Study of Dasatinib (BMS-354825) in Patients With Accelerated Phase Chronic Myeloid Leukemia

Chronic Myelogenous Leukemia Clinical Trial

Official title:

A Phase II Study of BMS-354825 in Subjects With Accelerated Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00101647
• Other study ID #: CA180-005
• Status: Completed
• Phase: Phase 2
• First received: January 12, 2005
• Last updated: April 13, 2011
• Start date: December 2004
• Est. completion date: March 2008

Study information

• Verified date: April 2011
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical research study is to learn if BMS-354825 will have activity, defined by hematologic response, in subjects who have accelerated phase chronic myeloid leukemia (CML) who are resistant to or intolerant to imatinib mesylate. The safety of this treatment will also be studied.

Other known NCT identifiers

• NCT00108693

Recruitment information / eligibility

• Status: Completed
• Enrollment: 197
• Est. completion date: March 2008
• Est. primary completion date: August 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects with Philadelphia chromosome positive (PH+) or the fused gene BCR/ABL positive (BCR/ABL+) accelerated phase chronic myeloid leukemia (CML) whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate.

• Subjects must have had prior exposure to imatinib. However, imatinib mesylate does not need to be their most recent CML treatment prior to coming on this study.

• Men and women, 18 years of age or older.

• Adequate hepatic function.

• Adequate renal function.

• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

• Women who are pregnant or breastfeeding.

• Subjects who are eligible and willing to undergo transplantation during the screening period.

• A serious uncontrolled medical disorder or active infection that would impair the ability of the subjects to receive protocol therapy.

• Uncontrolled or significant cardiovascular disease.

• Medications that increase bleeding risk.

• Medications that change heart rhythms.

• Dementia or altered mental status that would prohibit the understanding or rendering of informed consent.

• History of significant bleeding disorder unrelated to CML.

• Concurrent incurable malignancy other than CML.

• Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy.

• Prior therapy with dasatinib (BMS-354825).

• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myelogenous Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• Dasatinib
Tablets, Oral, 70 mg, twice daily, until disease progression or intolerable toxicity, switch to the roll-over study or study closure

Locations

Country	Name	City	State
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Cordoba
Australia	Local Institution	East Melbourne	Victoria
Australia	Local Institution	Parkville	Victoria
Australia	Local Institution	South Brisbane	Queensland
Australia	Local Institution	St. Leonards	New South Wales
Australia	Local Institution	Wien
Belgium	Local Institution	B-Leuven
Belgium	Local Institution	Edegem
Brazil	Local Institution	Campinas
Brazil	Local Institution	Rio De Janeiro
Brazil	Local Institution	Sao Paulo
Canada	Local Institution	Toronto	Ontario
Denmark	Local Institution	Aarhus
Finland	Local Institution	Helsinki
France	Local Institution	LIlle
France	Local Institution	Lyon Cedex 03
France	Local Institution	Nantes
France	Local Institution	Paris
France	Local Institution	Pessac
France	Local Institution	Poitiers Cedex
France	Local Institution	Strasbourg Cedex
Germany	Local Institution	Hamburg
Germany	Local Institution	Mainz
Germany	Local Institution	Mannheim
Israel	Local Institution	Ramat-Gan
Italy	Local Institution	Bologna
Italy	Local Institution	Napoli
Italy	Local Institution	Orbassano
Italy	Local Institution	Roma
Korea, Republic of	Local Institution	Jeollanam-Do
Korea, Republic of	Local Institution	Kyunggi-Do
Korea, Republic of	Local Institution	Seoul
Netherlands	Local Institution	Nijmegen
Netherlands	Local Institution	Rotterdam
Norway	Local Institution	Trondheim
Peru	Local Institution	Lima
Philippines	Local Institution	Quezon City
Singapore	Local Institution	Singapore
Sweden	Local Institution	Gothenburg
Sweden	Local Institution	Lund
Sweden	Local Institution	Umea
Sweden	Local Institution	Uppsala
Switzerland	Local Institution	Basel
Taiwan	Local Institution	Taipei
Taiwan	Local Institution	Taoyuan
Thailand	Local Institution	Bangkok
United Kingdom	Local Institution	Glasgow	Central
United Kingdom	Local Institution	London	Greater London
United States	Local Institution	Anaheim	California
United States	Local Institution	Atlanta	Georgia
United States	Local Institution	Baltimore	Maryland
United States	Local Institution	Birmingham	Alabama
United States	Local Institution	Boston	Massachusetts
United States	Local Institution	Chicago	Illinois
United States	Local Institution	Dallas	Texas
United States	Local Institution	Detroit	Michigan
United States	Local Institution	Hackensack	New Jersey
United States	Local Institution	Houston	Texas
United States	Local Institution	Jacksonville	Florida
United States	Local Institution	Kansas City	Kansas
United States	Local Institution	Los Angeles	California
United States	Local Institution	Nashville	Tennessee
United States	Local Institution	New York	New York
United States	Local Institution	Pittsburgh	Pennsylvania
United States	Local Institution	Portland	Oregon
United States	Local Institution	St. Louis	Missouri
United States	Local Institution	Stanford	California
United States	Local Institution	Tampa	Florida
United States	Local Institution	Vallejo	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  Denmark,  Finland,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Norway,  Peru,  Philippines,  Singapore,  Sweden,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (2)

Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G, Bullorsky EO, Abruzzese E, Hochhaus A, Heim D, de Souza CA, Larson RA, Lipton JH, Khoury HJ, Kim HJ, Sillaber C, Hughes TP, Erben P, Van Tornout J, Stone RM. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 2009 Jul 20;27(21):3472-9. doi: 10.1200/JCO.2007.14.3339. Epub 2009 Jun 1. — View Citation

Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, Heim D, Larson RA, Branford S, Muller MC, Agarwal P, Gollerkeri A, Talpaz M. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007 May 15;109(10):4143-50. Epub 2007 Jan 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major and Overall Hematologic Response (MaHR and OHR)	MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). OHR=best confirmed response of MaHR or minor hematologic response (MiHR). Confirmed hematologic response=response confirmed =4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea. Maintaining a response=no 2 consecutive records of nonresponse at assessment. Criteria for CHR and NEL specified in Outcome Measure 2 and criteria for MiHR in Outcome Measure 4.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment	No
Secondary	Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response)	MaHR=best response of CHR or NEL. CHR=white blood cells =institutional upper limit of normal (iULN); absolute neutrophil count (ANC) =1000/mm3; platelets =100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts =5%; <5% myelocytes+metamyelocytes in PB; PB basophils = iULN; no extramedullary involvement. NEL=WBC =iULN; no blasts/promyelocytes in PB; bone marrow blasts =5%; <5% myelocytes+metamyelocytes in PB; PB basophils =iULN; no extramedullary involvement; at least 1 of: ANC =500/mm3 & <1000/mm3; platelets =20,000/mm3 & <100,000/mm3.	12 months	No
Secondary	Percentage of Participants Who Achieved MaHR and Did Not Progress at 24 Months in the Imatinib-Resistant Group (Based on the Kaplan-Meier Estimate of the Duration of Response)	Percentage of participants in the Imatinib-Resistant Group who achieved MaHR and did not progress at Month 24, based on the Kaplan-Meier estimate of the duration of response. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR and NEL are specified in Outcome Measure 2.	24 months	No
Secondary	Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months	Percentage of participants who achieved OHR and did not progress at specified timepoints, based on the Kaplan-Meier estimate of the duration of response. OHR=best confirmed response of MaHR or MiHR. MaHR criteria in Outcome Measure 2. MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts+promyelocytes in bone marrow and <30% blasts+promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response= confirmed =4 weeks after 1st documented event with no concomitant use of anagrelide or hydroxyurea.	12 months, 24 months	No
Secondary	Median Time in Days From First Dosing Date to Date of MaHR	MaHR=best response of CHR or NEL. CHR=white blood cells =institutional upper limit of normal (iULN); absolute neutrophil count (ANC) =1000/mm3; platelets =100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts =5%; <5% myelocytes+metamyelocytes in PB; PB basophils = iULN; no extramedullary involvement. NEL=WBC =iULN; no blasts/promyelocytes in PB; bone marrow blasts =5%; <5% myelocytes+metamyelocytes in PB; PB basophils =iULN; no extramedullary involvement; at least 1 of: ANC =500/mm3 & <1000/mm3; platelets =20,000/mm3 & <100,000/mm3.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment	No
Secondary	Time to OHR	Median time (in months) from first dosing date to date of OHR. OHR=best confirmed response of MaHR or MiHR. Criteria for MaHR specified in Outcome Measure 2. MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts+promyelocytes in bone marrow and <30% blasts+promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response = response confirmed =4 weeks after 1st documented event with no concomitant use of anagrelide or hydroxyurea.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment	No
Secondary	Best Cytogenetic Response	Number of participants with complete, partial, minor, minimal, or no cytogenetic response. Determination of cytogenetic response based on the prevalence (percentage) of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase in a bone marrow sample (aspirates/biopsies).	Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment	No
Secondary	Best Confirmed Hematologic Response	Number of participants with confirmed complete hematologic response (CHR) or No Evidence of Leukemia (NEL), minor hematologic response (MiHR), or no hematologic response. Confirmed hematologic response=response that is confirmed after at least 4 weeks with no concomitant use of anagrelide or hydroxyurea use during this interval. Criteria for CHR and NEL are specified in Outcome Measure 2; criteria for MiHR are specified in Outcome Measure 4.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment	No
Secondary	Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period	Number of participants who achieved an MMR at any time during the treatment period. MMR was calculated by measuring BCR-ABL transcripts in blood during treatment using quantitative reverse transcription-polymerase chain reaction (RT-PCR). BCR-ABL=the fused gene found in subjects with this type of Chronic Myeloid Leukemia (CML).	Baseline, every 12 weeks throughout study (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).	No
Secondary	MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations	Major hematologic and cytogenetic responses (MaHR and MCyR) to dasatinib in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). BCR-ABL=the fused gene found in subjects with this type of CML. Criteria for MaHR are specified in Outcome Measure 2. MCyR=combined complete cytogenetic and partial cytogenetic response rate. Complete Cytogenetic Response= 0% Ph+ Cells in Metaphase in Bone Marrow, Partial Cytogenetic Response > 0% to 35% Ph+ Cells in Metaphase in Bone Marrow.	Baseline, at time of disease progression. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).	No
Secondary	Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G)	Number of subjects with minimally significant changes from baseline in the health-related quality of life questionnaire FACT-G. FACT-G=27 questions in 4 domains: physical, social/family, emotional, and functional well-being (PWB, SWB, EWB, FWB). Total score=0 to 108; higher score=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, and FWB score change of 3 or more, and SWB score change of 2 or more=minimal clinically important change.	Baseline, every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up.(treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).	No
Secondary	Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition regardless of causal relationship with treatment. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)	Continuous from pretreatment through each 4-week cycle and at follow-up. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).	Yes
Secondary	Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax)	The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.	No
Secondary	Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 Hours (AUC[0-T])	The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were less than the lower limit of quantitation (LLQ) were assigned a value of zero.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.	No
Secondary	Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax)	The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.	No
Secondary	Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF)	The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.	No
Secondary	Population PK of Dasatinib	Population pharmacokinetic analysis was not done because it is not meaningful for this single study	Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose.	No

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