A Phase I Study of Dasatinib (D) in Combination with Weekly (w) Paclitaxel (P) for Patients (Pts) with Metastatic Breast Carcinoma (MBC): Activity Despite Prior Taxane Exposure.
Authors: Morris P. , Abbruzzi A. , Chang J. , Patil S. , D'Andrea G. , Dang C. , Gilewski T. , Modi S. , Seidman A. , Sklarin N. , Jeselsohn R. , Hudis C. , Fornier M. 
Published: December 2010

Abstract
Background: D is an inhibitor of multiple tyrosine kinases; BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Pre-clinical data show inhibition of BC cell lines; predominantly those of “basal-like” subtype or “triple-negative” (TN) and single agent activity has been seen in refractory MBC. In pre-clinical models, the combination of D and P had antitumor activity that was significantly better than either agent alone. We designed this phase 1 trial to translate this observation.Methods: Eligibility criteria included evaluable or measurable MBC with normal hepatic, renal, and bone marrow function, and ECOG PS 0-1. Prior taxane therapy (Rx), stable brain metastases and baseline neuropathy grade (G) ≤1 were allowed. Pts with pleural or pericardial effusions were excluded. wP 80 mg/m2 was given by 1-hr IV infusion 3 weeks out of 4 (1 cycle); D was given daily by mouth, starting with 70 mg and escalating 100 mg, 120 mg and 150 mg in cohorts of 3 pts, using a standard 3+3 dose escalation scheme. Supportive medications were given per institutional policy for wP. Where possible, pts discontinued inhibitors of CYP3A4. Safety assessments occurred q2 weeks; additional hematologic toxicity was assessed weekly. Toxicities were graded per CTCAE v3.0 and maximum tolerated dose (MTD) defined accordingly. Response was assessed after cycle 2 and every 3 cycles thereafter.Results: Nine evaluable pts (8 females, 1 male) have enrolled; median age 54 (range 35-67), median PS=1 (range 0-1). 6 pts received prior adjuvant chemoRx, 7 received prior chemoRx for MBC and only 3 were taxane-naïve. Pts received a median of 2 cycles (range 1-3). No dose limiting toxicity has been observed up to a daily D dose of 120 mg. The most common Rx-related toxicities have been hematologic and low G (table 1). 1 pt was admitted with G3 hypotension, urosepsis and G2 diarrhea, possibly Rx-related. Per protocol she continues on D 100mg. 5 of 6 (83%) pts treated with D ≥100mg developed diarrhea (2pts; G1, 3pts; G2). Other GI side-effects have been mild; 3pts G1 nausea, 1pt G2 vomiting. 8pts (89%) have complained of fatigue (6pts; G1, 1pt; G2, 1 pt; G3). 1pt developed G1 acneiform rash secondary to D. No pts have developed edema or effusions. 6 pts are evaluable for response; 2 stable disease and 1 partial response in a pt with TNBC who had received prior adjuvant taxane. Dose escalation continues.Conclusion: Our data show that treatment with wP and D is feasible in pts with MBC. The MTD has not yet been reached and dose escalation of D continues to the target dose of 150 mg daily. There is preliminary evidence of activity in TNBC. A phase II trial of wP and D will follow once a recommended dose level is reached.Common ToxicitiesAdverse EventTotal N(%)Grade 1 N(%)Grade 2 N(%)Grade 3 N(%)Grade 4 N(%)Grade 5 N(%)Anemia7 (78)5 (56)1 (11)1 (11) Leukopenia3 (33)2 (22)1 (11) Neutropenia1 (11) 1 (11) Thrombocytopenia1 (11)1 (11) Hypoalbuminemia2 (22)1 (11)1 (11) Alkaline Phosphatase2 (22)2 (22) ALT4 (44)3 (33)1 (11) AST5 (56)5 (56) Hyperglycemia8 (89)5 (56)3 (22) Hypophosphatemia3 (33) 2 (22)1 (11) Hypokalemia2 (22)1 (11) 1 (11) Diarrhea5 (56)2 (22)3 (33) Neuropathy7 (78)7 (78)
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5070.