Dasatinib (BMS-354825) in Subjects With Myeloid Blast Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate

Chronic Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00101816
• Other study ID #: CA180-006
• Status: Completed
• Phase: Phase 2
• First received: January 13, 2005
• Last updated: August 3, 2010
• Start date: December 2004
• Est. completion date: March 2008

Study information

• Verified date: June 2010
• 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 study is to see what effect an investigational drug (BMS-354825) has on subjects who are currently in the myeloid blast phase of chronic myeloid leukemia (CML) and who are either resistant to or intolerant of imatinib mesylate. Another purpose of the study is to see what side effects this drug may have on subjects.

Other known NCT identifiers

• NCT00108719

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• 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 myeloid blast phase chronic myeloid leukemia

• Subjects who are either resistant or intolerant of imatinib mesylate

Exclusion Criteria:

• Subjects who are eligible and willing to undergo transplantation

• Serious uncontrolled medical disorder or active infection

• Uncontrolled or significant heart problems, such as congestive heart failure, recent heart attack, etc

• Subjects receiving medications that may affect heart rhythm

• Other malignancy/cancer other than CML

• History of significant bleeding disorder unrelated to CML

• Pregnant or breastfeeding women (subjects must avoid becoming pregnant)

• Subjects received imatinib within 7 days, interferon or cytarabine within 14 days, a targeted anticancer medication within 14 days, an antineoplastic agent (other than hydroxyurea or anagrelide) within 28 days, or any other investigation medication in 28 days

• Subject is receiving medications that affect platelet function or an anticoagulant

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

• Blast Crisis
• Chronic Myeloid 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
Australia	Local Institution	Adelaide	South Australia
Austria	Local Institution	Wien
Belgium	Local Institution	B-Leuven
Belgium	Local Institution	Edegem
Canada	Local Institution	Montreal	Quebec
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 Cedex 10
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
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
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	Denver	Colorado
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 Brunswick	New Jersey
United States	Local Institution	New York	New York
United States	Local Institution	Pittsburgh	Pennsylvania
United States	Local Institution	Portland	Oregon
United States	Local Institution	Seattle	Washington
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,  Australia,  Austria,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Norway,  Philippines,  Singapore,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

References & Publications (2)

Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, Hochhaus A, Guilhot F, Saglio G, Apperley J, Ottmann O, Shah N, Erben P, Branford S, Agarwal P, Gollerkeri A, Baccarani M. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007 Apr 15;109(8):3207-13. Epub 2006 Dec 21. — View Citation

Porkka K, Koskenvesa P, Lundán T, Rimpiläinen J, Mustjoki S, Smykla R, Wild R, Luo R, Arnan M, Brethon B, Eccersley L, Hjorth-Hansen H, Höglund M, Klamova H, Knutsen H, Parikh S, Raffoux E, Gruber F, Brito-Babapulle F, Dombret H, Duarte RF, Elonen E, Paquette R, Zwaan CM, Lee FY. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008 Aug 15;112(4):1005-12. doi: 10.1182/blood-2008-02-140665. Epub 2008 May 13. — 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). Criteria for MaHR are specified in Outcome Measure 2. OHR=best confirmed response of MaHR or minor HR (MiHR). 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 first documented event with no concomitant use of anagrelide or hydroxyurea.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment	No
Secondary	Median Duration of Major Hematologic Response (MaHR)	MaHR=best confirmed 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 the following: 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 Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment	No
Secondary	Median Duration of Overall Hematologic Response (OHR)	OHR=best confirmed response of MaHR or MiHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1. Maintaining a response was defined as no 2 consecutive records of non-response (ie, a single record of non-response between 2 assessments of response was not considered a loss of response).	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment	No
Secondary	Time to MaHR and OHR	Median time from first dosing to date of OHR and/or MaHR in subjects who achieved OHR and MaHR. 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). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment	No
Secondary	Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response	Best confirmed cytogenetic response. Determination of cytogenetic response is 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	Number of Participants With CHR or NEL, MiHR, or no Hematologic Response	Best confirmed 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 complete hematologic response (CHR) or No Evidence of Leukemia (NEL) are specified in Outcome Measure 2. Criteria for minor hematologic response (MiHR) are specified in Outcome Measure 1.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycles 1 and 2; After every 2nd cycle for Cycles 3+; at end of treatment	No
Secondary	Number of Participants Achieving Major Molecular Response (MMR)	Number of participants who achieved an MMR at any time during the treatment period. MMR was calulated 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, and at time of Complete Cytogenetic Response (CCyR) for quantitative Polyermase Chain Reaction (qPCR) analysis	No
Secondary	MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations	MaHR and MCyR in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). Criteria for MaHR are specified in Outcome Measure 2. MCyR=rate of complete cytogenetic responses + the rate of partial cytogenetic responses, as defined in Outcome Measure 5. BCR-ABL=the fused gene found in subjects with this type of CML. This table contains those mutations observed in at least 3 participants. The categories "1 IRM w/2-4-fold increase in resistance" and "=1 IRM w/=5-fold increase in resistance" refer to increase in resistance to imatinib.	baseline, at time of disease progression	No
Secondary	Minimally Significant Changes 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, & functional well-being (PWB, SWB, EWB, FWB). Score range: 0-108; higher scores=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, & FWB score change of 3 or more, & SWB score change of 2 or more=minimal clinical important change.	Baseline, Every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up	No
Secondary	Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs	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)	Continuously throughout study, from pre-treatment visit through end of study (due to death, unacceptable toxicity, treatment failure, etc) and follow-up period	Yes
Secondary	Pharmacokinetics (PK) of Dasatinib - 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 - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h or 24 h(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 < lower limit of qualtitation 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 - 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 - 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	Pharmacokinetics (PK) of Dasatinib's 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's 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 h (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's 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

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm