Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia: Interim Results of the CA180-018 Phase I Study from the ITCC Consortium.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3241-3241 ◽  
Author(s):  
C. Michel Zwaan ◽  
Carmelo Rizzari ◽  
Vincent H.J. van der Velden ◽  
Berna Beverloo ◽  
M. L. den Boer ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Pediatric Population ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Finding ◽  
Cell Transplant ◽  
Hematological Response ◽  
Advanced Phase ◽  
Grade 3

Abstract Relapsed/refractory leukemia in childhood carries a grave prognosis. Dasatinib (SPRYCEL®) is a potent oral kinase inhibitor of BCR-ABL, KIT, and SRC kinases. Dasatinib is approved for adults with Philadelphia chromosome-positive (Ph(+) CML and ALL, resistant or intolerant to prior imatinib therapy. An investigational phase I dose- finding study of dasatinib treatment of patients aged 1–21 years with various leukemia subtypes is currently being conducted in 12 European centers. The aim of the study is to establish a safe and effective dose for each of the leukemia sub-types. Patients were stratified into three treatment groups - Stratum 1: CML in chronic phase, resistant or intolerant to imatinib; Stratum 2/3: advanced-phase CML resistant or intolerant to imatinib, Ph(+) ALL, relapsed/ refractory after imatinib, or Ph(+) AML, ≥ 2nd relapse; Stratum 4: Ph(−) ALL, or Ph(−) AML in second/subsequent relapse. The starting dose was 60mg/m2 once daily for all strata. Intra-patient dose escalation was allowed for lack of initial response and dose reductions for toxicity. Current data reflect the first 41 patients (median age 11 years, range 1–21) treated from March 2006 through May 2008, including eight in Stratum 1, twelve in Stratum 2/3, and twenty-one in Stratum 4. The patients were heavily pretreated and prior therapy included chemotherapy (n=35), imatinib (n=20), and stem cell transplant (n=24). Dasatinib was well tolerated up to the current 120mg/m2 dose. Treatment-related toxicities were mostly mild to moderate in severity with nausea (34% grade 1/2; 2% grade 3/4) and diarrhea (15% grade 1/2; 0% grade 3/4) occurring most frequently. In Stratum 4, two dose-limiting toxicities were seen: anaphylaxis 5 hours after the first dose (60mg/m2) and upper-GI bleed on Day 6 of dasatinib dosing (120mg/ m2). Only one of the 41 patients experienced a malignant/hemorrhagic pleural effusion at 100mg/m2 dose. A maximum tolerated dose has not been established. PK studies were performed on samples from 32 patients after 60 mg/m2, 80 mg/m2 and 100 mg/m2 dosing. Absorption occurred rapidly (median Tmax 0.75 – 1.0 hour). The area under the curve (AUC) and maximum concentration (Cmax) proportionately increased with higher dose levels, but the difference was much greater between 60 and 80 mg/m2 than between 80 and 100 mg/m2. Complete Hematological Response (CHR) occurred in 75% of patients with CML-CP. Major Hematological Response (MaHR) was achieved in 25% of patients with advanced CML/Ph(+) and Ph(+) ALL/ AML. Major Cytogenetic Response occurred in 88% of CML-CP patients and 50% of patients with advanced Ph(+) CML and Ph(+) ALL/ AML. Stratum 4 observations included a temporary decrease in peripheral blood (PB) blast count in one Ph(−) ALL patient and in PB and bone marrow (BM) blast counts in two Ph(−) AML patients (one with AML7 and one with Down’s syndrome). Additionally, three Ph(+) ALL patients had a CSF response. These interim data demonstrate a favorable safety profile for dasatinib. Clear efficacy was seen in patients with CML-CP, and other Ph(+) leukemias. Further exploration is needed in the Ph(−) leukemias in the pediatric population. Updated data will be presented.

