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

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.

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

Blood ◽

10.1182/blood.v112.11.3241.3241 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3241-3241 ◽

Cited By ~ 6

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.

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A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14018 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14018-14018 ◽

Cited By ~ 2

Author(s):

C. R. Garrett ◽

L. L. Siu ◽

G. Giaccone ◽

A. El-Khoueiry ◽

J. Marshall ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Fdg Pet ◽

Kinase Inhibitor ◽

Imaging Modality ◽

Single Agent ◽

Dual Inhibitor ◽

Gastrointestinal Malignancies ◽

Full Dose ◽

Prior Therapy

14018 Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of single-agent brivanib is 800 mg qd (ASCO #3051, 2006). Methods: An open-label Phase I dose-escalation study of brivanib in combination with cetuximab was conducted in pts with AGM who failed prior therapy. Brivanib was given po Day 1 and qd from Day 8, starting at 320 mg. Cetuximab was given IV Day 8 (400 mg/m2) then weekly (250 mg/m2). Dose escalation of brivanib continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and pharmacokinetic (PK) analysis was performed. FDG-PET was obtained at Baseline X 2, Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 18 pts (15 CRC, 2 esophageal, 1 other) were treated with 320, 600 or 800 mg qd of brivanib in combination with cetuximab for a median of 8 weeks (range 1 - 20+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg qd. Few treatment-related AEs occurred across the 3 cohorts (Table). PK/biomarker data is pending. Available FDG-PET results from measurements in 8 pts with 2–3 target lesions showed good baseline reproducibility in SUVpeak, SUVmean and SUVmax, with intra-subject CV of 3.6%, 7.2% and 9.3%, respectively. Conclusions: Brivanib in combination with full-dose cetuximab was well tolerated at ≤800 mg qd and did not result in enhancement of cetuximab associated AEs. Pre-treatment FDG-PET is a highly reproducible imaging modality. [Table: see text] [Table: see text]

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.7549 ◽

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]

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

Blood ◽

10.1182/blood.v108.11.2162.2162 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2162-2162 ◽

Cited By ~ 2

Author(s):

Christian M. Zwaan ◽

M.L. den Boer ◽

B. Beverloo ◽

V. van der Velden ◽

A. Countouriotis ◽

...

Keyword(s):

Stem Cell ◽

Phase I ◽

Dose Escalation ◽

Pediatric Patients ◽

Stem Cell Transplant ◽

Patient Dose ◽

Cell Transplant ◽

Molecular Responses ◽

Preliminary Results ◽

Prior Therapy

Abstract Leukemia is the most common type of cancer in pediatric patients (pts). Treatment options for Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) include: risk-adapted chemotherapy, imatinib (im) and stem cell transplant (SCT). Relapsed leukemia has few therapeutic options. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, KIT, and SRC kinases that was recently granted approval for adults with CML, and Ph+ ALL with resistance or intolerance to prior therapy. CA180018 is the first trial evaluating dasatinib in pediatric patients pts and Ph+ and in Ph- leukemias. CA180018 is a phase I/II dose-finding study of dasatinib in pts aged 1–20 with CML or relapsed Ph+ ALL resistant or intolerant to im, or Ph- ALL or AML in ≥2nd relapse performed in collaboration with 12 centers (6 countries) from the ITCC Consortium. Preliminary data are available on the first 15 pts treated from March-July 2006 (2 chronic phase (CP) CML, 7 Ph+ ALL, 1 accelerated phase (AP) CML, 3 Ph- ALL, and 2 Ph- AML) at a starting dose of 60 mg/m2 daily (course = 3 weeks). Intra-patient dose escalation was allowed for lack of initial response, and a 3+3 design for maximum tolerated dose (MTD) determination. Hematologic, cytogenetic, and molecular responses, as well as plasma and cerebrospinal fluid (CSF) pharmacokinetic (PK) analysis and BCR-ABL mutational analysis are ongoing. Median age was 11 yrs (range 4–17), median time from diagnosis of leukemia was 19.5 months (range 1.4–89.9). Prior therapy included chemotherapy, im, and stem cell transplant. Median duration on study is 0.69 month (range 0.03–3.45). Intra-patient dose escalation to 80 or 100 mg/m2 occurred in 7 pts. Six pts remain on study. There have been 7 responders: 4 complete hematologic responses (CHR): 1 CP CML, 1 AP CML, 2 Ph+ ALL; 5 cytogenetic responses (CyR): 2 Ph+ ALL complete CyR (CCyR), 1 AP CML CCyR, 1 CP CML partial CyR (PCyR), 1 Ph+ ALL minor CyR who never achieved a CHR, and then progressed; and 2 Ph+ ALL pts with CNS disease who cleared the CSF of leukemic blasts with single agent dasatinib. Preliminary PK in 7 pts showed rapid absorption with a median Tmax of 1.0 h, and mean terminal phase half-life (SD) of 2.7 (1.1) h. There is one dose-limiting toxicity (DLT): grade 4 anaphylactic shock which occurred 5 hours after the first dose. Dasatinib has otherwise been well tolerated up to 100 mg/m2 with toxicities including grade 3/4 thrombocytopenia, and sepsis. Nine pts are off study: 8 for progressive disease (2 Ph+ ALL pts with a resistant T315I BCR-ABL mutation), and 1 DLT. These preliminary results provide evidence supporting the safety and efficacy of dasatinib in pediatric pts with relapsed or refractory leukemia. An updated analysis including further enrollment, safety data, PK, cytogenetic and molecular responses, and mutational analyses will be presented.

