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Biomarker‐driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer
Ist Teil von
Cancer medicine (Malden, MA), 2012-10, Vol.1 (2), p.207-217
Ort / Verlag
United States: Blackwell Publishing Ltd
Erscheinungsjahr
2012
Link zum Volltext
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
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.
We conducted a multicenter phase II clinical trial of saracatinib in gemcitabine‐resistant metastatic pancreas cancer patients. Initially, the trial was conducted in unselected patients. Due to lack of a minimum number of patients achieving a 6‐month overall survival endpoint in the first 17 patients, the study was amended and a biomarker‐driven study based on human tumor explant experiments was conducted. The study was closed due to a low number of biomarker‐positive patients, but demonstrates the feasibility of prospective biomarker (DNA) testing study in pancreas cancer.