Final Clinical Study Report for CA180003 - Bristol-Myers Squibb

Dasatinib
BMS-354825
Name of Sponsor/Company:
Bristol-Myers Squibb
Name of Finished Product:
Individual Study Table Referring
to the Dossier
CA180003
Clinical Study Report
(For National Authority Use
Only)
Name of Active Ingredient:
SYNOPSIS
Final Clinical Study Report for CA180003
TITLE OF STUDY: A Phase I Dose-Escalation Study of BMS-354825 in Patients with Refractory Solid
Tumors
INVESTIGATORS/STUDY CENTERS: 2 sites in the United States and 1 site in the European Union
PUBLICATIONS: None
STUDY PERIOD: Study Initiation Date: 28-Jun-2004 CLINICAL PHASE: 1
(First Subject First Visit)
Study Completion Date: 12-Jul-2007
(Last Subject Last Visit)
OBJECTIVES: The primary objective of this study was to establish the maximum tolerated dose (MTD),
dose limiting toxicity (DLT), and a recommended Phase 2 dose of dasatinib when administered orally on an
(i) every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) schedule and
(ii) on a twice daily continuous dosing (CDD) schedule in subjects with metastatic solid tumors that were
refractory to standard therapies or for which no effective standard therapy existed. Secondary objectives
were:
1) To assess the safety and tolerability of dasatinib when administered orally on a (i) 5D2 and (ii) CDD
schedule
2) To characterize the plasma pharmacokinetics (PK) of dasatinib when administered orally on a (i) 5D2
and (ii) CDD schedule
3) To assess the effect of food (high-fat breakfast) on the PK of dose levels 1 and 5 of dasatinib
4) To assess the effect of predose administration of a single dose of famotidine 40 mg on the PK of (i)
dose levels 2 and 6 of dasatinib, and (ii) dose levels 3 and 7 of dasatinib administered 5 minutes after a
high-fat breakfast
5) To assess the effect of predose and postdose administration of aluminum hydroxide/magnesium
hydroxide/simethicone or aluminum hydroxide/magnesium hydroxide on the PK of dose levels 4 and 8
of dasatinib
6) To describe any preliminary evidence of efficacy of dasatinib in the treatment of solid tumors as
defined by the modified World Health Organization (WHO) criteria
7) To perform correlative scientific studies to explore effects of dasatinib on several biomarkers of kinase
activity, signaling, response and/or toxicity (eg, SRC, KIT, FAK, EPH) in peripheral blood cells,
plasma and, whenever possible, in serial tumor biopsy samples from subjects with solid tumors
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
8) To describe any preliminary evidence of modulation by dasatinib of tumor glycolytic pathways using
18F-FDG positron emission tomography (PET)
9) To describe any preliminary effect of dasatinib on platelet function as assessed by bleeding time
measurements and/or platelet aggregometry
10) To analyze mRNA expression in pretreatment blood and archived tumor samples and identify potential
predictors of response and toxicity to dasatinib
METHODOLOGY: This was an open-label, Phase 1 dose-escalation study. Treatment began at 70 mg
total daily dose (TDD) on the 5D2 regimen and was escalated as shown in the following table. At least
3 subjects were enrolled per cohort and followed for 4 weeks on study drug. If a DLT was reported, that
dose cohort was expanded to 6 subjects. Dose escalation continued as long as fewer than one-third of
subjects in a cohort had a DLT in their first 2 weeks of treatment. Once the MTD was reached on the 5D2
schedule, new subjects were enrolled on the CDD schedule beginning at 2 dose levels below the MTD with
the 5D2 schedule. Dose escalation on the CDD schedule continued until an MTD was reached.
Dose Level of Dasatinib
Dose Every 12 hours
(Total Daily Dose)
1 35 mg q 12 hr (70 mg TDD)
2 50 mg q 12 hr (100 mg TDD)
3 70 mg q 12 hr (140 mg TDD)
4 90 mg q 12 hr (180 mg TDD)
5 120 mg q 12 hr (240 mg TDD)
6 160 mg q 12 hr (320 mg TDD)
7 200 mg q 12 hr (400 mg TDD)
8 250 mg q 12 hr (500 mg TDD)
A treatment cycle was defined as 4 weeks (28 days). Dasatinib was administered according to the assigned
concomitant treatments (ie, with food and/or famotidine, or aluminum hydroxide/magnesium hydroxide, as
described in secondary objectives 3 through 5) with the morning dose on Day 1 of Cycle 1. Thereafter,
dasatinib was administered without these treatments.
