2 pts with CML-CP, both of whom had CHR at baseline. Of 13 evaluable pts with CML-AP, 3 (23%) demonstrated no evidence of leukemia and 3 (23%) had a return to chronic phase (RTC) after 4 months of nilotinib therapy. No pts with CML-AP had disease progression at 4 months. Of 20 evaluable pts with CML-BC, 3 (15%) achieved CHR, 1 (5%) had RTC, and 6 (30%) had disease progression. For all pts (N=67), the most common grade 3/4 hematologic adverse events reported were neutropenia (51%), thrombocytopenia (44%), and anemia (21%). The most frequent grade 3/4 nonhematologic adverse events reported were pyrexia (8%), anorexia and headache (3%), and diarrhea, asthenia, constipation, fatigue, and myalgia (2% each). 3 pts had pleural effusion and 1 had pericardial effusion during nilotinib therapy. Conclusion: Nilotinib has impressive clinical activity in these heavily pretreated pts with CML-CP, -AP, or -BC in whom both imatinib and dasatinib have failed. In addition, nilotinib tolerability and safety profile in this subset of pts was similar to that reported for pts who failed only imatinib.

A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Imatinib Resistant or Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Blast Crisis (BC) or Relapsed/Refractory Ph+ Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1862-1862 ◽  
Author(s):  
Oliver Ottmann ◽  
Hagop Kantarjian ◽  
Richard Larson ◽  
Philipp le Courte ◽  
Michele Baccarani ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Tolerability Profile ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Nilotinib is a highly selective, aminopyrimidine which is 30-fold more potent in vitro than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. This open-label study was designed to evaluate the safety and efficacy of Nilotinib administered at a dose of 400 mg bid by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant or intolerant BC patients or patients with relapsed/refractory Ph+ALL. Preliminary data are presented for 96 BC and 34 Ph+ALL patients. The median age for the Ph+ALL patients was 47 years (range 26 to 75) and for the BC patients 54 years (range 19 to 78). There were 16 males and 18 females with Ph+ALL and 60 males and 36 females with BC. Chromosomal abnormalities other than Ph+ were noted in 12 (35%) and 48 (50%) of BC patients. Extramedullary involvement was present in 3 (9%) Ph+ALL patients and 35 (37%) of BC patients. Treatment is ongoing for 8 (24%) of Ph+ALL patients and 31 (32%) of BC patients. The majority of discontinuations were due to disease progression and occurred in 18 (53%) BC patients and 41 (43%) Ph+ALL. CHR was reported in 12 (13%) BC patients, marrow responses in 6 (6%), return to chronic phase and stable disease in 17 (18%) patients each. Complete responses were reported in 2 (6%) Ph+ALL 1 relapsed/refractory and 1 patient with minimal residual disease). The most frequent Grade 3 or 4 adverse events occurring in patients with Ph+ALL were thrombocytopenia in 3 (9%) patients, and 2 (6%) patients each had neutropenia, blood bilirubin increased, ALT elevation and bone pain. The most frequent Grade 3 or 4 adverse events occurring in patients with BC were thrombocytopenia 23 (24%), neutropenia 17 (18%), and anemia in 9 (9%) of patients. Nilotinib has clinical activity and an acceptable safety and tolerability profile in pts with imatinib resistant or intolerant BC and relapsed/refractory Ph+ ALL patients.

A phase II study of nilotinib administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who also failed dasatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7038-7038 ◽  
Author(s):  
F. J. Giles ◽  
P. le Coutre ◽  
K. Bhalla ◽  
G. Rosti ◽  
G. Ossenkoppele ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Open Label ◽  
Imatinib Resistant

7038 Background: Nilotinib and dasatinib are two new second generation tyrosine kinase inhibitors used in the treatment of imatinib-resistant/intolerant CML. There is limited data regarding the efficacy and safety of these therapies when given sequentially. Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib at a dose of 400mg BID in CML-CP, -AP, and -BC pts who previously received and either failed or were intolerant to imatinib and dasatinib. Results: A total of 42 pts are reported - CP (16), AP (9), and BC (17 total; 13 myeloid, 4 lymphoid). Overall 10 (24%) pts had extramedullary disease at baseline. For all pts, median time from first diagnosis was 16.8 (0.6–265) months. The median duration of nilotinib exposure was 81 days with median dose intensity of 800mg/day. A total of 13 (31%) pts with dasatinib failure remain on treatment, 29 (69%) discontinued (6 for AEs, 16 for disease progression). CP: Of the 16 pts, 5 (31%) had a MCyR (3 complete, 2 partial). Complete hematologic response (CHR) was reported in 5/13 (39%) pts without CHR at baseline. Disease progression only occurred in 2 pts. AP: 2/9 (22%) pts had a return to chronic phase (RTC), 6 pts were not evaluable and there was 1 death. Disease progression occurred in 5 pts. BC: 3/17 (18%) achieved CHR, 1 (6%) had RTC, and 4 (24%) pts had disease progression. For all pts, the most common Grade 3/4 AEs reported were thrombocytopenia (26%), neutropenia (24%), and anemia (7%) pts. Conclusions: Nilotinib has significant clinical activity in CML-CP, AP, and BC patients who have failed imatinib and dasatinib. Nilotinib is safe and well tolerated, consistent with its kinase selectivity profile. No significant financial relationships to disclose.

