Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 30-30 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Charles Koller ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Once Daily ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with CML-CP who are resistant to or intolerant of imatinib (IM), we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤ 0.05% in our lab) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD) schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Thirty-seven pts have been enrolled between November 2005 and June 2007 (19 on the QD schedule, 18 BID). Median age was 41 years (yrs) (range 18–76 yrs). Nine (24%) of the pts were Sokal intermediate-risk and 3 (8%) were high-risk. Median baseline WBC count was 29.1 x 109/L (range 3.4–300.0). Three pts had clonal evolution at start of therapy. At 3 mo, complete hematologic response (CHR) was achieved in all pts,major cytogenetic response occurred 31/33 (94%), and complete cytogenetic response (CCyR) in 26/33 (79%) evaluable pts. After 6 mo of therapy, 30/32 (94%) evaluable pts had achieved CCyR. This compares favorably with results obtained in historical controls with IM at standard (400 mg) and high-dose (800 mg) at our institution: At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. Responses are similar in both treatment schedule groups. The most common non-hematologic adverse events (AE) included fatigue (n=22), musculoskeletal pain (n=20), headache (n=19), and dizziness (n=14), and were predominantly grade (grade 1–2). Grade 3–4 non-hematologic toxicity (regardless of causality) included headache, pain, rash, neuropathy and memory impairment (1 each). Pleural effusion occurred in 5 (14%) pts (all grade 1–2). Grade 3–4 hematologic toxicity (transient) included neutropenia in 4 (11%) pts, thrombocytopenia in 4 (11) pts, and anemia in (5%). With a median duration of therapy of 10 mo, 18 (49%) pts required transient treatment interruption, 14 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. Sixteen pts (43%) have required dose reductions. The actual median daily dose for all pts was 100 mg; it was 100 mg for pts treated on the QD schedule, and 90 mg for those in the BID schedule. There is no significant difference in grade 3–4 toxicity by treatment schedule. Conclusion: Rapid, complete cytogenetic responses to dasatinib 100 mg/day occur in a high percentage of patients with previously untreated CML-CP. Once daily dosing appears to be associated with less toxicity. Accrual to this trial continues. Percent with CCyR (No. evaluable) Months on Therapy Dasatinib Imatinib 400 mg Imatinib 800 mg P value 3mo 79 (33) 37 (49) 62 (202) 0.0003 6mo 94 (32) 54 (48) 82 (199) <0.0001 12mo 100 (24) 65 (48) 86 (197) 0.0001

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 182-182 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
Dan Jones ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCRABL and SRC with significant activity in pts with CML-CP resistant to or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45 years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45 (98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Mo on therapy Dasatinib Imatinib 400mg Imatinib 800mg P value 3 78 (45) 37 (49) 62 (202) 0.0003 6 93 (41) 54 (48) 82 (199) &lt;0.0001 12 97 (35) 65 (48) 86 (197) 0.0001 18 88 (33) 68 (38) 89 (179) 0.004 24 80 (25) 70 (40) 88 (173) 0.006 MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last assessment). Grade 3–4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%), neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3–4 in 2%). Grade 3–4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Four pts came off study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 81%. Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.

Efficacy and Safety of Bosutinib (SKI-606) in Patients with Chronic Phase (CP) Ph+ Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1098-1098 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M Kantarjian ◽  
Dong- Wook Kim ◽  
H. Jean Khoury ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
Cytogenetic Response ◽  
Fluid Retention ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor demonstrating inhibitory activity against BCR-Abl phosphorylation, and is 200 times more potent than imatinib but with minimal inhibition of platelet-derived growth factor receptor (PDGFR) or c-kit. The phase I portion of this study identified a treatment dose of 500 mg daily and showed evidence of clinical efficacy. The phase II portion of the study to investigate the efficacy and safety of bosutinib in patients (pts) with CP Ph+ CML who have failed imatinib therapy is ongoing. Preliminary data for 283 treated pts, median age 54 yrs (range 18 – 91 yrs) and 52% male are reported. A subset of pts received treatment in addition to imatinib, including interferon (91 pts), dasatinib (71 pts), nilotinib (7 pts) and stem cell transplant (13 pts). Among pts who failed imatinib (and received no other tyrosine kinase inhibitor treatment), 137 were imatinib-resistant (all received imatinib ≥600mg) and 64 pts were imatinib-intolerant; median duration of bosutinib treatment to date is 7.7 mos (range 0.2 – 28.2 mos) and 4.5 mos (range 0.5 – 21.5 mos), respectively. Among 67 imatinibresistant pts evaluable for hematological response, 53 (79%) had complete hematological response (CHR). Of 84 imatinib-resistant pts evaluable for cytogenetic response, 34 (40%), achieved a major cytogenetic response (MCyR), including 24 (29%) with a complete cytogenetic response (CCyR). Of 34 pts with MCyR, 31 have maintained their response to date. Of 60 evaluable imatinib-resistant pts, 20 (33%) achieved major molecular response, 10 (17%) of which were complete. Among imatinib-intolerant pts, 22 of 29 evaluable (76%) achieved CHR, and 13 of 22 evaluable (59%) achieved MCyR, including 11 (50%) with CCyR. Of 25 evaluable imatinib-intolerant pts, 7 (28%) achieved major molecular response, 5 (20%) of which were complete. Of 105 pts with baseline samples tested for mutations, 17 different mutations were found in 45 pts (43%). CHR occurred in 5/6 pts (83%) with P-loop mutations and 13/17 (76%) with non-P-loop mutations; MCyR occurred in 3/6 pts (50%) and 11/24 pts (46%), with P-loop and non-P-loop mutations, respectively. Treatment was generally well tolerated. The most common adverse events among treated pts (n=283) were gastrointestinal (nausea, vomiting, diarrhea), these were usually grade 1 – 2, manageable and transient, diminishing in frequency and severity after the first 3 – 4 weeks of treatment. Grade 3 – 4 non-hematologic toxicity occurring in ≥5% of pts were diarrhea (8%), rash (8%) and increased ALT (5%). 27 pts (10%) reported grade 1/2 fluid retention adverse events, including 21 pts with edema, and 6 pts with effusions: 4 pleural, 1 pericardial, and 1 pleural and pericardial. A single patient experienced grade 3 pleural effusion possibly related to bosutinib with concomitant pneumonia and a pre-treatment history of recurrent pleural effusions. Grade 3 – 4 hematologic laboratory abnormalities included thrombocytopenia in 65 pts (23%), neutropenia in 37 pts (13%) and anemia in 17 pts (6%). 124 pts (44%) had at least 1 temporary treatment interruption and 85 pts (30%) had at least 1 dose reduction due to toxicity. 37 pts (13%) have permanently discontinued treatment due to adverse event. Bosutinib is effective in pts with CP CML with resistance or intolerance to imatinib across a range of mutations. Unlike other tyrosine kinase inhibitors, bosutinib does not significantly inhibit PDGFR or c-kit, and this may be responsible for the relatively favorable toxicity profile with few pts experiencing hematologic toxicity or fluid retention.

Bosutinib (SKI-606) Demonstrates Clinical Activity and Is Well Tolerated among Patients with AP and BP CML and Ph+ ALL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 473-473 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
H. Kantarjian ◽  
T. Bruemmendorf ◽  
G. Martinelli ◽  
M. Baccarani ◽  
...  
Keyword(s):  
Philadelphia Chromosome ◽  
Fluid Retention ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Major Molecular Response ◽  
Wide Range ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor. Biochemical assays have shown it to be up to 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation. Unlike imatinib, bosutinib does not exhibit significant inhibition of c-kit or platelet-derived growth factor receptor (PDGFR), which may result in a relatively favorable safety profile. This is an ongoing open-label study in patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase chronic myelogenous leukemia and (Ph+) ALL who failed prior imatinib therapy or other TKIs. Objectives are to assess safety and clinical activity of bosutinib. Pts receive bosutinib 500 mg/day. We report preliminary data for 57 pts, median age 54 yrs (range 22–83 yrs), 54% male. 23 pts (40%) were in AP, 15 (26%) in blast crisis (BC), 14 (25%) had Ph+ALL, and 5 (9%) were unclassified. Prior therapy included interferon (22 pts), imatinib (55 pts; data missing for 2 pts), dasatinib (17 pts), nilotinib (10 pts), stem cell transplant (5 pts). Overall median duration of bosutinib treatment was 2.7 mos (range 0.03–10.8 mos). Complete hematological response (CHR) was obtained in 7/25 evaluable pts (28%), including 4/14 (29%) pts with AP-CML, 2/8 (25%) pts with BC-CML, and 1/3 (33%) pts with Ph+ ALL. Among pts with no other TKI exposure, major cytogenetic responses (MCyR) were observed in 5/14 evaluable pts (36%), including 3/6 (50%) pts with AP-CML, 2/5 (40%) pts with BC-CML. Among pts with prior TKI exposure, 3/10 (30%) had MCyR, including 0/3 AP, 1/4 BP, and 2/3 ALL pts. Median time to MCyR was 8.9 weeks for pts previously exposed and 12 wks for unexposed to other TKIs. Duration of MCyR was 18 wks. 19 previously unexposed patients were evaluable for major molecular response. 4 (21%) had major molecular response, 3 (16%) of which were complete. Of 42 pts with samples tested for mutations, 13 different mutations were found in 20 pts (48%), including 5 cases of T315I. CHR occurred in 2/3 pts with P-loop mutations and 5/17 with non-P-loop mutations; MCyR occurred in 2/2 pts and 4/9 pts, respectively. Treatment was generally well tolerated in this cohort of heavily pretreated patients. The most common adverse events were gastrointestinal (diarrhea [56%], nausea [37%], vomiting [35%]) but these were usually grade 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 weeks of therapy. Grade 3–4 hematologic laboratory abnormalities reported included thrombocytopenia in 31 pts (59%), neutropenia in 20 pts (38%), and anemia in 13 pt (25%). Grade 3–4 non-hematologic toxicities were diarrhea (9%) and vomiting (9%). Fluid retention was reported in 8 pts (14%), including 2 cases (3%) of pleural effusion (grade 2 and 3). Both were considered unrelated to treatment. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations. Bosutinib has a favorable toxicity profile with a small number of pts experiencing hematologic toxicity and fluid retention, possibly due to the lack of c-kit inhibition and PDGFR inhibition, respectively.

Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-C (CA180-013).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 734-734 ◽  
Author(s):  
Richard M. Stone ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Jeffrey H. Lipton ◽  
Timothy Hughes ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32–50). Prior therapy included interferon-α in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87–93%), major cytogenetic response (MCyR) in 59% (95% CI 54–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11–171). Reports of grade 3–4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1–2 in 21% and grade 3–4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 338-338 ◽  
Author(s):  
Jorge Cortes ◽  
Gautam Borthakur ◽  
Susan O'Brien ◽  
Dan Jones ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Grade 3

Abstract Abstract 338 Dasatinib, a potent inhibitor of ABL and SRC, is approximately 300 times more potent than imatinib in vitro and has significant activity in pts with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP within 6 months from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Sixty-two pts have been enrolled (31 on the QD schedule, 31 BID). Median age was 47 years (yrs) (range 18–76 yrs). Median follow-up is 24 months (mo) (range, 1 to 39 mo). All 45 pts who were not in CHR at the start of therapy achieved CHR. Among 50 pts followed for at least 3 months, 49 (98%) achieved complete cytogenetic response (CCyR). Major molecular response has been achieved in 35 (70%), including 5 (10%) with complete molecular response. The CCyR rate at different timepoints (intention-to-treat) compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Major molecular response was achieved by 45% by 12 mo and 71% by 24 mo (corresponding rates with imatinib 400mg 34% and 55%, and with imatinib 800mg 58% and 66%, respectively). There was a trend for higher MMR rate with the QD schedule: overall 75% vs 65% (p=0.54), and by 12 months 52% and 38% (p=0.54). Grade 3-4 non-hematologic toxicity (regardless of causality) included fatigue (6%), pain (muscle or joint) (6%), dyspnea, neuropathy and memory impairment (5% each). Pleural effusion occurred in 13% evaluable pts (grade 3-4 in 2%). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 10%, neutropenia 21%, and anemia 6%. Thirty (48%) of 62 pts required transient treatment interruptions. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule but there was a trend for less pleural effusion with QD (3%) vs BID (10%; p=0.26). Three pts lost CCyR: 2 because of non-compliance, 1 due to treatment interruption because of pleural effusion. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 88%. All patients are alive. Conclusion: Rapid CCyR occurs in nearly all patients with previously untreated CML-CP treated with frontline dasatinib therapy; the MMR rate at 18 months was 71%, with a favorable toxicity profile. Because of favorable trends in response and toxicity, only QD arm will continue accrual. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of dasatinib as initial therapy for CML, and indication for which dasatinib is not approved.. Borthakur:BMS: Speakers Bureau. O'Brien:BMS: Research Funding. Jabbour:BMS: Speakers Bureau; Novartis: Speakers Bureau. Ravandi:BMS: Consultancy, Honoraria, Research Funding. Kantarjian:Genzyme: Research Funding; BMS: Research Funding; MGI Pharma (Eisai): Research Funding; Novartis: Research Funding.

Use of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in chronic phase (CML-CP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7005-7005 ◽  
Author(s):  
E. L. Atallah ◽  
H. Kantarjian ◽  
S. O'Brien ◽  
D. Jones ◽  
G. Borthakur ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Poor Response ◽  
Treatment Interruption ◽  
Cytogenetic Response ◽  
Primary Objective ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Major Molecular Response

7005 Background: Dasatinib (formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with imatinib (im) resistant/intolerant CML-CP, the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio =0.05% by qPCR) at 12 months (mo). Methods: All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Of the 31 pts enrolled between 11/05 and 12/06; 52% were female; median age was 41 years (range 18–76). At 3 mo, complete hematologic response (CHR) and major cytogenetic response both occurred in 21 (81%) of 26 evaluable pts and complete cytogenetic response (CCyR) in 19 (73%) pts. After 6 mo of therapy, 20/21 (95%) evaluable pts had achieved CCyR. This compares favorably with a CCyR at 6 mo of 54% with im 400 mg/day and 85% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. At 9 mo, 4/15 (27%) evaluable pts had achieved a major molecular response. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in only 3 pts (gr 1–2 in all). Grade 3–4 hematologic toxicity (transient) included anemia in 4 pts, neutropenia in 7 pts, and thrombocytopenia in 4 pts. With a median duration of therapy of 10 mo, 13 pts required transient treatment interruption, 9 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. The actual median daily dose for all pts was 100mg. No difference in AEs has been observed between dose schedules. Conclusions: Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML- CP. Accrual to this trial continues. No significant financial relationships to disclose.

Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5143-5150 ◽  
Author(s):  
Hagop Kantarjian ◽  
Ricardo Pasquini ◽  
Nelson Hamerschlak ◽  
Philippe Rousselot ◽  
Jerzy Holowiecki ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Grade 3

