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

Abstract

Purpose: Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC).

Methods: Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28).

Results: Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007).

Conclusions: The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Trial registration: ClinicalTrials.gov NCT00920868.

Conflict of interest statement

Conflict of Interest Statement: A.B. Nixon, H.E. Uronis, M.A. Morse and H. I. Hurwitz currently have research funding with Bristol-Myers Squibb (BMS). M.A. Morse has received honoraria for speaking from Bristol-Myers Squibb. All other authors have declared no conflict of interest with BMS.

Figures

Figure 1. (A): Control sample from benign epithelium (IHC Grade 0); (B)-(E) were obtained from tumor specimens of enrolled subjects: B) IHC Grade 0; C) IHC Grade 1; D) IHC Grade 2; E) IHC Grade 3

Figure 2. Patient with metastatic cholangiocarcinoma to lung

Figure 3. Clinical activity of dasatinib, capecitabine, oxaliplatin, and bevacizumab

* Clinical progression prior to first restaging Best response by srcact status for 20 evaluable subjects. Cohort: Exp (expansion), Esc (dose escalation); Dx (Diagnosis): COL (colon cancer), GB (gallbladder cancer), GI (adenocarcinoma of the small bowel), PANC (pancreatic cancer), RECT (rectal cancer); Prior lines (number of prior lines of treatment for metastatic disease); srcact (activated src expression): 0=none; 1= weak/faint; 2= moderate; 3= strong/circumferential; KRAS: n/a (not assessed), MUT (mutation detected), WT (no mutation detected).