Dasatinib (SPRYCEL®) in Children and Adolescents with Relapsed or Refractory Leukemia: Preliminary Results of the CA180018 Phase I/II Study from the ITCC Consortium.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1049-1049 ◽  
Author(s):  
Christian M. Zwaan ◽  
M.L. den Boer ◽  
H.B. Beverloo ◽  
V.H.J. van der Velden ◽  
J.M.A. Van Tornout ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Cell Transplant ◽  
Pediatric Leukemia ◽  
Prior Therapy ◽  
Advanced Phase

Abstract Outcome for children with relapsed/refractory leukemia is unsatisfactory. Dasatinib is a novel oral kinase inhibitor of BCR-ABL, KIT, and SRC family kinases. Recently, approval was granted for adult CML and Ph+ ALL with resistance to prior therapy. CA180018, the 1st trial evaluating dasatinib in children (age 1–20 yrs) and conducted in 12 centres from the ITCC Consortium, is a phase I/II dose-finding study in patients (pts) with either imatinib resistant/intolerant CML, relapsed/refractory Ph+ or Ph− ALL, or AML in 2nd or greater relapse. The starting dose was 60 mg/m2 QD; intra-pt dose escalation for lack of initial response and dose-(de)escalations were safety and efficacy guided and aimed at establishing a safe and effective dose for each leukemia sub-type. These data reflect the first 34 pts (median age 12.6 y, range 1.6–20) treated from Mar 06 to Aug 07: 6 chronic phase [CP] CML, 2 advanced phase [AP] CML, 8 Ph+ ALL, 6 Ph− ALL, and 12 Ph− AML. Prior therapy included chemotherapy, imatinib, and stem cell transplant. Intra-pt dose escalation to 80 or 100 mg/m2 occurred in 21 pts. 7 pts remain on study. Safety: 51 SAEs in 22 patients were noted, and included febrile neutropenia/infections (n=27), GI toxicity (n=8), rash (n=4), and grade 3/4 thrombocytopenia (n=3). One dose-limiting toxicity (DLT) was observed: a grade 4 anaphylactic reaction 5 h after the first dose in a pt with a history of hypensensitivity reactions. One pt had a pleural effusion that also contained leukemic cells. Responses: 5/6 CP CML pts are evaluable for response: 3 pts went into complete hematologic remission; 2 had a complete and 1 had a partial cytogenetic response (CygR). One pt was enrolled with molecular disease only, and PCR values became undetectable after 3 months. One pt never achieved a hematological or CygR, yet no resistance mutations were detected. The pt with myeloid AP CML had a major CygR for ∼3 months; the pt with lymphoid BP CML had a complete CygR (14% BCR-ABL+ cells using FISH), but experienced clonal evolution with ∼28% blasts in the marrow at the same time. Of the 8 pts with Ph+ ALL, 3 showed complete morphologic and cytogenetic remission, lasting for 6 weeks, 1 month, and >2 months for one pt still on study. One other pt with isolated CSF relapse cleared the CSF for ∼7 months with dasatinib only, has subsequently received additional intrathecal chemotherapy, and remains on study 17 months later. Four pts did not respond, 2 of who harbored the T315I mutation. Of the 6 Ph− ALL pts, 4 were evaluable, and none achieved a CR. In 1/4 pts there was a significant drop in WBC for approximately 2 months. Among the 12 Ph− AML pts, one had a drop in BM blasts from 60 to 2% (without full PB regeneration), and one pt from 60 to 15% blasts. None of the AMLs appeared to be KIT-mutated. These data show that dasatinib was well tolerated up to 100 mg/m2; the encouraging early signs of response in Ph+ disease support its further exploration in relapsed/refractory pediatric leukemia pts. Higher dose levels are currently being explored and updated clinical and PK data will be presented.

