Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Leukemia, Myeloid, Chronic-Phase

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Translocation, Genetic

Chromosome Aberrations

Chronic Graft Versus Host Disease

Myeloid Leukemia

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Dasatinib

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

dasatinib

Bristol-Myers Squibb

The objective is to evaluate the cytogenetic response to Dasatinib (BMS-354825) administered for 24 weeks in subjects with Imatinib resistant or intolerant chronic phase chronic myeloid leukemia (CML) once daily (QD) or twice daily. (BID)

A Study of Dasatinib in Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia

A Randomized, Multicenter, Open-label Phase II Study of Dasatinib (BMS-354825) Administered Orally at a Dose of 50mg Twice Daily or 100mg Once Daily in Subjects With Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia Who Are Resistant or Intolerant to Imatinib

MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in BM: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35

CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date.

Progressed disease=achieving a CHR and subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose and an increase in white blood cell count (doubling of the count from lowest value to \>20,000/mm3 or an increase by \>50,000/mm3 on 2 assessments done at least 2 weeks apart); meeting the criteria of accelerated or blastic phase CML at any time; having an MCyR and subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a \>=30% absolute increase in number of Ph+ metaphases.

Cytogenetic responses (CyR) are based on the percentage of Philadelphia-positive (Ph+) metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), and Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM).

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

Time to MCyR is defined as the time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met. MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35

Blood sample collection for pharmacokinetic (PK) analysis that will contribute to PK modeling.

The duration of MCyR will be measured from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death. Subjects who neither progress nor die will be censored on the date of their last cytogenetic assessment.MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Philadelphia-positive (Ph+) Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35

Time to CHR = time from first dose of Dasatinib until the first day CHR criteria are met (provided subjects achieved a cCHR). CHR=all of the following criteria: white blood cell count ≤ upper limit of normal; platelets \<450,000/mm³; no blasts or promyelocytes in peripheral blood; \<5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \<20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date.

The duration of CHR were measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death. Subjects who neither progress nor die were censored on the date of their last hematologic assessment.

Progressed disease=achieving a CHR \& subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose \& increase in white blood cell count (doubling of count from lowest value to \>20,000/mm3 or an increase by \>50,000/mm3 on 2 assessments done ≥2 weeks apart); meeting the criteria of accelerated or blastic phase chronic myeloid leukemia at any time; having an MCyR \& subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a \>=30% absolute increase in number of Ph+ metaphases.

Number of participants with positive (\>= 2.0 log copies/mg) and negative (\<2.0 log copies/mg) expression of mRNA at Baseline and at end of study.

Number of participants with a particular BCR-ABL mutation at Baseline and End-of-Study.

Cytogenetic response (CyR) as reflected in the major cytogenetic response was determined by bone marrow (BM) aspirates and are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each BM sample. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), or Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM).

Study Director

Starting dose of 100 mg QD oral continuous daily dosing of Dasatinib (BMS-354825) for 24 weeks. One dose escalation allowed for nonresponding participants; dose reduction mandated according to the observed toxicity.

Dasatinib 100 mg Once-daily (QD) Starting Dose

Starting dose of 50 mg BID oral continuous daily dosing of Dasatinib (BMS-354825) for 24 weeks. One dose escalation allowed for nonresponding participants; dose reduction mandated according to the observed toxicity.

Dasatinib 50 mg Twice-daily (BID) Starting Dose

Total

Age Continuous

<65 years

>=65 years

Age, Customized

Sex: Female, Male

Japan

Region of Enrollment

Status=0

Status=1

Status=2

Status=3

Status=4

Status=5

ECOG PS scale is a 6-item scale to assess disease progression, daily functioning, and appropriate treatment and prognosis. Scale=0-5, with 0=fully active, 1=restricted in physically strenuous activity but ambulatory, 2=ambulatory and capable of all selfcare but unable to work, 3= limited selfcare ability and confined to bed/chair \>50% of waking hours, 4=completely disabled and no selfcare ability and confined to bed/chair, and 5=death

Eastern Cooperative Oncology Group Performace Status (ECOG-PS)

Imatinib-resistant

Imatinib-intolerant

Resistance to Imatinib=Previously treated with imatinib at a dose of ≥ 400 mg/day AND developed progressive disease while receiving imatinib at that dose. Intolerance to Imatinib=development of a Grade ≥3 toxicity considered at least possibly related to imatinib at a dose of ≤400 mg/day which led to discontinuation of therapy.

Imatinib Status

BMS Study Director

MCyR

CCyR

All participants treated with a starting Dasatinib (BMS-354825) dose of 100 mg QD oral continuous daily dosing (CCD) for 24 weeks.

Dasatinib 100 mg QD Starting Dose Cohort

Imatinib-resistant participants treated with a starting Dasatinib (BMS-354825) dose of 100 mg QD oral continuous daily dosing (CCD) for 24 weeks.

Dasatinib 100 mg QD Starting Dose - Imatinib-resistant

Imatinib-intolerant participants treated with a starting Dasatinib (BMS-354825) dose of 100 mg QD oral continuous daily dosing (CCD) for 24 weeks.

Dasatinib 100 mg QD Starting Dose - Imatinib-intolerant

All participants treated with a starting Dasatinib (BMS-354825) dose of 50 mg BID oral continuous daily dosing (CCD) for 24 weeks.

Dasatinib 50 mg BID Starting Dose Cohort

Imatinib-resistant participants treated with a starting Dasatinib (BMS-354825) dose of 50 mg BID oral continuous daily dosing (CCD) for 24 weeks.

Dasatinib 50 mg BID Starting Dose - Imatinib-resistant

Imatinib-intolerant participants treated with a starting Dasatinib (BMS-354825) dose of 50 mg BID oral continuous daily dosing (CCD) for 24 weeks.

Dasatinib 50 mg BID Starting Dose - Imatinib-intolerant

Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24

AEs (symptoms/signs and laboratory abnormalities)

SAEs (symptoms/signs and laboratory abnormalities)

Deaths

AEs that led to discontinuation

All participants treated with a starting dose of Dasatinib (BMS-354825) 100 mg QD oral continuous daily dosing (CCD) for 24 weeks.

Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment

Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24

Time to Major Cytogenetic Response (MCyR)

Blood samples were collected for PK to be included in separate population PK analyses. No study specific PK analyses were planned for this report.

Pharmacokinetics of Dasatinib (BMS-354825) as Characterized by Population Pharmacokinetics

Median duration was not reached at the time of this report; see Outcome Measure 14 for corresponding life table.

Duration of MCyR

Time to CHR

Median duration of CHR was not reach at the time of this report. See corresponding life table presented in Outcome Measure 15.

Duration of CHR

Median months of progression-free survival was not reached at the time of this report. See corresponding life table in Outcome Measure 16.

Progression-Free Survival (PFS)

Positive at Baseline

Negative at Baseline

Positive at End-of-Study

Negative at End-of-Study

Expression of BCR-ABL Gene Mutations of RNA (mRNA)

G250E mutation at Baseline

G250E mutation at End-of-Study

F317L mutation at Baseline

F317L mutation at End-of-Study

T315I mutation at Baseline

T315I mutation at End-of-Study

Mutational Spectrum of BCR-ABL

Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study

Hematologic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study

Month 0

Month 4

Month 8

Month 12

Month 16

Month 20

Month 24

Treated participants. Median duration was not reached at the time of this report (see Outcome Measure 6)

Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table)

Treated participants. Median duration was not reached at the time of this report (see Outcome Measure 7)

Spots Global Cancer Trial Database for imatinib resistant or intolerant chronic phase cml