Effect of PHY906 on capecitabine (CAP)-induced diarrhea in patients with GI malignancies

Abstract

e20595 Background: 15.4% of pts with GI cancers treated with CAP alone at 1250mg/m2 BID D1–14 q 3 wks (14/7) develop G3/4 diarrhea (Hoff et al. JCO, 2001). PHY906 composed of 4 herbs, Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Ziziphus jujuba Mill., and Paeonia lactiflora Palla, has been used to treat diarrhea since approximately 300AD. Preliminary studies showed synergistic activity of PHY906 with chemotherapeutics and reduction of chemotherapy-induced GI toxicities, especially chemotherapy-induced diarrhea (CID). Methods: We prospectively evaluated 44 pts treated on a clinical study with CAP plus PHY906 for diarrhea (experimental arm) and compared to historical data by Hoff et al., CAP 14/7 alone arm (control arm). Experimental arm consisted of pts with refractory solid tumors in phase I and gemcitabine-refractory advanced pancreatic cancer (APC) in phase II. Ph I pts received PHY906 800mg BID D1–4 with escalating doses of CAP (1000mg/m2→1250mg/m2→1500 mg/m2→1750mg/m2 BID) D1 -7 q 2 wks (7/7), until MTD. Ph II treated pts with APC at 1500 mg/m2 and PHY906 800mg BID D1–4. Toxicity was assessed per NCI-CTCAE-v3.0. In addition, correlative chemokine (IL-2, IL-4, IL-5, etc) levels will be quantified by cytometric bead array. Results: 44 pts (30M/14F; median 64yr) received 209 cycles (median:3, r:<1–14) of PHY906 in the four CAP-7/7 escalation cohorts in Phase I (19 pts), then at the MTD of 1500mg/m2 BID in Phase II (25 pts). Phase I pts had GI malignancies; 15 (63%) had APC and 6 (25%) colorectal. Of all phase I and phase II pts, G3/4 diarrhea was observed in 5 (11.4%) pts, without G3/4 constipation. One pt with APC who received 3 cycles at the 1500mg/m2 dose level was diarrhea-free until he was removed from the study; he continued on single-agent CAP at 1000mg/m2 BID and developed G3 diarrhea. Conclusions: In this study, G3/4 diarrhea was reduced by 19.5% in pts treated with PHY906 (experimental arm) when combined with CAP 7/7 compared to historical controls (control arm). As an underlying mechanism of CID may include cytokine activation, evalation of cytokines is ongoing. [Table: see text]