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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1101-1101 ◽  
Author(s):  
Carlo Gambacorti- Passerini ◽  
Enrico Maria Pogliani ◽  
Michele Baccarani ◽  
Giovanni Martinelli ◽  
Hagop M Kantarjian ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Growth Factor Receptor ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Open Label ◽  
Wide Range ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally available, Src/Abl kinase inhibitor with minimal activity against platelet derived growth factor receptor (PDGFR) and c-kit. An open-label study of patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase (BP) CML and Ph+ ALL who failed prior imatinib therapy is ongoing. Patients receive 500 mg/day of bosutinib. Preliminary data for 101 subjects, median age 51.5 yrs (range 18 – 84 yrs) and 56% male are reported. 44 pts were in AP, 35 in BP, 21 had Ph+ ALL, and 1 was unclassified. Prior therapy in addition to imatinib included interferon (35 pts), dasatinib (40 pts), nilotinib (15 pts) and stem cell transplant (11 pts). 49 pts failed imatinib (and received no other tyrosine kinase inhibitor [TKI]) and 52 pts failed both imatinib and other TKIs, with median duration of bosutinib treatment to date 4.4 mos (range 0.3 – 21.3 mos) and 2.0 mos (range 0.3 – 18.8), respectively. Among pts with no TKI exposure other than imatinib, complete hematological response (CHR) was obtained in 12/25 evaluable pts (48%), including 7/11 pts (64%) with AP-CML, 4/11 pts (36%) with BP-CML and 1 pt with Ph+ ALL. Major cytogenetic response (MCyR) was achieved in 16/22 evaluable pts (73%) with no TKI exposure other than imatinib, including 9/13 pts (69%) with AP-CML and 6/8 pts (75%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Major molecular response (MMR) was achieved in 9/25 evaluable pts (36%) with no TKI exposure other than imatinib, including 1/7 pts (14%) with AP-CML, 4/10 pts (40%) with BP-CML and 4/8 pts (50%) with Ph+ ALL. Among pts with other TKI exposure in addition to imatinib, CHR was obtained in 3/15 evaluable pts (20%), all with AP-CML; MCyR was achieved in 6/20 evaluable pts (30%), including 3/12 pts (25%) with AP-CML and 2/7 pts (29%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Of the 20 pts with other TKI exposure in addition to imatinib who were evaluable for MMR, 1 pt with Ph+ ALL (5%) achieved this response. Of 60 pts with baseline samples tested for mutations, 15 different mutations were found in 32 pts (53%), including 8 instances of T315I. CHR occurred in 2/8 evaluable pts (25%) with non-P-loop mutations; the 1 evaluable pt with a P-loop mutation did not achieve CHR. MCyR occurred in 4/11 evaluable pts (36%) with non-P-loop mutations and in 1/2 evaluable pts (50%) with P-loop mutations. Treatment was generally well tolerated. The most common adverse events among treated pts (n=101) were gastrointestinal (diarrhea [66%], nausea [46%] and vomiting [42%]) 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 non-hematologic toxicities occurring in ≥ 5% of pts were diarrhea (7%), vomiting (6%), pneumonia (6%) and increased ALT (5%). Fluid retention was reported as grade 1 – 2 in 18 pts and grade 3 – 4 in only 3 pts (including 2 pleural effusions, neither related to bosutinib). Grade 3 – 4 hematologic laboratory abnormalities reported include thrombocytopenia (68%), neutropenia (48%) and anemia (37%). 38 pts had at least 1 temporary treatment interruption and 22 pts had at least 1 dose reduction due to toxicity. 11 pts have permanently discontinued treatment due to adverse event. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations.