The plasma PK of dasatinib and BMS-606181 were evaluated for all treated subjects after the morning dose
on Day 1. The plasma PK of dasatinib were also to be evaluated after the morning dose once on Days 3 to 5
(fasted), and once on Days 24 to 26 (fasted). However, examination of the data revealed that the majority
of data from subjects on the 5D2 schedule was collected on Day 8, after the 2-day drug holiday. Subjects
were monitored continuously for toxicity.
NUMBER OF SUBJECTS (Planned and Analyzed): Subjects were accrued to each dose level in
cohorts of 3 to 6. A total of 85 subjects were enrolled and 67 were treated, 33 on the 5D2 schedule and
34 on the CDD schedule. Data from all treated subjects were included in the analyses of safety and
efficacy, data from those with adequate concentration profiles were included in the PK analyses, and data
from those with a baseline and at least 1 postdose assessment were included in the pharmacodynamic
analyses.
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Subjects were ≥ 18 years of age with an
Eastern Cooperative Oncology Group (ECOG) performance status score 0 – 1, had histologic or cytologic
diagnosis of a primary solid (ie, nonhematologic) malignancy and evidence (radiographic or tissue
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
confirmation) of metastatic disease which had progressed on or following currently available standard
therapies or for which no standard therapy existed.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT,
BATCH NUMBERS: Dasatinib doses of 70 mg to 320 mg TDD were administered orally on the 5D2
schedule and doses of 140 to 240 mg TDD were administered orally on the CDD schedule. Overall, the
median duration of therapy ranged from 0.8 to 4.0 months/subject across dose cohorts and the median
cumulative dose ranged from 1400 to 20,875 mg/subject. Excluding dose interruptions, the net dose
intensity ranged from 54 to 198.5 mg/day/subject. Dasatinib tablets were provided in the 5-mg strength
(batch numbers 5F02041, 3C72889, 4C88975, 4G78659, 5A01426, 5C02739) and in the 50-mg strength
(batch numbers 3C72907, 4A81197, 4C91969, 4G78663, 5A01431, 5C04559).
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, DURATION OF
TREATMENT, BATCH NUMBERS: There was no reference therapy in this study.
CRITERIA FOR EVALUATION:
Efficacy: Tumor response was assessed after every second cycle (i.e., every 8 weeks), every 12 weeks
after 24 weeks of treatment, and at the end of treatment and classified as complete response, partial
response, stable disease, or progressive disease. Subjects with a complete or partial response were to have
confirmatory tumor measurements within 4 to 6 weeks after response. Safety: Dose limiting toxicity was
defined as any of the following events which were judged to be at least possibly related to dasatinib and
occurred during the first 4 weeks of drug administration:Grade 3 or 4 nausea, vomiting, or diarrhea despite
the use of adequate/ maximal medical intervention and/or prophylaxis
• Any other drug-related Grade 3 or greater nonhematological toxicity except alopecia or fatigue
• Any grade toxicity which in the judgment of the investigator or sponsor required dose reduction or
removal from the study
• Delayed recovery from toxicity related to treatment with dasatinib which delayed scheduled
retreatment for > 14 days
• A QTc interval ≥ 500 msec
• Grade 4 neutropenia (ANC < 500 cells/mm 3 )for ≥ 5 consecutive days or febrile neutropenia (ie, fever ≥
38.5° C with ANC < 1000/mm 3 )
• Thrombocytopenia ≤ 25,000 cells/mm 3 or bleeding requiring a platelet transfusion
For each schedule, the dose level below the maximum administered dose (MAD) was considered the MTD,
providing DLT was reported in less than one-third of subjects at that dose level. The determination of the
MTD and recommended Phase 2 dose were defined by DLT occurring in the first 4 weeks of treatment.
