Phase I study of dasatinib in combination with capecitabine, oxaliplatin, and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.

Journal Article

513 Background: SRC is a non-receptor tyrosine kinase involved in normal and tumor cell signaling functions including cell proliferation, angiogenesis and survival. Dasatinib (D) is a potent inhibitor of SRC kinase activity. Preclinical data suggests the addition of D to standard chemotherapy agents for colon cancer may increase anti-tumor activity. We evaluated D in combination with capecitabine (C), oxaliplatin (O) and bevacizumab (B) in a phase I dose escalation study followed by an expanded cohort in 1st line colorectal.For dose escalation, eligible patients had advanced solid tumors with adequate organ and bone marrow function and no increased risk for class-related toxicities. B and O were given intravenously, and C and D were orally administered; cycle length was 21 days. C was dosed at 850 mg/m2 on days 1-14; O was dosed at 130 mg/m2 and B was dosed at 7.5 mg/kg on day one of each cycle. D was dosed at 50 mg twice daily in cohort one and 70 mg once daily in cohort -1. Dose limiting toxicity (DLT) was assessed in cycle 1.Dose escalation is complete with 10 subjects evaluable for toxicity and 11 subjects evaluable for efficacy. Two DLTs were observed out of 5 evaluable subjects in cohort one. Six evaluable subjects were enrolled in the -1 cohort with 1 DLT. Possible grade ≥ 3 treatment-related adverse events (AEs) included neutropenia, febrile neutropenia, anorexia, diarrhea, fatigue, anemia, hypophosphatemia, hyponatremia and grade 5 GI-perforation. One non-treatment related death was due to disease progression. D-related nausea and fatigue were responsive to low dose oral steroids; fluid retention was responsive to diuretics. Of 10 subjects evaluable for efficacy, 1 subject had a partial response (PR), 2 had a minor response (MR), and 4 had stable disease (SD). Four subjects had disease control (PR, MR, or SD) ≥ 6 months.D in combination with C, O and B is well-tolerated with a toxicity profile similar to standard C, O and B.The recommended phase II dose is C at 850 mg/m2 on days 1-14, O at 130 mg/m2 and B at 7.5 mg/kg on day one of each cycle, and D at 70 mg once daily. Enrollment in the expanded cohort of 1st line colorectal is ongoing. [Table: see text].

Duke Authors

Cited Authors

  • Starodub, A; Cohn, AL; Arrowood, C; Haley, S; Morse, M; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, Y; Hurwitz, H

Published Date

  • February 2011

Published In

Volume / Issue

  • 29 / 4_suppl

Start / End Page

  • 513 -

PubMed ID

  • 27985744

Electronic International Standard Serial Number (EISSN)

  • 1527-7755

International Standard Serial Number (ISSN)

  • 0732-183X

Language

  • eng