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 Dasatinib-Induced Colitis with Rectal Sparing in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy: Case Report

2021 ◽  
Vol 14 (3) ◽  
pp. 1441-1446
Author(s):  
Zakaria Maat ◽  
Kamran Mushtaq ◽  
Mohamed A. Yassin
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Prior Therapy ◽  
Abl Tyrosine Kinase ◽  
Upfront Therapy ◽  
Abl Tyrosine Kinase Inhibitor

Dasatinib is a BCR-ABL tyrosine kinase inhibitor which was approved in 2006 for the treatment of adults diagnosed with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) and accelerated (myeloid or lymphoid blast) phase and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia. Common adverse reactions (&#x3e;15%) in patients diagnosed with CP-CML include myelosuppression, fluid retention, and diarrhea. We report a 34-year-old Filipino female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for 2 months, which progressed to colitis.

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.

Primary results of the phase 4 BYOND study of bosutinib (BOS) for pretreated chronic phase (CP) chronic myeloid leukemia (CML).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7012-7012 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Camille N. Abboud ◽  
Bjorn T. Gjertsen ◽  
Tim H. Brümmendorf ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Prior Therapy ◽  
Starting Dose ◽  
Insufficient Response ◽  
Grade 3

7012 Background: The tyrosine kinase inhibitor (TKI) BOS is approved for patients (pts) with Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed pts in CP. Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior TKIs. Primary endpoint (not powered) in Ph+ CP CML cohorts is cumulative confirmed major cytogenetic response (MCyR) by 1 y. Results: Of 163 pts who received BOS, 156 had Ph+ CP CML (46, 61 and 49 after 1, 2 and 3 prior TKIs, respectively). Across Ph+ CP CML cohorts, 51.9% of pts were male; median age was 61 y. As of 1 y after last enrolled pt (median follow-up 30.4 mo), 56.4% remained on BOS. Median BOS duration was 23.7 mo and median dose intensity after adjustment due to adverse events (AEs) 313 mg/d. Of 144 evaluable pts with a valid baseline assessment, cumulative confirmed MCyR by 1 y was 71.5% (95% confidence interval [CI] 63.4–78.7). Cumulative complete cytogenetic response rate anytime on treatment was 81.3% (95% CI 73.9–87.3). Cumulative molecular response (MR) rates were high across lines of therapy (Table). 10 deaths occurred (5 on treatment); 1-y overall survival rate was 98.0%. No pt progressed to accelerated/blast phase on treatment. 25.0% discontinued BOS due to AEs and 5.1% due to insufficient response. Most common treatment-emergent AEs (TEAEs) were diarrhea (87.8%) and nausea (41.0%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.7%) and increased alanine aminotransferase (ALT; 14.7%). The only TEAE leading to discontinuation in > 5% of pts was increased ALT (5.1%). Conclusions: Most pretreated pts with Ph+ CP CML had MCyR by 1 y with BOS; a substantial proportion achieved or preserved major MR (MMR) and deep MR in all therapy lines. Results further support BOS use for Ph+ CP CML resistant/intolerant to prior TKIs. Clinical trial information: NCT02228382. [Table: see text]