Additional safety evaluations included monitoring of adverse events (AEs), serious adverse events (SAEs),
electrocardiograms (ECG), vital signs, physical examinations, and clinical laboratory tests. Adverse events
and other symptoms were graded according to the National Cancer Institute Common Terminology Criteria
for Adverse Events (NCI-CTCAE) Version 3.0.
Pharmacokinetics: Pharmacokinetic blood samples for determination of dasatinib and the metabolite
BMS-606181 concentrations were collected during Cycle 1 following the morning doses on Day 1, once on
nominal Day 8, and once on nominal Days 24 to 26 at the following time points: predose, 30 minutes, and
1, 1.5, 2, 3, 4, 5, 6, 8, and 10 hours post dose. The PK parameters determined for dasatinib and BMS-
686181 were: maximum plasma concentration (Cmax), time to Cmax (Tmax), plasma half-life (T-HALF),
apparent oral clearance (CLo), apparent volume of distribution in the terminal phase (Vz/F), and area under
the curve (AUC) from zero extrapolated to infinity [AUC (INF)], within the dosing interval [AUC(TAU)],
and from zero to the last quantifiable sampling time (AUCt). Since samples had been collected after the 2-
day drug holiday, AUC(INF) on Day 8 instead of AUC(TAU) was used for the 5D2 schedule while
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
AUC(TAU) was used for the CDD schedule for statistical analyses of AUC. The PK parameters
determined for BMS-606181 were Cmax, AUCt, and Tmax.
Pharmacodynamics: Blood samples were collected for phosphorylated SRC and phosphorylated FAK in
peripheral blood mononuclear cells on Day 1, once on Days 3 to 5, and once on Days 24 to 26 of Cycle 1
predose and 4, 8 and 24 hours post dose. Assessment of KIT and stem cell factor was optional and no site
elected to participate. Blood samples for potential plasma markers of response or toxicity were collected
pre-dose and within 1 month after clinical determination of either response or progression. Tumor
metabolism was assessed with 18F-FDG PET 1 to 2 times within 21 days prior to dosing on Day 1, and
following dosing during Weeks 1, 4, and 8 of treatment.
Pharmacogenomics: Freshly obtained tumor sample was collected (as feasible) pretreatment or up to
2 times while on-treatment for immunohistochemistry (IHC), mRNA expression, and genotyping. Archived
tumor tissue was collected (as feasible) pretreatment and/or on-treatment for IHC, mRNA expression and
genotyping.
STATISTICAL CONSIDERATIONS: Descriptive statistics were used to summarize efficacy, safety,
PK, and pharmacodynamic observations. Categorical variables were summarized in frequency tables.
Continuous variables were summarized with mean, median, and minimum and maximum values. For the
PK analyses, geometric means and coefficients of variation were presented for Cmax, AUCt, AUC(TAU),
and AUC(INF). Medians, minima, and maxima were reported for Tmax. To estimate the effect of food on
the PK of dasatinib, an analysis of variance was performed on log(Cmax) and log(AUC), for each dose
separately and across doses. Similar analyses were performed to estimate the effects of famotidine,
famotidine after food, and aluminum hydroxide/magnesium hydroxide on the PK of dasatinib. To assess
dose proportionality, a statistical linear regression analyses of log(AUC) on log(dose), for Day 8 and Day
26 was conducted.
SUMMARY OF RESULTS:
Disposition, Demographics, and Other Pertinent Baseline Characteristics: Of the 67 treated subjects,
33 received dasatinib on the 5D2 schedule and 34 on the the CDD schedule. Two subjects, both in the CDD
group, completed treatment. The majority of subjects went off study due to documented disease
progression (34/67, 50.7%), deterioration without documented progression (15/67, 22.4%), or study drug
toxicity (12/67, 17.9%). Two subjects went off study due to death, 1 at subject request, and 1 due to an
adverse event (AE) unrelated to study treatment The median age of all 67 subjects was 56.4 years, 92.5%
were white, and all had a baseline ECOG performance status score of 0 or 1. Sixty-six subjects (98.5%) had
a target lesion at baseline; a majority had more than 1. The most frequent sites of disease (in ≥10% of
subjects) were visceral (liver and lung), skin/soft tissue, lymph node, other sites, pelvis, and peritoneum.
