Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors.
OBJECTIVE
To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists.


METHODS
In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing.


RESULTS
Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.


CONCLUSIONS
Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.
Demetri
George D
GD
Ludwig Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. gdemetri@partners.org
Lo Russo
Patricia
P
MacPherson
Iain R J
IR
Wang
Ding
D
Morgan
Jeffrey A
JA
Brunton
Valerie G
VG
Paliwal
Prashni
P
Agrawal
Shruti
S
Voi
Maurizio
M
Evans
T R Jeffry
TR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib