Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 2, pp 373–380 | Cite as

First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer

  • Muhammad Wasif Saif
  • Jia Li
  • Lynne Lamb
  • Kristin Kaley
  • Kyle Elligers
  • Zaoli Jiang
  • Scott Bussom
  • Shwu-Huey Liu
  • Yung-Chi Cheng
Original Article



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.


Capecitabine 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. 1.
    American Cancer Society (2013) Cancer facts and figures 2013. American Cancer Society, AtlantaGoogle Scholar
  2. 2.
    Burris HA 3rd, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  3. 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. 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
  5. 5.
    Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ (2002) Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 20(1):160–164PubMedCrossRefGoogle Scholar
  6. 6.
    Boeck S, Wilkowski R, Bruns CJ, Issels RD, Schulz C, Moosmann N, Laessig D, Haas M, Golf A, Heinemann V (2007) Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer. Oncology 73(3–4):221–227PubMedCrossRefGoogle Scholar
  7. 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. 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. 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. 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. 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. 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
  13. 13.
    Yen Y, So S, Rose M, Saif MW, Chu E, Liu SH, Foo A, Jiang Z, Su T, Cheng YC (2009) Phase I/II study of PHY906/capecitabine in advanced hepatocellular carcinoma. Anticancer Res 29(10):4083–4092PubMedGoogle Scholar
  14. 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. 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
  16. 16.
    Saif MW, Lansigan F, Ruta S, Lamb L, Mezes M, Elligers K, Grant N, Jiang ZL, Liu SH, Cheng YC (2010) Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies. Phytomedicine 17(3–4):161–169PubMedCrossRefGoogle Scholar
  17. 17.
  18. 18.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  19. 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
  20. 20.
    Morgan E, Varro R, Sepulveda H, Ember JA, Apgar J, Wilson J, Lowe L, Chen R, Shivraj L, Agadir A, Campos R, Ernst D, Gaur A (2004) Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol 110(3):252–266PubMedCrossRefGoogle Scholar
  21. 21.
    Kang SP, Saif MW (2008) Optimal second line treatment options for gemcitabine refractory advanced pancreatic cancer patients. Can we establish standard of care with available data? JOP 9(2):83–90PubMedGoogle Scholar
  22. 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
  23. 23.
    Traina TA, Theodoulou M, Feigin K et al (2008) Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer. J Clin Oncol 26(11):1797–1802PubMedCrossRefGoogle Scholar
  24. 24.
    Le J, Vilcek I (1989) Interleukin-6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 61:588–602PubMedGoogle Scholar
  25. 25.
    Berek JS, Chung C, Kaldi K, Watson JM, Knox RM, Martínez-Maza O (1991) Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. Am J Obstet Gynecol 164(4):1038–1042 discussion 1042–3PubMedCrossRefGoogle Scholar
  26. 26.
    Martínez-Maza O, Berek JS (1991) Interleukin 6 and cancer treatment. In Vivo 5(6):583–588PubMedGoogle Scholar
  27. 27.
    Strassmann G, Fong M, Kenney JS, Jacob CO (1992) Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89(5):1681PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Gougelet A, Mansuy A, Blay JY (2008) Interleukin-6 and epithelial tumours: new convincing arguments in favour of the use of IL-6 targeted therapies. Med Sci (Paris) 24(8–9):694–696CrossRefGoogle Scholar
  29. 29.
    Jarboe J, Saif MW (2013) First line therapy for metastatic pancreatic cancer. JOP 14(4):340–343PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Muhammad Wasif Saif
    • 1
  • Jia Li
    • 2
  • Lynne Lamb
    • 3
  • Kristin Kaley
    • 3
  • Kyle Elligers
    • 3
  • Zaoli Jiang
    • 3
  • Scott Bussom
    • 3
  • Shwu-Huey Liu
    • 4
  • Yung-Chi Cheng
    • 3
  1. 1.Section of GI Cancers and Experimental TherapeuticsTufts University School of MedicineBostonUSA
  2. 2.VA Connecticut Healthcare SystemWest HavenUSA
  3. 3.Yale University School of MedicineNew HavenUSA
  4. 4.Phytoceutica Inc.New HavenUSA

Personalised recommendations