The median time from cancer diagnosis to study start was 43.1 months. Sixty-six (98.5%) subjects reported
at least 1 medical condition at baseline and 32 (47.8%) reported at least 1 pretreatment clinical complaint or
finding. Prior treatments for cancer included chemotherapy (63/67, 94.0%), surgery (67/67, 100%),
radiotherapy (19/67, 28.4%), hormonal/immuno/biologic therapy (4/67, 6.0%), and other investigational
agents (8/67, 11.9%).
Efficacy Results: No confirmed objective tumor responses were achieved in this study. Eleven (16.4%)
subjects had a best clinical response rating of stable disease while on therapy, including 7/33 (21.2%) of
subjects on the 5D2 schedule and 4/34 (11.8%) of subjects on the CDD schedule. Thirty-one subjects
(46.3%) had progressive disease, including 19/33 (57.6%) treated on the 5D2 schedule and 12/34 (35.3%)
on the CDD schedule. Thirteen (19.4%) subjects had a rating of clinical progression, which was based on
information included in the CRF providing evidence that patients had symptoms of progression in the
absence of radiographic evidence. Ten subjects, all of whom were treated on the CDD schedule, were
discontinued due to drug toxicity. Two subjects (one on each schedule) had no data available.
Safety Results: The MTD on the 5D2 schedule was 240 mg TDD, with 1 of 6 evaluable subjects reporting
DLT (Grade 3 tumor lysis syndrome). The 240-mg dose was 1 level below the MAD of 320 mg, at which 3
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
of 4 evaluable subjects had DLT (recurrent Grade 2 rash; Grade 3 lethargy; and 1 subject with Grade 3
prolonged bleeding time and Grade 3 hypocalcemia).
The MTD on the CDD schedule was 140 mg TDD, at which no subjects reported DLT. Treatment on this
schedule was initiated at 140 mg and escalated to the MAD of 240 mg, at which 3 of 4 evaluable subjects
reported DLT (Grade 3 nausea; Grade 3 fatigue; and 1 subject with Grade 2 proteinuria and Grade 3 rash).
The first 4 subjects at an intermediate dose level of 200 mg TDD reported no DLT; however, when this
cohort was expanded with an additional 12 subjects, 6 of the 13 evaluable subjects reported DLT( Grade 3
dyspnea; Grade 3 constipation; Grade 2 proteinuria; Grade 4 fatigue; Grade 3 lethargy; and 1 subject with
Grade 2 myocardial toxicity, Grade 4 elevated cardiac troponin, and Grade 2 ECG T-wave inversion). At
the 180-mg dose, which was 1 level below the MAD, 2 of 7 evaluable subjects reported DLT (Grade 3
proteinuria and Grade 2 rash in 1 subject and Grade 1 cognitive impairment, and Grade 2 somnolence,
altered taste, slurred speech, and unsteady gait in the other subject).
All but 1 of the 67 subjects (98.5%) reported at least 1 AE. Grade 3 to 5 AEs were reported at a similar
incidence among subjects treated on the 5D2 (17/33, 52%) and CDD (20/34, 59%) schedules. A total of
64/67 subjects (95.5%) reported at least 1 drug-related AE; the incidence was 33/33 subjects (100%) on the
5D2 schedule and 31/34 subjects (91.2%) on the CDD schedule. The most frequent AEs (regardless of
relationship) were nausea, anorexia, and fatigue. Nausea and fatigue were reported at a similar incidence on
either schedule; anorexia was reported more frequently among subjects on the CDD schedule (21/34,
61.8%) compared with the 5D2 schedule (13/33, 39.4%). The incidence of AEs and drug-related AEs was
not dose related.