Bosutinib (BOS) for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib (IMA) failure: ≥8-y update of a phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7549-7549
Author(s):  
Tim H. Brümmendorf ◽  
Jorge E. Cortes ◽  
Yeow Tee Goh ◽  
Musa Yilmaz ◽  
Rebecca B. Klisovic ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Term Treatment ◽  
Prior Therapy ◽  
Long Term Treatment ◽  
New Treatment

7549 Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (<1–155) mo and dose intensity 438 (87–599) mg/d; responses were durable (Table) and overall survival (OS) at 9 y was 74% vs 84% at 5 y. OS at 8 y was 69% in CP3L, 54% in AP CML and 23% in BP CML pts vs 78%, 59% and 23% at 4 y. 55 CP2L, 29 CP3L and 98 ADV pts died on study (10, 3 and 2 since the 4/5-y reports); 15, 5 and 3 had on-treatment transformations to AP/BP. Most common new treatment-emergent adverse events since y 5 in CP2L pts were pleural effusion (n=13), arthralgia (n=12) and increased blood creatinine (n=11). Conclusions: After ≥8 y, BOS continued to show durable efficacy and no new safety signals in pts with CP CML on long-term treatment, providing further support for BOS use after prior TKIs. Clinical trial information: NCT00261846 and NCT01903733 . [Table: see text]

scholarly journals Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium

2011 ◽  
Vol 29 (7) ◽  
pp. 839-844 ◽  
Author(s):  
Richard Aplenc ◽  
Susan M. Blaney ◽  
Lewis C. Strauss ◽  
Frank M. Balis ◽  
Suzanne Shusterman ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Drug Disposition ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Pharmacokinetic Studies ◽  
Grade 3 ◽  
Β Receptor ◽  
Dose Levels

Purpose Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. Patients and Methods A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome–positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m2/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. Results A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m2 dose levels. At 110 mg/m2, two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m2), grade 3 diarrhea (85 mg/m2), and grade 2 creatinine elevation (50 mg/m2) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. Conclusion Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.

scholarly journals Initial treatment for patients with CML

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 453-460 ◽  
Author(s):  
John M. Goldman
Keyword(s):  
Initial Treatment ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Log Reduction ◽  
Advanced Phase

AbstractFor adult patients who present with chronic myeloid leukemia (CML) in chronic phase it is now generally agreed that initial treatment should start with the tyrosine kinase inhibitor (TKI) imatinib at 400 mg daily. Five years after starting imatinib about 60% of these patients will be in complete cytogenetic response (CCyR), still taking imatinib; an appreciable proportion of these will have achieved a major molecular response, defined as a 3-log reduction in the level of BCR-ABL1 transcripts in their blood. The patients in CCyR seem to have a very low risk of relapse to chronic phase or of progression to advanced phase. Other patients may be resistant to imatinib or may experience significant side effects that require change of therapy. The best method of monitoring responding patients is to enumerate Philadelphia chromosome–positive marrow metaphases at 3-month intervals until CCyR and to perform RQ-PCR for BCR-ABL1 transcripts at 3-month intervals after starting imatinib. The recommendations for defining “failure” and “sub-optimal response” proposed by the European LeukemiaNet in 2006 have proved to be a major contribution to assessing responses in individual patients and are now being updated. Patients who fail imatinib may respond to second-generation TKIs, but allogeneic stem cell transplantation still plays an important role for eligible patients who fare badly with TKIs. Patients who present in advanced phases of CML should be treated initially with TKI alone or with TKI in conjunction with cytotoxic drugs, but their overall prognosis is likely to be much inferior to that of those presenting in early chronic phase.

Efficacy of Dasatinib in Patients with Chronic Phase Philadelphia Chromosome-Positive CML Resistant or Intolerant to Imatinib: First Results of the CA180013 ‘START-C’ Phase II Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 41-41 ◽  
Author(s):  
Andreas Hochhaus ◽  
M. Baccarani ◽  
C. Sawyers ◽  
A. Nagler ◽  
T. Facon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
White Blood Cells ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Biomarker Analysis ◽  
Grade 3