AbstractTherapeutic options for chronic myelogenous leukemia (CML) resistant to 400 to 600 mg imatinib are limited. Escalating imatinib doses may overcome resistance. Dasatinib, a significantly more potent inhibitor of BCR-ABL, is safe and effective in this population. Patients with imatinib-resistant chronic-phase (CP) CML were randomized 2:1 to 140 mg dasatinib (n = 101) or 800 mg imatinib (n = 49). With a median follow up of 15 months, complete hematologic responses were observed in 93% and 82% of patients receiving dasatinib and high-dose imatinib (P = .034), respectively. Dasatinib resulted in higher major cytogenetic response rates (52%) than high-dose imatinib (33%) (P = .023); this included complete cytogenetic response in 40% and 16% (P = .004). Major molecular responses were also more frequent with dasatinib (16% versus 4%; P = 0.038). Treatment failure (hazard ratio [HR], 0.16; P < .001) and progression-free survival (HR, 0.14; P < .001) both favored dasatinib. Superficial edema (42% versus 15%) and fluid retention (45% versus 30%) were more prevalent with imatinib; pleural effusion was more common with dasatinib (17% versus 0%). Grade 3 to 4 nonhematologic toxicity was minimal. Cytopenias were more frequent and severe with dasatinib. Dasatinib represents a safe and effective therapy for CP-CML resistant to conventional imatinib doses with improved cytogenetic and molecular response rates and progression-free survival relative to high-dose imatinib.

Dasatinib (SPRYCEL®) vs Escalated Dose of Imatinib (im) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Resistant to Imatinib: Results of the CA180-017 START-R Randomized Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 167-167 ◽  
Author(s):  
Neil Shah ◽  
R. Pasquini ◽  
P. Rousselot ◽  
S. Jootar ◽  
J. Holowiecki ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Inadequate Response ◽  
Grade 3

Abstract Pts with CML resistant to im have few therapeutic options. A growing body of evidence suggests that treatment outcomes can be improved with increased potency of BCR-ABL inhibition. Escalating the dose of im to 800mg/day (d) can overcome some cases of im-resistance, but tolerability and durability of response are significant issues. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, SRC, and other kinases that is approximately 300 times more potent than im in vitro. Dasatinib has been shown to be effective and safe in pts with CML resistant or intolerant to im, leading to recent FDA approval. START-R is an international trial of dasatinib 70mg twice daily (BID) and im 800mg/d in pts with CP-CML resistant to prior im 400–600mg/d. Crossover was allowed upon confirmed progression or intolerance despite dose reduction (grade 3/4 non-hematologic toxicity). Dasatinib dose escalation to 90mg BID was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40mg BID for toxicity. Dose reduction of im to 600mg/d was allowed for patients who had not previously received that dose. Major cytogenetic response (MCyR) rate at 12 weeks was the primary endpoint. From Feb–Nov 2005, 150 pts were randomized (2:1), 101 to dasatinib, 49 to im. MCyR to prior im had been seen in 28% of dasatinib and 29% of im pts. With a minimum follow-up of 10 mo, complete hematologic response (CHR) rate was 92% (93 dasatinib pts) vs 82% (40 im pts), and MCyR rate was 48% dasatinib vs 33% im. Of importance, the primary difference was the complete cytogenetic response (CCyR) rate of 35% (35/101) dasatinib vs 16% (8/49) im, suggesting that dasatinib can achieve deeper responses in this patient population. Of pts with no prior CyR to im, 44% (17/39) achieved a MCyR with dasatinib vs 7% (1/15) with higher dose im. MCyR rates of 40% to dasatinib and 20% to im were achieved in pts with baseline im-resistant BCR-ABL mutations, with 47% of dasatinib pts vs 0 im pts with difficult-to-treat P-loop mutations achieving a MCyR. Pts with no prior CyR to im were able to achieve MCyR with dasatinib, but dose escalation of im was not effective. 23% dasatinib pts vs 80% im pts had treatment failure (TF, defined as progression, lack of response, crossover for intolerance, or off treatment). Median time to TF was not reached for dasatinib, and was 3.5 mo (95% CI: 3.3-3.8) for im. 61 pts discontinued the initially assigned treatment, of whom 50 (12 dasatinib; 38 im) crossed over after progression, no response, or intolerance. Of 45 post-crossover pts (38 dasatinib; 7 im), 17 (45%) dasatinib pts achieved MCyR, but no (0%) im pts with 800mg/d achieved MCyR after crossover following dasatinib. Grade 3/4 non-hematologic toxicity was minimal in both arms. All grades of superficial edema and fluid retention were more common with im than dasatinib (41% im vs 15% dasatinib; and 43% im vs 28% dasatinib respectively), whereas pleural effusion was 13% (3% grade 3/4) dasatinib vs 0 im. Cytopenia was more frequent and severe with dasatinib. This is the first clinical trial in pts with CML to include both im and dasatinib arms. Based on nearly 1 year of follow-up, dasatinib clearly appears to be more effective in achieving MCyR than high-dose im in pts who fail 400–600mg/d im. An update with molecular response data and detailed mutational analysis will be presented.

Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8505-8505
Author(s):  
Jeffrey A Bogart ◽  
Xiaofei F. Wang ◽  
Gregory A. Masters ◽  
Junheng Gao ◽  
Ritsuko Komaki ◽  
...  
Keyword(s):  
Regional Lymph Node ◽  
Performance Status ◽  
Lymph Node Involvement ◽  
High Dose ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
Once Daily ◽  
Concomitant Boost ◽  
Significant Difference ◽  
Grade 3

8505 Background: Although level 1 evidence is lacking, the majority of patients (pts) with LSCLC are treated with a high dose QD TRT regimen in clinical practice. CALGB 30610/RTOG 0538 was designed to determine if administering high dose TRT would improve overall survival (OS), compared with standard 45 Gy BID TRT, in LSCLC pts treated with chemoradiotherapy. Methods: Eligible pts had LSCLC, ECOG performance status (PS) 0-2 and regional lymph node involvement excluding contralateral hilar or supraclavicular nodes. This phase 3 trial was conducted in 2 stages. In the first stage, pts were randomized 1:1:1 to 45 Gy BID over 3 weeks, 70 Gy QD over 7 weeks, or 61.2 Gy concomitant boost (CB) over 5 weeks. For the second stage, the study planned discontinuation of one high dose arm based on interim toxicity analysis with patients then randomized 1:1 in the two remaining arms. TRT was given starting with either the 1st or 2nd (of 4 total) chemotherapy cycles. The primary endpoint was OS measured from date of randomization. Results: The trial opened 03/15/2008 and closed 12/01/2019 upon completing accrual, with the CB arm discontinued 3/11/2013 after interim analysis. This analysis includes 638 pts randomized to 45 Gy BID TRT (n = 313) or 70 Gy QD TRT (n = 325). Median age was 63 years (range 37-81), the majority of pts were Caucasian (86%), female (52%), and with ECOG PS 0-1 (95%). After median follow-up of 2.84 years (IQR:1.35 -5.61) for surviving pts, QD compared to BID did not result in a significant difference in OS (HR 0.94, 95% CI: 0.76-1.2, p = 0.9). Median, 2- and 4-year OS for QD were 30.5 months (95% CI: 24.4-39.6), 56% (95% CI: 0.51-0.62), and 39% (95% CI: 0.33-0.45), and for BID 28.7 months (95% CI: 26.2-35.5), 59% (95% CI: 0.53-0.65), and 35% (95% CI: 0.29-0.42). QD also did not result in a significant difference in PFS (HR 0.96, 95% CI: 0.78-1.18, p = 0.94). Most grade 3+ hematologic and non-hematologic adverse events (AEs) were similar between cohorts. Rates of grade 3+ febrile neutropenia, dyspnea, esophageal pain and dysphagia for QD were 12.6%,7%, 11.6% and 11.3%, and for BID 13.6%, 4%, 11.2 % and 9.5%. Grade 5 AEs were reported in 3.7% and 1.7% of the QD and BID cohorts, respectively. Results will be updated at presentation. Conclusions: High dose QD TRT to 70 Gy did not significantly improve OS compared with standard 45 Gy BID TRT. Nevertheless, favorable outcomes on the QD arm provide the most robust evidence available supporting high dose once-daily TRT as an acceptable option in LSCLC. Outcomes from this study, the largest conducted in LSCLC to date, will help guide TRT decisions for this patient population. Support: U10CA180821, U10CA180882; Clinical trial information: NCT00632853.

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

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