Study of Dasatinib in Patients With Chronic Phase Chronic Myeloid Leukemia and a Suboptimal Response to Imatinib

An Open-label, Randomized Study of Dasatinib vs High-dose (800-mg) Imatinib in the Treatment of Subjects With Chronic Phase Chronic Myeloid Leukemia Who Have Had a Suboptimal Response After at Least 3 Months of Therapy With 400 mg Imatinib

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00320190

Enrollment

Registered

2006-05-03

Start date

2006-08-31

Completion date

2010-01-31

Last updated

2013-10-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Leukemia, Myeloid, Chronic

Keywords

Chronic phase CML, with a suboptimal response after treatment with imatinib

Brief summary

The purpose of this study is to compare the efficacy of dasatinib with that of high-dose (800-mg) imatinib in participants with chronic phase chronic myeloid leukemia who achieved only a suboptimal response after at least 3 months of monotherapy with 400-mg imatinib. The safety of these treatments will also be evaluated.

Detailed description

Participants were randomized 2:1 to dasatinib or high-dose imatinib, respectively. Randomization was stratified by a suboptimal response, defined as a hematologic response less than a complete hematologic response after at least 3 months of monotherapy with 400-mg imatinib; a cytogenic response (CgR) less than a partial CgR (PCgR) after at least 6 months of monotherapy with 400-mg; a PCgR after at least 12 months of monotherapy with 400-mg imatinib; or less than a major molecular response with a complete CgR after at least 18 months of monotherapy with 400-mg imatinib. Participants received either dasatinib or imatinib for 12 months or until disease progression, unacceptable toxicity, consent withdrawal, or study discontinuation. After 12 months, who had a confirmed major molecular response and were still receiving dasatinib, 100 mg, or imatinib, 800 mg, were eligible to extend treatment for an additional 12 months. Participants permanently discontinuing treatment before 12 months were considered treatment failures and withdrawn from the study.

Interventions

DRUGImatinib

Imatinib tablets administered orally at a dose of 400 mg twice daily. Each 400- mg dose to be taken with a meal and a large glass of water.

DRUGDasatinib

Dasatinib tablets administered orally at a dose of 100 mg once daily.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Chronic phase Ph\^+ chronic myeloid leukemia (CML) demonstrating only a suboptimal response, defined as a hematologic response that is less than a complete hematologic response after at least 3 months of monotherapy with imatinib, 400 mg; a cytogenic response (CgR) that is less than a partial CgR (PCgR) after at least 6 months of monotherapy with imatinib, 400 mg; a PCgR after at least 12 months of monotherapy with imatinib, 400 mg; or less than a major molecular response with a complete CgR after at least 18 months of monotherapy with imatinib, 400 mg. * Either gender * Age of 18 years or older

Exclusion criteria

* Previous diagnosis of accelerated phase or blast crisis CML * Uncontrolled or significant cardiovascular disease * History of significant bleeding disorder unrelated to CML * Concurrent malignancies * Intolerance of imatinib, 400 mg * Prior treatment with imatinib at a dose higher than 400 mg * Prior stem cell transplantation and/or high-dose chemotherapy for CML

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Chronic Phase Chronic Myeloid Leukemia Who Have a Major Molecular Response (MMolR)	At 12 months from baseline	MMolR is defined as reduction in transcript levels of the breakpoint cluster region (BCR)-V-abl Abelson murine leukemia viral oncogene homolog 1 (ABL) gene of at least 3 log. The BCR-ABL gene has a role in the production of a mutated protein that converts bone marrow stem cells from normal to leukemic.

Secondary

Measure	Time frame	Description
Percentage of Participants With On-study AEs of Special Interest	Months 1 to 12, continuously, and Months 12 to 24, continuously	GI=gastrointestinal. AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. Grade 1=mild; Grade 2=moderate; Grade 3=severe and undesirable; Grade 4=life-threatening or disabling; Grade 5=death. Percentages based on the number of participants with a specific grade at baseline. Participants without on-study test values for a particular laboratory analyte are not included in the reporting of that analyte.
Median Time to MMolR	At 3, 6, 9, and 12 months from baseline	Time to MMolR is defined as the time from first treatment dose until measurement criteria are first met for MMolR. MMolR is defined as a reduction in transcript levels of the BCR-ABL gene of at least 3 log from baseline.
Percentage of Participants With Death as Outcome, Adverse Events (AEs), Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, and AEs Leading to Discontinuation	Months 1 to 12, continuously, and Months 12 to 24, continuously	AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. SAE=any untoward medical occurrence that at any dose results in death, persistent or significant disability/incapacity, drug dependency, or drug abuse; prolongs inpatient hospitalization; or is life-threatening, a congenital anomaly/birth defect, or an important medical event. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment.
Median Time to Treatment Failure	Randomization to disease progression, death, or discontinuation (to 12 months)	Time to treatment failure is defined as the time in days from randomization to progressive disease documented by the investigator, to death from any cause without prior progression, or to early treatment discontinuation for any reason, whichever occurs first. Participants without disease progression or who do not die and complete the 12-month study treatment are censored on the date of their last molecular, cytogenetic, or hematologic assessment.
Median Time to Progression-free Survival	Randomization to disease progression or death (to 12 months)	Progression-free survival is defined as the time in days from randomization to progressive disease documented by the investigator or to death from any cause without prior progression. Participants without progressive disease or who do not die and complete the 12-month treatment are censored on the date of their last molecular, cytogenetic, or hematologic assessment.
Percentage of Participants With Complete Cytogenetic Response	At 6 and 12 months from baseline	Cytogenetic response is based on the prevalence of Ph+ metaphases among cells in metaphase in a bone marrow sample.

Countries

Belgium, Finland, France, Germany, Italy, Norway, Portugal, Russia, Spain, Sweden, United Kingdom

Participant flow

Pre-assignment details

Of 52 participants enrolled, 32 were randomized to treatment. Of the 20 not randomized, 17 no longer met study criteria, 1 participant had an adverse event prior to randomization, 1 participant was enrolled after the sponsor stopped recruitment, and 1 participant was stopped due to administrative reasons.

Participants by arm

Arm	Count
Dasatinib, 100 mg Dasatinib, 100 mg, administered orally once daily.	19
Imatinib, 800 mg Imatinib, 400 mg, administered orally twice daily.	13
Total	32

Withdrawals & dropouts

Period	Reason	FG000	FG001
First 12 Months	Adverse event unrelated to study drug	1	0
First 12 Months	Completed but did not enter extension	5	3
First 12 Months	Enrollment failure	0	1
First 12 Months	Investigator request	0	1
First 12 Months	Lost to Follow-up	0	1
First 12 Months	Sponsor terminated study	2	2
First 12 Months	Study drug toxicity	0	1
First 12 Months	Withdrawal by Subject	0	1
Long-term (12-month) Extension	Lack of major molecular response	1	2
Long-term (12-month) Extension	Sponsor terminated study	7	0
Long-term (12-month) Extension	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Imatinib, 800 mg	Total	Dasatinib, 100 mg
Age, Customized	53.2 Years STANDARD_DEVIATION 14.24	48.6 Years STANDARD_DEVIATION 14.85	45.5 Years STANDARD_DEVIATION 14.83
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	13 Participants	31 Participants	18 Participants
Sex: Female, Male Female	3 Participants	9 Participants	6 Participants
Sex: Female, Male Male	10 Participants	23 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	18 / 19	12 / 13
serious Total, serious adverse events	3 / 19	1 / 13

Outcome results

Primary

Percentage of Participants With Chronic Phase Chronic Myeloid Leukemia Who Have a Major Molecular Response (MMolR)

MMolR is defined as reduction in transcript levels of the breakpoint cluster region (BCR)-V-abl Abelson murine leukemia viral oncogene homolog 1 (ABL) gene of at least 3 log. The BCR-ABL gene has a role in the production of a mutated protein that converts bone marrow stem cells from normal to leukemic.

Time frame: At 12 months from baseline