Eighteen subjects died, 10 during the study period or within 30 days of their last dose of dasatinib and 8
more than 30 days after their last dose of dasatinib. All but 1 of these deaths were due to disease
progression; 1 subject died due to gastrointestinal bleeding that the investigator considered most likely due
to disease progression but could not rule out a possible contribution by the study drug. Thirty-four (34/67,
50.7%) subjects reported SAEs, 13 (19.4%) of whom reported SAEs that were considered drug-related.
Drug-related SAEs were more frequent among subjects treated on the 5D2 schedule (9/33, 27.3%)
compared with subjects treated on the CDD schedule (4/34, 11.8%). Twenty-four (24/67, 35.8%) subjects
discontinued study treatment due to AEs. Discontinuation due to AEs was more frequent among subjects
on the CDD schedule (15/34, 44.1%) compared with subjects on the 5D2 schedule (9/33, 27.3%).
Grade 3 to 4 abnormalities in selected clinical laboratory values for hematologic parameters and
electrolytes were infrequent and were not related to the treatment schedule. No clinically meaningful
changes in vital signs measurements or physical examination findings were noted; ECG results will be
reported separately.
Pharmacokinetic Results: Dasatinib was detectable in plasma 30 minutes after oral administration and
reached Cmax at median Tmax values of 0.5 to 3.1 h in absence of any treatment effects (Days 8 and 26).
The AUC increased approximately proportionally to dose; the slope (90% CI) was 1.08 (0.63, 1.54) on Day
8 and 1.07 (0.63, 1.51) on Day 26. The Cmax and AUC values of Day 8 and 26 appeared to be similar,
indicating no clinically relevant accumulation on repeated dosing. Across the range of 70 to 320 mg, the
mean T-HALF of dasatinib was consistent on Days 8 and 26. Although consistent across the dose groups,
the variability for both CLo and Vz/F was large.
At the MTD of 140 mg TDD on the CDD schedule, median (min, max) dasatinib Tmax was similar across
days. The Tmax and T-HALF values of dasatinib on Days 8 and 26 were similar to Day 1, indicating no
change in absorption or elimination in the presence of food or famotidine, or after multiple dosing. The
geometric mean (CV%) Cmax and AUC(TAU) values suggested minimal accumulation.
Food decreased dasatinib Cmax by 20% and increased AUC by 1% at 70-mg TDD, and decreased Cmax by
34% and AUC by 9% at 240 mg. Overall, food decreased Cmax by 29% and AUC by 5%; the ratio of
geometric means (90% CI) was 0.71 (0.47, 1.09) for Cmax and 0.95 (0.73, 1.22) for AUC. Famotidine
decreased dasatinib Cmax by 87% and AUC by 82% at 100 mg, and by 82% and 74%, respectively at
320 mg. Overall, famotidine decreased Cmax by 85% and AUC by 79%; the ratio of geomtric means (90%
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
CI) was 0.15 (0.05, 0.50) for Cmax and 0.21 (0.10, 0.45) for AUC. Administration of famotidine with a
high-fat breakfast decreased dasatinib Cmax by 73% and AUC by 25%; the ratio of geometric means was
0.27 (0.08, 0.95) for Cmax and 0.75 (0.38, 1.50) for AUC. Administration of aluminum
hydroxide/magnesium hydroxide resulted in 36% and 24% decrease in dasatinib Cmax and no apparent
decrease in dasatinib AUC; the ratio of geometric means was 0.64 (0.46, 0.89) for Cmax and 0.76 (0.54,
1.06) for AUC.
Dose
(mg TDD)
/Schedule
Cmax
(ng/mL)
Geom.
Mean
(CV%)
AUC
(ng•h/mL)
Geom.
