Phase I Study of Irinotecan/5-Fluorouracil/Leucovorin (FOLFIRI) with Sunitinib for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

  • Sarbajit MukherjeeEmail author
  • Christos Fountzilas
  • Patrick M. Boland
  • Rohit Gosain
  • Kristopher Attwood
  • Wei Tan
  • Nikhil Khushalani
  • Renuka Iyer
Original Research Article



Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor. It is synergistic with chemotherapy in preclinical models. We hypothesized that sunitinib in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) would be a tolerable and effective regimen in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.


Since the outcomes of advanced gastric and GEJ adenocarcinoma patients are poor, we decided to study a combination of FOLFIRI + S, to establish tolerability and efficacy.

Patients and methods

This was a phase I study for patients with advanced chemo-naïve gastric or GEJ adenocarcinoma. Dose escalation used a standard 3 + 3 design. The primary objective was to determine the tolerability and safety of FOLFIRI + S. Secondary objectives were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).


A total of 23 patients participated in the study (male 78%, female 22%). The median age was 61 (range: 38–77) years. Median follow-up time was 67.5 (95% CI 58.9–76) months. The most frequently reported adverse events were anemia (78%; G3/4: 4%), neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%), and fatigue (52%; G3/4:17%). Two dose-limiting toxicities were noted each at dose level (DL) 1 and 1A, one at DL 1B, and three at DL 2. Maximum tolerated dose was determined at DL 1B. At the time of data reporting, 21 patients had died. The median OS and PFS were 12.4 (95% CI 8.9, 16.5) months and 6.2 (95% CI 3.4, 13.5) months, respectively. Of all patients, 35% (eight out of 23) had a partial response.


FOLFIRI + S has signs of clinical activity in patients with advanced gastric and GEJ adenocarcinoma, and the side-effect profile was similar to previously reported studies. Current treatment paradigms in gastric cancer probably negate further study of this regimen. identifier: NCT00524186.


Compliance with Ethical Standards


This study was support by a research grant from Pfizer, Inc. This work was partially supported by National Cancer Institute (NCI) Grant P30CA016056 involving the use of Roswell Park’s Bioanalytics, Metabolomics and Pharmacokinetics (BMPK).

Conflict of interest

Sarbajit Mukherjee: Research funding from National Comprehensive Cancer Network (NCCN) and North American Neuroendocrine Tumor Society (NANETS). Christos Fountzilas: Consultation for AstraZeneca—fees paid to the institute. Patrick M Boland: Research funding from Merck, Boehringer Ingelheim, Theradiagnostics—consulting fees Merrimack, Boston Biomedical. Nikhil Khushalani: Advisory Board: Array, BMS, HUYA, Merck, EMD Serono, Regeneron, Immunocore, Genentech Honorarium: Sanofi Data Safety Monitoring Board: Astra Zeneca Research Grants (to institute): BMS, Merck, Celgene, Regeneron, GSK, HUYA, Amgen, Novartis Stock Ownership: Bellicum, Mazor Robotics, Amarin, TransEnterix. Rohit Gosain, Kristopher Atwood, Wei Tan, Renuka Iyer: No potential conflicts of interest that might be relevant to the content of this article.

Supplementary material

11523_2019_692_MOESM1_ESM.pdf (110 kb)
Supplementary material 1 (PDF 110 kb)


  1. 1.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRefGoogle Scholar
  2. 2.
    Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26(9):1435–42.CrossRefGoogle Scholar
  3. 3.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36–46.CrossRefGoogle Scholar
  4. 4.
    Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267(16):10931–4.PubMedGoogle Scholar
  5. 5.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407(6801):242–8.CrossRefGoogle Scholar
  6. 6.
    Ohta M, Konno H, Tanaka T, Baba M, Kamiya K, Syouji T, et al. The significance of circulating vascular endothelial growth factor (VEGF) protein in gastric cancer. Cancer Lett. 2003;192(2):215–25.CrossRefGoogle Scholar
  7. 7.
    Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29(30):3968–76.CrossRefGoogle Scholar
  8. 8.
    Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):420–35.CrossRefGoogle Scholar
  9. 9.
    Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004;40(5):689–95.CrossRefGoogle Scholar
  10. 10.
    Zhang SXL, Gozal D, Sachleben LR, Rane M, Klein JB, Gozal E. Hypoxia induces an autocrine-paracrine survival pathway via platelet-derived growth factor (PDGF)-B/PDGF-beta receptor/phosphatidylinositol 3-kinase/Akt signaling in RN46A neuronal cells. FASEB J. 2003;17(12):1709–11.CrossRefGoogle Scholar
  11. 11.
    Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2(10):727–39.CrossRefGoogle Scholar
  12. 12.
    Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive. Féd J Clin Oncol. 2014;32(31):3520–6.CrossRefGoogle Scholar
  13. 13.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9.CrossRefGoogle Scholar
  14. 14.
    Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):490–9.CrossRefGoogle Scholar
  15. 15.
    Waddell T, Chau I, Cunningham D, Gonzalez D, Frances A, Okines C, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):481–9.CrossRefGoogle Scholar
  16. 16.
    Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(11):1467–82.CrossRefGoogle Scholar
  17. 17.
    Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. 2017;3(5):620–7.CrossRefGoogle Scholar
  18. 18.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Moehler M, Gepfner-Tuma I, Maderer A, Thuss-Patience PC, Ruessel J, Hegewisch-Becker S, et al. Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program. BMC Cancer. 2016;16:699.CrossRefGoogle Scholar
  20. 20.
    Yoon HH, Bendell JC, Braiteh FS, Firdaus I, Philip PA, Cohn AL, et al. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol. 2016;27(12):2196–203.CrossRefGoogle Scholar
  21. 21.
    Shen L, Li J, Xu J, Pan H, Dai G, Qin S, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015;18(1):168–76.CrossRefGoogle Scholar
  22. 22.
    Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35.CrossRefGoogle Scholar
  23. 23.
    Van Cutsem E, De Haas S, Kang YK, Ohtsu A, Tebbutt NC, Xu JM, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30(17):2119–27.CrossRefGoogle Scholar
  24. 24.
    Innocenti F, Ou FS, Qu X, Zemla TJ, Niedzwiecki D, Tam R, et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol. 2019;37(14):1217–27.CrossRefGoogle Scholar
  25. 25.
    Aparicio-Gallego G, Blanco M, Figueroa A, Garciá-Campelo R, Valladares-Ayerbes M, Grande-Pulido E, et al. New insights into molecular mechanisms of sunitinib-associated side effects. Mol Cancer Ther. 2011;10(12):2215–23.CrossRefGoogle Scholar
  26. 26.
    Koyasu S. The role of PI3K in immune cells. Nat Immunol. 2003;4(4):313–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Roswell Park Comprehensive Cancer CenterBuffaloUSA
  2. 2.H. Lee Moffitt Cancer CenterTampaUSA

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