Abstract After 3 years of imatinib (IM) therapy, hematologic relapse occurred in 7% of newly diagnosed chronic myeloid leukemia (CML) pts, and 20% of chronic phase (CP)-CML pts after failure to interferon alpha (IFN), which was mostly associated with BCR-ABL mutations and/or clonal evolution. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Dasatinib has been shown to have 325-fold greater potency compared with imatinib in cells transduced with BCR-ABL and is active against 18/19 BCR-ABL mutants tested that confer imatinib resistance. A Phase I dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients in CP-CML, which was followed by ‘START-C’ (CA180013), the first Phase II open-label study in dasatinib in CP IM-R or IM-I CML pts. Between February-May 2005, 186 pts (86 male, median age 60 yrs [range 25–82]) were recruited from 40 institutions. Data from 30 pts accrued prior to March 20, 2005, are available for the initial analysis. The definition of IM-R required a failure of IM doses &gt;600 mg/d or the occurrence of BCR-ABL mutations associated with virtual insensitivity to IM. Dasatinib was administered at 70 mg twice daily (BID), based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in pts lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. In the group of 30 evaluable pts, median age was 59 yrs (range 25–78), 50% were male. Median time from diagnosis of CML was 70.8 months (range 7.9–202.1). Prior therapy included IFN in 77% and stem cell transplantation in 10% of pts. 60% of pts were considered IM-R, with the maximum prior IM dose of &gt;600 mg in 60% of pts. 60% of pts received IM for &gt;3 yrs. Best response to prior IM therapy was a complete hematologic response in 83%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 17% and 13% of pts, respectively. Median (range) baseline hematologic parameters were: white blood cells 16.1/nl (4.3–84.3); platelets 437/nl (173–960). IM-R BCR-ABL mutations were documented in 6/12 pts with currently available data. Within the first 3 months, 2 pts required dose escalations and 6 had a dose reduction, mostly due to thrombocytopenia. Hematologic responses were documented in 21/24 pts with available data. From 16 pts evaluable for 3-month cytogenetic analysis, 7 cytogenetic responses were observed, including CCyR (n=4) and PCyR (n=1). Analysis of molecular response is in progress. Grade 3/4 neutropenia or thrombocytopenia were reported in 6 pts each. Most common non-hematologic toxicities were diarrhea (6 pts, 1 grade 3), rash (5 pts, all grade 1), edema (3 pts, all grade 1) and pleural effusion (1 pt, grade 2). In conclusion, despite the short follow up, major hematologic and cytogenetic responses were seen in a group of pretreated CP-CML pts, which further supports the activity of dasatinib in this disease. An updated analysis based on 186 pts with 6-month follow up will be presented.

Preliminary Activity of Nilotinib (AMN107), a Novel Selective Potent Oral Bcr-Abl Tyrosine Kinase Inhibitor, in Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Phase Chronic Myelogenous Leukemia (CML-CP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2172-2172 ◽  
Author(s):  
Elias Jabbour ◽  
Jorge Cortes ◽  
Francis Giles ◽  
Susan O’Brien ◽  
Laurie Letvak ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Patient Choice ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Early Results ◽  
Grade 3

Nilotinib is a novel, highly selective oral Bcr-Abl inhibitor which is approximately 30-fold more potent than imatinib. High response rates with nilotinib were observed in all CML phases post imatinib failure. We evaluated the efficacy of nilotinib in newly diagnosed Ph-positive CML-CP. Thirteen patients with newly diagnosed Ph-positive CML-CP were treated with nilotinib 400 mg orally twice daily. The median age was 49 years (range, 24–72 years). The Sokal risk at pretreatment was low in 10 patients, intermediate in 2, and high in 1. The median follow-up is 8 months (range, 3–12 months). All patients have reached the 6-month evaluation. The rate of complete cytogenetic response [CGCR] (Ph 0%) at 3 and 6 months was 93% and 100%, respectively. This is compared with a CGCR at 3 months of 37% and with imatinib 400 mg/d and 61% with imatinib 800 mg/d (p=0.0002) and 54% and 85% at 6 months, respectively (p<0.0001), in historical data of newly diagnosed patients treated in studies at M. D. Anderson. Six patients were evaluable at 9 months and all were in CGCR. The median QPCR with nilotinib at 3, 6, and 9 months were, respectively, 3.4% (range, 0.02–29.5%), 1.8% (range, 0.004–9.13%), and 0.54% (range, 0.04–1.28%). At 3-month follow-up, major molecular response (BCR-ABL/ABL ratio<0.05%) was observed in 1/13 patients (8%) and in 6/11 (55%) at 6-month. Grade 3–4 myelosuppression was observed in 3 of the 13 patients and other grade 3–4 side effects in 3 patients (increased lipase in 2 and musculo-skeletal pain in 1). Four patients had their dose reduced to 400 mg daily due to extramedullary toxicity. Two patients were taken off after 6 and 8 months (patient choice) and switched to imatinib. In conclusion, early results with nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile.

Dasatinib (SPRYCEL®, BMS-354825) Phase-I/II Study of Patients with Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Imatinib: Results of the CA180031 Study in Japan (Phase I Portion).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4809-4809
Author(s):  
Hisashi Sakamaki ◽  
Shin Fujisawa ◽  
Kensei Tobinai ◽  
Masafumi Taniwaki ◽  
Shuichi Miyawaki ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Japanese Patients ◽  
Cytogenetic Response ◽  
Maximum Tolerated Dose

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a potent, orally active, multi-targeted kinase inhibitor active against BCR-ABL and SRC family kinases. Studies outside Japan have demonstrated that dasatinib is highly effective in overcoming resistance and intolerance to imatinib (im), inducing durable cytogenetic and hematologic responses in this CML patient population. In establishing the dose for non-Japanese patients, the maximum tolerated dose failed to be reached and the 70-mg-twice-daily (BID) dose was determined to provide the optimal benefit-risk profile. Based on clinical experience to date, dasatinib has the potential to have a major impact on the current treatment paradigm for patients with CML resistant or intolerant to prior therapy, including im. To assess the safety and efficacy of dasatinib in Japanese patients, a phase-I/II study was conducted in patients with all phases of im-resistant or -intolerant CML. In the phase-I portion of this study, dasatinib was administered at one of three escalating dose levels for a period of 4 weeks: 50 mg, 70 mg, or 90 mg BID. As of July 2006, 15 eligible patients have been enrolled and treated. Six evaluable patients (4F, 2M; median age 43 y [range 27–56]; 4 im-resistant, 2 im-intolerant) were treated at the 50 mg BID dose level and one dose-limiting toxicity (DLT) was observed (grade 4 thrombocytopenia). Two patients experienced transient grade 3 ALT elevations but as treatment was uninterrupted, these were not considered DLTs. A further 6 evaluable patients (6M; median age 42 y [range 27–55]; 3 im-resistant, 3 im-intolerant) were treated at the 70 mg BID dose level and one DLT was observed (grade 4 thrombocytopenia). Three patients have recently been enrolled at the 90 mg BID dose level. As the safety of the 70 mg BID dose was established in the phase-I portion of the study, the use of this dose is being expanded into the phase-II element, which plans to evaluate cytogenetic response in chronic phase CML patients at 24 weeks, and hematologic response rate in accelerated- or blast-phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients at 12 weeks. Accrual to the phase-II portion of this study is ongoing. Updated data including baseline mutational analyses will be presented at the meeting.

Efficacy of Nilotinib (AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 29-29 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Elias Jabbour ◽  
Alexandra Ferrajoli ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is a novel, oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl that is approximately 30-fold more potent than imatinib. High response rates have been reported with nilotinib therapy in CML after imatinib failure. Methods: We evaluated the efficacy of nilotinib as first line therapy in pts with newly diagnosed Ph-positive CML-CP. 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). Results: Thirty-two pts have been treated with nilotinib 400 mg orally twice daily for a median of 5 months (mo) (range, 1 to 31 mo). The median age was 47 years (yrs) (range, 24–73 yrs). The Sokal risk at pretreatment was low in 21 (70%) pts, intermediate in 6 (20%), and high in 3 (10%). The rate of complete cytogenetic response [CCyR] (Ph 0%) at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400 mg or 800 mg daily: The median QPCR with nilotinib at 3, 6, and 12 months were, respectively, 0.52% (range, 0.0–29.5%), 0.03% (range, 0.0–9.13%), and 0.09% (range, 0.0–16.21%). At 3 mo follow-up, major molecular response (MMR; BCR-ABL/ABL ratio ≤0.05%) was observed in 3/22 patients (14%), 7/13 (54%) at 6 mo, and 5/11 (45%) at 12 mo. 12-mo rates of MMR for the historical imatinib groups treated at 400 mg and 800 mg were 24% and 47%, respectively (p=0.02). None of the molecular responses has been lost while on therapy. Grade 3–4 neutropenia was observed in 2 (7%) pts, and thrombocytopenia in 1 (3%). Other grade 3–4 adverse events included elevation of lipase (n=3, 9%), or bilirubin (n=2; 6%), and amylase elevation, back pain, and infection (1 each). Twelve pts had transient treatment interruptions (median 11 days), most frequently due to pain (n=3; musculoskeletal 2, abdominal 1), lipase elevation (n=2). Seven patients had their dose reduced to 400 mg daily, 2 to 200 mg twice daily, and 1 to 200 mg daily due to extramedullary toxicity. Three patients decided to change therapy after 4, 6 and 8 months; 2 switched to imatinib and 1 received SCT. Conclusion: Nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Percent with CCyR (No. evaluable) Months on Therapy Nilotinib Imatinib 400 mg Imatinib 800 mg P value 3mo 95 (22) 37 (49) 62 (202) < 0.0001 6mo 100 (13) 54 (48) 82 (199) <0.0001 12mo 100 (11) 65 (48) 86 (197) 0.0007

Efficacy of Nilotinib (formerly AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 446-446 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Alessandra Ferrajoli ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is an oral tyrosine kinase inhibitor with high selectivity towards Bcr-Abl and approximately 30-fold more potent than imatinib, and is effective in patients with CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib 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 untreated CML-CP (or with &lt;1 months of therapy with imatinib) were eligible and received nilotinib 400mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Forty-nine pts have been treated for a median of 13 months (mo). The median age was 47 years (yrs) (range, 21 to 81); 69% are Sokal low risk. Eight (16%) had received imatinib for &lt;1 months. Overall, 46/48 (96%) of evaluable CP pts achieved a complete cytogenetic response [CCyR]. The rate of CCyR at 3, 6 and 12 mo for pts in CP compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Months on therapy Nilotinib Imatinib 400mg Imatinib 800mg P value 3 93 (45) 37 (49) 62 (202) &lt; 0.0001 6 100 (36) 54 (48) 82 (199) &lt; 0.0001 12 96 (27) 65 (48) 86 (197) 0.0003 18 92 (12) 68 (38) 89 (179) 0.0042 24 91 (11) 70 (40) 88 (173) 0.0151 MMR was observed in 45% at 6 mo and 52% at 12 mo. Two of 44 (5%) evaluable pts have achieved confirmed complete molecular response, and 3 others unconfirmed (ie, only achieved on their last assessment). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia in 10%, neutropenia in 12%, and anemia in 2%. Grade 3–4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%. 19 (36%) pts had transient treatment interruptions and 17 (32%) had dose reductions. The actual median dose is 800mg daily. Three pts have come off study: 1 pt’s choice and 2 because of toxicity (1 liver, 1 pericardial effusion). One of them (liver toxicity) transformed to blast phase shortly after coming off study. Estimated 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 95%. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Accrual is ongoing.

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