A phase I study of PHY906 as a modulator of irinotecan (CPT-11) in patients with advanced solid tumors.

e13571 Background: The goal of this phase I study was to determine the maximum tolerated dose (MTD) of the oral Chinese herbal medication PHY906 when combined with CPT-11. PHY906 has been used in Asia since 300 AD for symptoms including abdominal cramps, nausea/vomiting, and diarrhea. In this study, PHY906 was tested as a cytoprotective agent to reduce the GI toxicities of diarrhea and nausea/vomiting associated with CPT-11. Methods: Patients with metastatic/unresectable malignancies without standard treatment options were included and assigned to dose levels 1-5 with CPT-11 administered iv once every 2 weeks, beginning at a dose of 180 mg/m2 and escalating to 215 mg/m2 in dose level 4 and 250mg/m2 in dose level 5. PHY906 was administered orally twice daily on days 1-4 every 2 weeks from cycle 2 (cycle 1 in dose levels 4 and 5) starting at 1,200 mg twice per day and escalated to 1,800 mg twice daily in dose level 2 and 2,400 mg twice daily in dose levels 3 through 5. Extensive pharmacokinetic (PK) analyses were performed looking at the role of PHY906 on metabolism of CPT-11. Results: A total of 25 patients have been accrued to this study, and accrual is ongoing for dose level 4. Common treatment related grade 1 or 2 toxicities included anemia, fatigue, anorexia, nausea, and diarrhea. Grade 3 toxicities included leukopenia (n=2) and neutropenia (n=3). No grade 3 or higher diarrhea was noted in any dose level. In each of dose levels 1 and 2, one patient had grade 3 anorexia and nausea, and in dose level 3 one patient had grade 3 anorexia and vomiting. Grade 4 and 5 toxicities included leukopenia in dose level 2 (n=1) and febrile neutropenia in dose level 3 (n=1). PK analyses showed that PHY906 did not interfere with the metabolism or pharmacokinetics of CPT-11 as studied up to a total dose of 4.8 grams daily. No changes were observed in AUC levels of CPT-11 or its metabolites SN 38 and SN 38G. Conclusions: The combination of PHY906 with CPT-11 has been well tolerated with a manageable safety profile. Accrual is ongoing at higher CPT-11 doses to determine the optimal dose for the phase II study in patients with colon cancer. GI toxicities in the form of diarrhea and nausea/vomiting have been minimal. PK analysis reveals no interference of PHY906 on the metabolism of CPT- 11. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PhytoCeutica PhytoCeutica Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, sanofi-aventis Enzon, ImClone Systems, Merck, PhytoCeutica, Roche, Taiho Pharmaceutical