A phase II study of nilotinib administered to imatinib resistant and intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7007-7007 ◽  
Author(s):  
G. Rosti ◽  
P. le Coutre ◽  
K. Bhalla ◽  
F. Giles ◽  
G. Ossenkoppele ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Median Duration ◽  
Dose Intensity ◽  
Response Rates ◽  
Myelogenous Leukemia ◽  
Average Dose ◽  
Imatinib Resistance ◽  
Imatinib Resistant

7007 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. The objective of this phase II open-label study was to evaluate the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP pts Methods: Imatinib-resistance was defined using standard criteria and had failed imatinib >/= 600mg/day. Imatinib intolerance was defined as intolerant symptoms and lack of MCyR. Primary endpoint was MCyR determined by conventional ITT analysis. Planned nilotinib dose was 400mg BID with escalation to 600mg BID for inadequate responses Results: 316 pts were enrolled and included for safety analysis; efficacy results are from 279 pts with at least 6 mos of follow up. 221 (70%) pts were imatinib-resistant and 95 (30%) were imatinib- intolerant. Median duration of CML was 58 mos; median prior imatinib use was 33 mos. 227 (73%) pts had prior imatinib dose >/= 600mg/day. Treatment with nilotinib is ongoing for 221 (70%) pts. 95 (30%) pts have discontinued treatment (41 for AEs, 32 for disease progression). Median duration of nilotinib exposure was 247 days; overall median average dose intensity was 797mg/day. Median cumulative duration of dose interruptions was 19 days. MCyR was achieved in 145 (52%), 96 (34%) were complete and 49 (18%) partial. Median time to MCyR was 2.8 mos. CHR was achieved in 137/185 (74%) pts without baseline CHR. Median time to CHR was 1.0 mos. Response rates were similar in imatinib- resistant and -intolerant pts. After 10 mos of follow up, the median duration of CHR and MCyR has not been reached. The most frequent Grade 3/4 laboratory abnormalities included thrombocytopenia in (29%), neutropenia in (28%), and asymptomatic lipase elevation in (15%) pts. Rare (<1%) pleural effusion, pericardial effusion, or pulmonary edema were observed. Requirements for growth factors and platelet transfusions were minimal. Conclusions: Nilotinib resulted in significant response rates in pts with imatinib-resistant or -intolerant CML-CP and excellent tolerability as indicated by high dose intensity, favorable rates of myelosuppression, and no serious episodes of fluid retention. No significant financial relationships to disclose.

Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7006-7006 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
T. Brummendorf ◽  
H. Kantarjian ◽  
G. Martinelli ◽  
D. Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Low Grade ◽  
Imatinib Resistant ◽  
Philadelphia Chromosome Positive

7006 Background: Bosutinib (SKI-606) is an orally available, dual Src/Abl kinase inhibitor. To assess safety and preliminary clinical activity of bosutinib, we conducted a phase 1/2 study in patients (pts) with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who were imatinib resistant/intolerant. Methods: In part 1, 18 pts with imatinib- relapsed/refractory chronic phase (CP) CML received bosutinib 400 mg/day (3 pts), 500 mg/day (3 pts), or 600 mg/day (12 pts). Part 2 was an expanded cohort of 51 pts with all phases of Ph+ CML and ALL dosed at 500 mg daily. Timed blood samples were collected on days 1–3, 15 for PK analysis. Results: Of 69 pts, median age was 59 yrs; 48 were CP; 90% imatinib resistant. Drug-related grade 1/2 adverse events (AEs) occurring in =10% of CP pts: diarrhea (69%), nausea (44%), vomiting (19%), abdominal pain (13%), rash (13%). Grade 3/4 AEs occurring in =5% of CP pts: rash (6%), thrombocytopenia (6%). 17 pts required dose reductions. In evaluable imatinib-resistant CP-CML pts with no prior exposure to other Abl inhibitors, 16/19 (84%) had complete hematologic response (CHR); 4/21 had partial and 7/21 had complete cytogenetic responses for major cytogenetic response (MCyR) rate of 52%. Of 58 pts evaluable for mutations, 13 different imatinib-resistant mutations were found in 32 pts. 12/14 CP pts with non-P-loop mutations and 3/3 with P-loop mutations achieved CHR. 5/11 CP pts with non-P- loop mutations and 1/1 with P-loop mutation achieved MCyR. 4/9 evaluable advanced leukemia pts had CHR, 2 had MCyR. After oral administration, steady state exposure of bosutinib was nearly 2-fold higher than single-dose exposure. Mean elimination half-life was approximately 22–27 hours, supporting a once-daily dosing regimen. Conclusions: Bosutinib was well tolerated in pts with CML, with primarily low-grade gastrointestinal and dermatologic AEs. Bosutinib showed clinical activity in imatinib-resistant pts with cytogenetic responses and CHR across a range of mutations. Durability of response continues to be assessed. [Table: see text]

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