A phase I/II study of PHY906 plus capecitabine (CAP) in patients (pts) with advanced pancreatic cancer (APC)

Abstract

15538 Background: PHY906 is a formulation of traditional Chinese medicine botanicals: Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Ziziphus jujuba Mill., and Paeonia lactiflora Palla. Our preclinical studies have indicated that PHY906 has synergistic anti-tumor activity with CAP in PANC-1 cell lines (Saif MW. ASCO 2007) and is a potent inhibitor of NF-κB. Studies in other tumor types have shown that PHY906 may reduce chemotherapy-induced GI toxicities, especially diarrhea and does not alter pharmacokinetics of CAP. These data have prompted phase I/II evaluation of safety and tolerability of a dose intense wkly (7/7) schedule for CAP plus PHY906. Methods: During phase I study, pts with advanced solid tumors (ST) who failed standard therapy or for which no standard therapy exists, ECOG PS ≤ 2, and adequate organ function were enrolled. Pts received PHY906 800 mg BID (D1–4) with escalating doses of CAP (1,000 mg/m2 →1,250 mg/m2 → 1,500 mg/m2 → 1,750 mg/m2 BID on D1 -7) followed by 7 days rest, until MTD was reached. During phase II study, pts with gemcitabine-refractory APC will be enrolled. Toxicity was assessed per NCI CTCAE v3.0 and response per RECIST q 6 wks. Results: To date, 23 pts [18 M/5 F; median age of 64 yr; PS 0: 7; PS 1: 14; PS 2: 2] have received 100 cycles [median (range)- 5 (1–18)] with PHY906 in 4 CAP (7/7) escalation cohorts: 1,000 mg/m2 (n = 6), 1,250 mg/m2 (n = 3), 1,500 mg/m2 (n = 6), and 1750 mg/m2 (n = 8). Dose-limiting toxicity (DLT) was observed in 1 of 6 pts at 1,000 mg/m2 dose [grade 4 AST/ALT]. No DLTs were seen at higher doses. However, delayed toxicities were seen at 1,750 mg/m2. Therefore, additional 3 pts have been added at 1,500 mg/m2 before moving onto the phase II part. Delayed grade ≥ 3 toxicities included hand-foot syndrome (n=3), nausea (n=3), mucositis (n=1), diarrhea (n=2), and hyperglycemia (n=2). One pt with cholangiocarcinoma had PR at cycle 3 and 9 pts experienced SD lasting ≥ 6 weeks (7 pancreas; 2 colon). Conclusions: Combination of CAP and PHY906 has acceptable toxicity in pts with ST. Phase II study will assess efficacy and quality of life in gemcitabine-refractory APC pts. Correlative chemokine (IL-2, IL-4, IL-5, IL-10, TNF-α, IFN-γ) levels, as surrogates for NF- κB expression, will be quantified by Cytometric Bead Array to help elucidate PHY906 mode of action. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Phytoceutica Phytoceutica Phytoceutica