Mean
(CV%)
Tmax
(h)
Median
(Min,
Max)
Dose
Day Condition N
70/5D2 1 Food 7 16.82 (141) 85.89 (58) a 3.0
8 Fasted 6 24.85 (99) 84.81 (73)
26 Fasted 4 18.56 (84) 84.15 (30)
100/5D2 1 Fam 3 5.0 (20) 24.99 (44)
8 Fasted 3 38.37 (45) 140.31 (22)
26 Fasted 3 43.35 (100) 157.96 (4)
(0.5, 6.0)
1.5
(0.5, 4.0)
1.4
(0.5, 1.6)
3.0
(3.0, 5.0)
1.0
(0.5, 3.0)
0.5
(0.5, 2.0)
140/5D2 1 Fam+Food 4 18.05 (65) 183.61 (8) b 6.5
(4.0, 10.0)
8 Fasted 3 46.29 (91) 165.08 (78)
0.5
(0.5, 2.0)
26 Fasted 4 25.02 (80) 160.65 (8)
2.0
(1.0, 6.0)
140/CDD 1 Fam+Food 5 14.78 (35) 141.29 (78)
4.0
(2.0, 5.0)
8 Fasted 3 78.41 (90) 245.31 (57)
1.0
(0.5, 6.0)
26 Fasted 3 50.19 (86)
325.34 3.1
(19) b (1.1, 6.1)
180/5D2 1 Maalox 6 63.65 (54) 248.91 (67)
2.3
(1.0, 4.0)
8 Fasted 5 88.94 (44) 251.02 (37)
1.0
(0.5, 4.0)
26 Fasted 5 83.43 (58)
492.07 3.0
(33) c (1.0, 8.0)
180/CDD 1 Maalox 6 41.30 (93) 170.13 (72)
2.2
(0.6, 5.0)
8 Fasted 6 51.80 (84) 204.08 (68)
1.6
(0.0, 3.1)
26 Fasted 5 71.69 (59) 273.54 (45)
1.5
(0.5, 5.0)
200/CDD 1 Fasted
1
227.57 2.0
44.01 (97)
7
(83) d (0.5, 9.8)
8 Fasted
1
218.14 1.5
55.96 (118)
2
(102) (0.5, 3.6)
T-HALF
(h)
Mean
(SD)
3.60
Clo
(L/h)
Mean
(SD)
Vz/F
(L)
Mean
(SD)
(1.63) a -- --
2.97 641.6 3083
(1.13) (650.6) (3866)
3.04 433.0 1842
(0.93) (146.2) (602)
2.84
(1.88)
-- --
3.76 402.4 2144
(0.58) (74.1) (205)
4.43 316.7 2034
(2.19) (12.6) (1052)
2.36 --
(0.43) b --
4.92 1187.7 9464
(1.45) (1715.9 (1417
) 5)
4.32 487.7 3649
(1.58) (37.1) (94)
7.13 --
(3.26)
--
4.00 326.9 2039
(0.82) (209.5) (1715)
2.46 217.2 739
(0.99) b (42.0) b (162) b
3.45 --
(0.92)
--
3.15 437.8 1922
(0.67) (310.5) (1204)
2.34 190.8 600
(0.74) c (64.2) c (82) c
3.32 --
(1.37)
--
4.07 544.9 3516
(1.25) (364.1) (2894)
3.08 409.2 2176
(1.15) (359.7) (2727)
3.65
(1.30) d -- --
4.34 666.9 4224
(1.72) (537.9) (3549)
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
Dose
(mg TDD)
/Schedule
Day
Dose
Condition
N
Cmax
(ng/mL)
Geom.
Mean
(CV%)
AUC
(ng•h/mL)
Geom.
Mean
(CV%)
26 Fasted 7 51.63 (96) 207.01 (79)
240/5D2 1 Food 9 76.92 (64) 352.18 (41)
8 Fasted 5 76.66 (73) 298.27 (66)
26 Fasted 7 98.17 (82)
395.76
(74)
240/CDD 1 Food 5 80.47 (70) 423.42 (64)
8 Fasted 5 130.80 (48) 526.14 (49)
26 Fasted 1 59.94 (.) 207.26 (.)
320/5D2 1 Fam 4 21.09 (164) 102.78 (83)
8 Fasted 2 203.39 (53) 436.39 (56)
26 Fasted 1 177.58 (.) 501.91 (.)
Tmax
(h)
Median
(Min,
Max)
2.0
(0.5, 5.0)
2.0
(0.5, 4.0)
1.0
(0.5, 2.0)
1.0
(0.5, 2.0)
2.0
(1.0, 6.5)
0.5
(0.0, 2.0)
1.5
(1.5, 1.5)
2.0
(0.5, 5.0)
0.8
(0.5, 1.0)
1.5
(1.5, 1.5)
T-HALF
(h)
Mean
(SD)
3.20
(1.71)
3.14
(1.10)
3.24
(0.75)
3.32
(1.53)
4.00
(1.91)
3.35
(0.73)
2.2 (.)
