Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer

Abstract

Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

Keywords: Biomarker; Src; clinical trial; pancreas cancer.

Figure 1

Kaplan–Meier survival curve of (A) overall survival and (B) progression-free survival.

Figure 2

Study design: in the unselected portion, 17 patients were enrolled in the study. To move on to enroll 34 patients at least three responses were required. Only two patients made it to the 6-month endpoint. Study was amended for a biomarker-driven study. Results from our preclinical study on 24 patient-derived pancreatic explants identified the KTSP classifier LRRC19 > IGFBP2 and PIK3CA mutant as markers of sensitivity. These markers were used to screen patients for the biomarker-driven study. One patient with a PIK3CA mutation was enrolled in the study.

Figure 3

(A) Representative figure of patients archival tumor or fresh liver biopsies analyzed for LRRC19 > IGFBP2 and (B) PIK3CA mutation (3′ UTR) of PH1715 (patient enrolled in the biomarker portion of the study).