Background: The combination of E with G remains the only approved targeted therapy for PC based on significant, yet modest, improved overall survival when compared to G alone in a phase III clinical trial. We have shown previously that adding the Src inhibitor D with E and G resulted in synergistic attenuation of tumor growth in vivo. The purpose of this study was to assess the safety of D given with E and G. Methods: This investigator-initiated study used 3+3 dose-escalation to determine the maximum tolerated dose in advanced PC patients (pts). Dose escalation started at 70 mg daily of D, 100 mg daily of E, and G on days 1, 8, and 15 (800 mg/m²) of a 28-day cycle. Diffusion-weighted MRI (DW-MRI) measurements (ADC) were collected prior to and at four weeks in a subset of pts (n=3). Results: Nineteen pts were enrolled. One pt experienced a DLT at the starting dose (L₀); however, given the side effects observed in the first two pts, D was reduced to 50 mg (L_-1). At L_-1, one DLT was observed in 1/6 pts and the dose was re-escalated to L₀. Zero DLTs were observed in the next four pts at L₀ thus D was escalated to 100 mg (L₁). Seven pts were treated at L₁ as one pt was not evaluable for safety. In this cohort, 1/6 pts experienced a DLT. Although L₁ was tolerable, dose escalation was stopped as it was felt L₁was within the therapeutic window and escalation would enhance toxicity with minimal benefit. Most frequent toxicities (%) were anemia (89), elevated aspartate aminotransferase (79), fatigue (79), nausea (79), elevated alanine aminotransferase (74), lymphopenia (74), leukopenia (74), neutropenia (63), and thrombocytopenia (63), most Gr1/2. Zero responses were observed, but disease stabilization (SD) occurred in 9/13 (69%). Median duration of SD was 4 months, and median OS was 7.7 mos. At the time of data cutoff, two pts are still alive and in follow-up. Increase in ADC on MRI reflected a decrease in tumor cellularity suggesting therapeutic benefit; disease assessment at 8 weeks was SD. Conclusions: The most tolerable dose was determined to be 70 mg of D, 100 mg of E, and 800 mg/m² of G. Clinical activity of this combination was observed as SD occurred in 69% of pts. DW-MRI could be a promising technique to assess clinical benefit early during the course of therapy. Clinical trial information: NCT01660971