First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer
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Preclinical studies showed a Chinese botanical formula, PHY906, has synergistic anti-tumor activity with capecitabine. Our phase I study determined maximal tolerated dose of capecitabine 1,500 mg/m2 BID day 1–7 and PHY906 800 mg BID day 1–4 every 2 weeks. We conducted this phase II study to explore the efficacy of capecitabine and PHY906 in patients with advanced pancreatic cancer who were previously treated with gemcitabine-based regimens.
Patients with pancreatic cancer and an Eastern Cooperative Oncology Group performance status of 0–2 received PHY906 and capecitabine. Toxicity was assessed per NCI-CTCAE v3.0 and response per response evaluation criteria in solid tumors q 6 weeks. Correlative studies of cytokines, chemokines and growth factors were tested using a cytometric bead array. Quality of life was assessed by utilizing Edmonton symptom assessment system. The primary objective was overall survival.
The study enrolled 25 patients. Median progression-free survival (mPFS) was 10.1 weeks (range 0.4–54.1) and median overall survival (mOS) was 21.6 weeks (range 0.4–84.1). Eighteen patients received at least 2 cycles, and achieved mPFS of 12.3 weeks and mOS of 28 weeks. Six-month survival rate was 44 % (11/25). Unsupervised clustering of patients grouped those with shortened survival together by their cytokine profile showed that only IL-6 had a significant difference (p < .001) between short- and long-term survivors.
Capecitabine plus PHY906 provides a safe and feasible salvage therapy after gemcitabine failure for APC. Role of IL-6 in tumor progression and tumor cachexia needs to be investigated with respect to its relation to pathophysiology of pancreatic cancer and development of anti-IL-6 therapeutics.
KeywordsCapecitabine PHY906 Herbal medicines Pancreatic cancer Diarrhea Hand-foot syndrome (HFS)
This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories; PO1CA154295; and Dr. Cheng is a Fellow of the National Foundation for Cancer Research.
- 1.American Cancer Society (2013) Cancer facts and figures 2013. American Cancer Society, AtlantaGoogle Scholar
- 3.Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H (2011) Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47(11):1676–1681PubMedCrossRefGoogle Scholar
- 4.Saif MW, Eloubeidi MA, Russo S, Steg A, Thornton J, Fiveash J, Carpenter M, Blanquicett C, Diasio RB, Johnson MR (2005) Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome. J Clin Oncol 23(34):8679–8687PubMedCrossRefGoogle Scholar
- 7.Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27(33):5513–5518PubMedCrossRefGoogle Scholar
- 8.Scheithauer W, Kornek GV, Raderer M, Schull B, Schmid K, Kovats E, Schneeweiss B, Lang F, Lenauer A, Depisch D (2003) Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 21(7):1307–1312PubMedCrossRefGoogle Scholar
- 9.Tempero MA, Arnoletti JP, Behrman SW, Ben-Josef E, Benson AB III, Casper ES, Cohen SJ, Czito B, Ellenhorn JD, Hawkins WG, Herman J, Hoffman JP, Ko A, Komanduri S, Koong A, Ma WW, Malafa MP, Merchant NB, Mulvihill SJ, Muscarella P II, Nakakura EK, Obando J, Pitman MB, Sasson AR, Tally A, Thayer SP, Whiting S, Wolff RA, Wolpin BM, Freedman-Cass DA, Shead DA (2012) National comprehensive cancer networks. Pancreatic adenocarcinoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 10(6):703–713PubMedCentralPubMedGoogle Scholar
- 10.Rilton R, Paiva AA, Guan J, Marathe R, Jiang Z, van Eyndhoven W, Bjoraker J, Wang H, Liu SH, Cheng Y-C (2010) PhytomicsQC: a comprehensive approach to define quality control of botanical drugs—a case study of PHY906. Chin Med 20(5):30Google Scholar
- 11.Zhang W, Saif MW, Dutschman GE, Li X, Lam W, Bussom S, Jiang Z, Ye M, Chu E, Cheng YC (2010) Identification of chemicals and their metabolites from PHY906, a Chinese medicine formulation, in the plasma of a patient treated with irinotecan and PHY906 using liquid chromatography/tandem mass spectrometry (LC/MS/MS). J Chromatogr A 1217(37):5785–5793PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, O’Rourke M, Brenckman W, Tilton R, Liu SH, Jiang Z, Su T, Cheng YC, Chu E (2011) A phase I study of the Chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorectal Cancer 10(2):85–96PubMedCrossRefGoogle Scholar
- 14.Liu S-H, Jiang Z, Gao W et al (2003) PHY906, a Chinese herbal formulation enhances the therapeutic effect of cancer chemotherapy in human colorectal and liver cancer. Proc Am Soc Clin Oncol. Abstr #864Google Scholar
- 15.Saif MW, Liu S, Elfiky A, Jiang Z, Cheng Y (2007) Synergistic activity of PHY906 with capecitabine in pancreatic carcinoma. J Clin Oncol; ASCO annual meeting proceedings part I. Vol 25, No. 18S (June 20 Supplement), 2007:15116Google Scholar
- 19.Moro C, Brunelli C, Miccinesi G, Fallai M, Morino P, Piazza M, Labianca R, Ripamonti C, Moro C, Brunelli C, Miccinesi G, Fallai M, Morino P, Piazza M, Labianca R, Ripamonti C (2006) Edmonton symptom assessment scale: Italian validation in two palliative care settings. Support Care Cancer 14(1):30–37PubMedCrossRefGoogle Scholar
- 22.Liu S-H, Jiang Z, Leung D, Lee Y, Cheng Y (2004) PHY906: enhancement of cancer chemotherapeutic agents and insights into mechanism of action. Proceedings of medicine in the 21st century tri-conference and bio-forum, vol 77Google Scholar