3.57
(1.23)
2.72
(0.56)
2.6 (.)
Clo
(L/h)
Mean
(SD)
696.5
(793.0)
Vz/F
(L)
Mean
(SD)
2740
(2541)
-- --
511.3
(325.6)
367.5
(234.4)
2223
(1079)
1679
(1145)
-- --
269.8
(195.0)
590.4
(.)
1401
(1336)
1877
(.)
-- --
411.0
(223.8)
318.8
(.)
1523
(549)
1195
(.)
Cmax = maximum plasma concentration; AUC = area under the plasma concentration-time curve, AUC(INF) for Day 1 and Day 8 for
5D2 schedule and AUC(TAU) for Day 8 for CDD schedule and Day 26 for both schedules ;Tmax = time to reach Cmax; T-HALF =
terminal elimination half-life; Geom. = geometric; -- = missing or not calculated; Fam = famotidine
a: N=6; b: N=2; c: N=4; d: N=14
BMS-606181 was rapidly formed after oral administration of dasatinib with Cmax reached at 1.0 to 10.0 h.
The summary statistics on Day 8 suggest that AUCt and Cmax increased in a dose-related manner.
Variability in Cmax and AUCt for BMS-606181 was greater than the parent drug. The ratio of the
geometric mean of the AUC of BMS-606181 over that of dasatinib on Days 8 and 26, unadjusted for the
molecular weight difference (which was less than 10%), ranged from less than 1% to 13%, except for the
140 mg/5D2 schedule where the metabolite ratio was 25%. At the proposed MTD dose of 140 mg TDD
with the CDD schedule, the ratios of geometric mean of the AUC of BMS-606181 over that of dasatinib
were 2.7%, 12.6% and 5.8% on Days 1, 8 and 26, respectively.
Pharmacodynamic Results: Results of other pharmacodynamic parameters will be reported separately.
Pharmacogenomic Results: The results of IHC, mRNA expression, and genotyping will be reported
separately.
CONCLUSIONS: These results indicate that:
• The MTD of dasatinib is 240 mg TDD on the 5D2 schedule and 140 mg TDD on the CDD schedule;
these are the recommended Phase 2 doses
• The DLTs among subjects treated on the 5D2 schedule are dehydration, anorexia, hyponatremia, tumor
lysis syndrome, rash, lethargy, increased bleeding time and hypocalcemia
• The DLTs among subjects treated on the the CDD schedule are cognitive impairment, somnolence,
altered taste, slurred speech, and unsteady gait, proteinuria, rash, dyspnea, constipation, fatigue,
lethargy, myocardial toxicity, troponin elevation, ECG alterations, and nausea
• Overall, dasatinib demonstrated an acceptable safety profile when given orally on a BID regimen in
subjects with advanced malignancies
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Dasatinib
BMS-354825
CA180003
Clinical Study Report
• No objective tumor responses were reported; long-lasting stabilization of disease was noted in some
subjects
• Pharmacokinetic parameters of dasatinib administered on the 5D2 and CDD schedules were reasonably
comparable. The PK parameters of dasatinib in solid tumor subjects were similar to PK parameters
obtained in CML subjects
• Administration of dasatinib with a high-fat breakfast had no clinically significant effect on the
exposure (AUC) of dasatinib
• Administration of dasatinib with famotidine under fasted condition markedly decreased the exposure
of dasatinib
• Administration of dasatinib with famotidine and a high-fat breakfast resulted in a larger decrease in
Cmax than in AUC; administration of dasatinib with famotidine and aluminum hydroxide/magnesium
hydroxide also resulted in a larger decrease in Cmax than in AUC
DATE OF REPORT: 19-Dec-2007
Approved v1.0 930024906 2.0