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Hematologic and Cytogenetic Responses in Imatinib-Resistant Chronic Phase Chronic Myeloid Leukemia Patients Treated with the Dual SRC/ABL Kinase Inhibitor BMS-354825: Results from a Phase I Dose Escalation Study.

Blood ◽

10.1182/blood.v104.11.1.1 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1-1 ◽

Cited By ~ 10

Author(s):

Charles L. Sawyers ◽

Neil P. Shah ◽

Hagop M. Kantarjian ◽

Nicholas Donato ◽

John Nicoll ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Clinical Benefit ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Pharmacokinetic Studies ◽

Imatinib Resistance ◽

Abl Kinase ◽

Imatinib Resistant

Abstract Disease relapse in CML patients treated with imatinib is often associated with mutations in the BCR-ABL gene that interfere with the ability of imatinib to block BCR-ABL kinase activity. BMS-354825 is a novel, orally available, dual SRC/ABL kinase inhibitor with more than 100-fold greater potency than imatinib that has in vitro and in vivo preclinical activity against 14 of 15 imatinib resistant BCR-ABL mutants (Shah et al, Science, 305:399, 2004). Here we report the phase I clinical results of BMS-354825 in Philadelphia chromosome positive (Ph+) CML patients in chronic phase with hematologic progression or intolerance while being treated with imatinib. To date (Aug 6, 2004), 29 patients have been treated on 9 cohorts with doses ranging from 15 to 180 mg of BMS-354825 per day given in single or divided doses for 5–7 days per week, for up to 9 months. Similar to imatinib, BMS-354825 has been well tolerated in all patients, with a single episode of grade 4 thrombocytopenia as the only potential drug related adverse event. BMS-354825 is rapidly absorbed with peak concentrations achieved within 2 hours and a terminal phase half-life of about 5 hours. Serum levels well above the concentration required to block CML cell proliferation in vitro have been readily achieved without side effects. Pharmacodynamic studies demonstrate greater than 50 percent inhibition of phosphorylation of the BCR-ABL substrate CRKL and the SRC kinase Lyn, consistent with the serum concentrations observed in pharmacokinetic studies. Patients not receiving optimal clinical benefit were escalated to the next higher dose for which safety parameters were available, thereby allowing a preliminary assessment of clinical activity. To date, 26 patients (22 with imatinib resistance, 4 with imatinib intolerance; average CML duration 6.1 years) have been followed for greater than 4 weeks and are eligible for assessment of hematologic benefit. 22 patients had detectable BCR-ABL kinase domain mutations prior to starting BMS-354825. All 26 patients have been treated with doses of 35 mg per day or greater and have had clinical benefit, including 19 with complete hematologic responses (73%). Of the 7 partial responders, two subsequently had disease progression, one of whom had expansion of a CML subclone containing the imatinib-resistant T315I mutation in BCR-ABL, which also confers resistance to BMS-354825 in preclinical studies. The other 5 partial responders are now being treated with higher doses to attempt conversion to complete hematologic response. 11 of 21 patients (52%) treated for greater than 3 months have cytogenetic benefit, including 6 major (1–35% Ph+), 1 minor (36–65% Ph+) and 4 minimal (66–95% Ph+) cytogenetic responses. One patient has achieved complete cytogenetic response. Dose escalation continues, and phase II studies in chronic, accelerated and blast crisis CML are currently being initiated. These data provide compelling evidence supporting the safety and efficacy of BMS-354825 in imatinib-resistant chronic phase CML.

