BACKGROUND: AZD0530 is a potent oral aniline quinazoline that is highly selective for the Src family of nonreceptor tyrosine kinases. In colorectal carcinoma, Src kinase activation plays a critical role in tumor cell migration and invasion and has been correlated with disease stage, with the highest activity in metastatic disease. Src is also an adverse prognostic indicator for disease-free survival (DFS) and overall survival (OS). Preclinically, Src inhibitors have been determined to have synergistic activity when combined with chemotherapy and/or biologic therapy. Src is involved in the transcription of VEGF through phosphorylation of STAT3, as well as increasing STAT3/HIF complexes leading to upregulation of VEGF. Hence, inhibition of Src kinase would appear to be a potential therapeutic target in the treatment of metastatic colorectal cancer (MCRC). METHODS: A NCI sponsored single institution phase II study of AZD0530 was conducted in MCRC patients (pts). Eligibility criteria included measurable disease, receipt of one prior chemotherapy regimen for metastatic disease; ECOG PS 0-2, and adequate organ function. Pts with brain metastases were excluded. The primary objective was progression-free survival (PFS); secondary objectives included response rate (RR) and overall survival (OS). Pts received AZD0530, 175 mg Po daily; one cycle was equivalent to 28-days. Pts were evaluated for radiological response by RECIST criteria every 8 weeks. A Bayesian statistical design was utilized. Optional laboratory correlatives included blood and tissue samples assessing the downstream effects of AZD0530 on focal adhesion kinases (FAK, paxillin), adherens junctions (E-cadherin), IL-8, STAT-3, VEGF, and CD31. RESULTS: Ten pts were enrolled; 6M:4F. The median age was 60 yrs (range 46-70). Median number of cycles administered was 2. All pts were evaluated for toxicity and response. Grade 3 toxicities included: hypophosphatemia (n=6), hypocalcemia (n=1), hyponatremia (n=2), nausea (n=1), and leukopenia (n=1). Three pts (30%) required a dose reduction. One pt developed a bowel perforation resulting in grade 4 sepsis attributed to progression of disease (PD); one pt died within 28 days of treatment, but radiographic studies confirmed PD. All pts demonstrated PD following < 2 cycles of therapy. Seven pts proceeded to receive 3rd line chemotherapy. The median PFS was 7.9 weeks; the median overall survival has not been reached to date. CONCLUSION: The novel oral Src kinase inhibitor, AZD0530, has minimal activity as a single agent in this population of patients with metastatic colorectal cancer. However, given the existing preclinical data suggesting a role for Src kinase in colorectal cancer, AZD0530 should be evaluated in combination with chemotherapy and/or biologic therapy. Final results including laboratory correlatives will be presented. Supported by NCI Grant N01-CM-62202.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA