Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results : A phase I clinical trial

Abstract

Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m²) of a 28-day cycle (L₀). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L₀, however dasatinib was reduced to 50 mg (L_-1) given side effects observed in the first two patients. At L_-1, a DLT occurred in 1/6 patients and dose was re-escalated to L₀, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L₁) where 1/6 patients experienced a DLT. Although L₁ was tolerable, dose escalation was stopped as investigators felt L₁ was within the optimal therapeutic window. 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 Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer.

Keywords: Dasatinib; Dual Src and EGFR inhibition; Erlotinib; Pancreatic cancer.

Figure 1. Consolidated Standards of Reporting Trials Diagram

Study diagram listing number of eligible subjects enrolled onto the study, and numbers of patients in the safety, efficacy, and biomarker correlate analyses.

Figure 2. Antitumor Activity

(A) Best percentage change from baseline in the sum of all target lesions is presented for each efficacy evaluable patient on study. Solid and dashed lines represent the RECIST v1.1 definition for partial response and progressive disease, respectively. Although no responses were observed, eight (62%) of patients had reductions in tumor size suggesting the triplet combination has some antitumor activity in patients with advanced pancreatic carcinoma. (B) Kaplan-Meier analysis of progression-free survival (dashed red line) and overall survival (block solid line). The overall median progression-free survival was 3.6 months whereas the median overall survival was 8.0 months.

Figure 3. Preliminary DW-MRI results

ADC maps overlaid onto T₂-weighted anatomical images. The baseline and post-treatment mean ADC values and percent change from baseline are presented for each patient. The corresponding baseline and 8-week RECIST measurement, as well as percent change in tumor size is also presented. The expected inverse relationship between changes in ADC and tumor size is observed in all three patients. Notably, a measureable change in ADC for all three patients is detected after one treatment cycle, which corresponds to later changes in tumor size.