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A Phase II Study of Dasatinib in Patients with Accelerated Phase Chronic Myeloid Leukemia (CML) Who Are Resistant or Intolerant to Imatinib: First Results of the CA180005 ‘START-A’ Study.

Blood ◽

10.1182/blood.v106.11.39.39 ◽

2005 ◽

Vol 106 (11) ◽

pp. 39-39 ◽

Cited By ~ 6

Author(s):

Francois Guilhot ◽

J.F. Apperley ◽

N. Shah ◽

D.W. Kim ◽

A. Grigg ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Phase Ii ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Open Label ◽

Biomarker Analysis

Abstract Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that targets BCR-ABL and SRC kinases. Results from a phase I trial showed dasatinib to be well-tolerated and to induce hematologic (HR) and cytogenetic responses (CyR) in pts with imatinib (IM)-resistant (IM-R)/intolerant (IM-I) CML at all stages of disease. Phase II evaluation of dasatinib in this group of pts is currently ongoing - this is an open-label study of dasatinib in accelerated phase (AP)-CML carried out in 39 centers worldwide. was originally designed to accrue 60 AP-CML pts, but was subsequently expanded to further assess safety and efficacy. Between December 2004 and May 2005, a total of 107 pts were treated (56 males; median age 49, range 24-74). We report our preliminary experience on the first 35 pts enrolled. Dasatinib was given orally at 70 mg twice daily (BID), based on phase I data, including complete inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 100 mg BID or reduction to 50 mg and 40 mg BID were allowed for poor initial response or persistent toxicity, respectively. Blood counts were performed weekly and bone marrow, including cytogenetic, evaluation monthly. A total of 35 pts (33 IM-R, 2 IM-I) are summarized. Mean age was 55 years (range 23–79), 86% of pts were Caucasian and 49% were male. Median time from diagnosis of CML was 91.4 months (range 30.8–176.6); 69% of pts had prior interferon and 14% had prior stem cell transplant. Most pts were extensively pretreated with IM, at doses >600 mg/day in 19 (54%) pts, and duration of IM treatment was >3 years in 25 (71%) pts; 30 pts (86%) had achieved a complete HR (CHR) on prior IM and 9 (26%) had a major CyR. At study entry, 13 (37%) pts had baseline WBC ≥20,000/ml and 13 (37%) pts had platelets <100,000/ml. 14 (40%) pts had ≥15% bone marrow blasts. Assessment of mutation in the ABL kinase domain was performed in all pts; 6/10 pts currently evaluable had mutations; none were of the T315I type. The median duration on study was 2 months. Dose interruptions occurred in 20 pts, dose reduction in 6 pts and dose escalation in 6 pts. 23 (66%) pts achieved a major hematologic response (7 CHR and 16 no evidence of leukemia [CHR without complete recovery of neutrophils or platelets]). CyR were documented in 13/24 pts (54%) including 4 complete CyR (0% Ph+) and 2 partial CyR (1–35% Ph+). Responses were seen in pts who never responded to IM (2 major HR and 1 minor CyR). Molecular responses are not yet available. Myelosuppression was profound, with PMN <500/ml in 17 pts and platelets <25,000 /ml in 20 pts. Non-hematologic toxicity consisted mainly of diarrhea (10 pts), nausea (5 pts), headache (5 pts), peripheral edema (3 pts) and pleural effusion (2 pts); all grade 1 or 2. In conclusion, despite a relatively short follow-up, dasatinib demonstrated substantial hematologic and cytogenetic activity in this heavily pretreated population of accelerated phase CML pts. Data will be updated at the time of the meeting on all 107 pts, with a minimum of 6 months’ follow-up.

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