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

A Pilot Study Evaluating the Safety and Efficacy of Imatinib Given Early after Transplant for High-Risk Philadelphia Chromosome-Postive Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1095-1095
Author(s):  
Paul A. Carpenter ◽  
David S. Snyder ◽  
Mary E. Flowers ◽  
Jean E. Sanders ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
Pilot Study ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Antigen Expression ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract Patients with Ph+ acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in stages other than first chronic phase (CP1) frequently have recurrent malignancy after allogeneic hematopoietic cell transplant (HCT). Imatinib given after HCT for the treatment of hematological relapse has been of limited success in Ph+ALL but may induce more durable remissions in CML. Hypothesis: We postulated that imatinib might be most effective for preventing hematological relapse after myeloablative HCT if given immediately after engraftment to patients without detectable leukemia, or with leukemia that can be detected only at the molecular level. Study design: A pilot study is ongoing to evaluate the safety and preliminary efficacy of imatinib begun early after myeloablative HCT and continued until post-transplant day 365 (D+365). Study participants became eligible to start imatinib (adults 400 mg/day, children 260 mg/m2/day) if the residual marrow leukemia burden at the time of initial engraftment (ANC&gt;500 on 2 consecutive days) did not exceed &gt;1/20 Ph+ metaphases, &gt;1% aberrant antigen expression on blasts by multidimensional flow, or presence of bcr/abl in &gt;5% interphase nuclei by FISH. The primary endpoint of safety was defined by ability to tolerate imatinib (adults ≥200 mg/day, children ≥100 mg/day) for ≥ 6 days/week until D+90. An attempt was made to administer higher daily doses of imatinib after D+90. Patient characteristics: Ten patients with Ph+ALL (8 CR1, 2 CR2) and 6 patients with CML (2 AP, 2 CP2, 2 CP3) have been enrolled; 13/16 had leukemia detected by molecular or cytogenetic methods at the time of transplant. Median age at transplant was 40 y (range 5–62 y). Stem cell sources were cord blood (n=1), marrow (n=4) or G-mobilized peripheral blood (n=11). Donors were unrelated (n=10) or related (n=6). Results: Imatinib therapy began in 15 patients at a median of 29 days (range 24–39 days) after HCT and has been administered for a median of 299 days (range, 33–380 days). The median of average daily doses during this time period was 400 mg/day (range 389 to 510 mg/day) among adults and 304 mg/m2/day for the 2 children. All patients tolerated imatinib at the intended dose intensity within the first 90 days after HCT. Toxicities (NCI CTC v3.0) possibly attributed to imatinib included grade 1–2 nausea (n=3), grade 1 edema (n=3), grade 1–2 anemia (n=2), and grade 3 neutropenia (n=2). Per protocol, one patient with neutropenia received 2 doses of G-CSF at D+75 and continued imatinib without neutropenia. The second patient was not given G-CSF and imatinib was held for 2 weeks from D+160 until the ANC was &gt;2000. All patients are surviving at a median of 333 days after HCT (range, 68–564), and 14/15 patients have no detectable bcr/abl transcripts in the blood or marrow. Seven patients (4 ALL, 3 CML) have completed imatinib therapy and survive at a median of 467 days after HCT (range, 410–564 days) and 6/7 have no detectable bcr/abl transcripts in blood or marrow. One patient (CML-CP3) with cytogenetic relapse at D+118 had a 4th remission after withdrawal of immunosuppression and continued imatinib but developed hematological relapse at D+429. Conclusions: We conclude that imatinib therapy can be safely prescribed early after myeloablative allogeneic HCT at a dose-intensity comparable to that used in general oncology. Preliminary efficacy data are encouraging and worthy of further study.

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.

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.

A phase II study of dasatinib therapy in children and adolescents with newly diagnosed chronic phase chronic myelogenous leukemia (CML-CP) or Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to imatinib.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS9594-TPS9594
Author(s):  
Michel Zwaan ◽  
Linda C. Stork ◽  
Yves Bertrand ◽  
Lia Gore ◽  
Nobuko Hijiya ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Dose Escalation Study

TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warranted. Methods: To evaluate the safety and efficacy of dasatinib monotherapy in children/adolescents with newly diagnosed CML-CP or Ph+ leukemias resistant/intolerant to imatinib, a phase II nonrandomized, global study of dasatinib in pts birth to <18 y is ongoing (NCT00777036): Cohort 1 (C1), Ph+ CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph+ ALL, accelerated or blast phase CML pts resistant/intolerant to or relapsed after imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph+ CML-CP pts. Treatments are once daily with dasatinib 60 mg/m2 (C1/C3) or 80 mg/m2 (C2) for ≥24 months. Primary endpoints are major CyR (C1), complete hematologic response (C2), and complete CyR (C3). Secondary endpoints include safety, tolerability, best response, time to/duration of response, survival, and molecular response rates. BCR-ABL mutations are evaluated. First patient first visit was March 2009; estimated trial completion is September 2016. As of January 2012, 63 pts (n=27 aged <12 y; n=36 aged ≥12 y) have been treated in C1/C2 (n=41) and C3 (n=22). Enrollment is ongoing at 79 sites.

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.

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.

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