Skip to main content

Advertisement

SpringerLink
Log in

A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer

  • PHASE II STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. Methods Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). Results Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. Conclusions Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (2010) SEER Cancer Statistics Review, 1975–2007, based on November 2009 SEER data submission, posted to the SEER web site. National Cancer Institute http://seer.cancer.gov/csr/1975_2007/index.html. Accessed November 18 2010

  2. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (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(6):2403–2413

    PubMed  CAS  Google Scholar 

  3. Colucci G, Labianca R, Di Costanzo F, Gebbia V, Carteni G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolo M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28 (10):1645–1651. doi:10.1200/JCO.2009.25.4433

  4. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O’Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd (2009) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27(23):3778–3785. doi:10.1200/JCO.2008.20.9007

    Article  PubMed  CAS  Google Scholar 

  5. 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):5513–5518. doi:10.1200/JCO.2009.24.2446

    Article  PubMed  CAS  Google Scholar 

  6. Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 28 (22):3605–3610. doi:10.1200/JCO.2009.25.7550

  7. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 28 (22):3617–3622. doi:10.1200/JCO.2010.28.1386

  8. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966. doi:10.1200/JCO.2006.07.9525

    Article  PubMed  CAS  Google Scholar 

  9. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. doi:10.1158/0008-5472.CAN-04-1443

    Article  PubMed  CAS  Google Scholar 

  10. He AR, Lindenberg AP, Marshall JL (2008) Biologic therapies for advanced pancreatic cancer. Expert Rev Anticancer Ther 8(8):1331–1338. doi:10.1586/14737140.8.8.1331

    Article  PubMed  CAS  Google Scholar 

  11. Klimstra DS, Longnecker DS (1994) K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 145(6):1547–1550

    PubMed  CAS  Google Scholar 

  12. Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, Kern SE (1997) Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 57(9):1731–1734

    PubMed  CAS  Google Scholar 

  13. Ulivi P, Arienti C, Amadori D, Fabbri F, Carloni S, Tesei A, Vannini I, Silvestrini R, Zoli W (2009) Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines. J Cell Physiol 220(1):214–221. doi:10.1002/jcp.21753

    Article  PubMed  CAS  Google Scholar 

  14. Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, Lathia C, Petrenciuc O, Moore MJ (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 12(1):144–151. doi:10.1158/1078-0432.CCR-05-1571

    Article  PubMed  CAS  Google Scholar 

  15. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10

    Article  PubMed  CAS  Google Scholar 

  16. Huang S, Sinicrope FA Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells. Mol Cancer Ther 9 (3):742–750. doi:10.1158/1535-7163.MCT-09-1004

  17. Kindler HL, Wroblewski K, Wallace JA, Hall MJ, Locker G, Nattam S, Agamah E, Stadler WM, Vokes EE Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs. doi:10.1007/s10637-010-9526-z

  18. Kindler HL, Wroblewski K, Wallace JA, Hall MJ, Locker G, Nattam S, Agamah E, Stadler WM, Vokes EE Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs. doi:10.1007/s10637-010-9526-z

  19. Conroy T, Desseigne F, Ychou M, Ducreux M, Bouche O, Guimbaud R, Becouarn Y, Montoto-Grillot C, Gourgou-Bourgade S, Adenis A Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. Abstract #4010. In: Proceedings of the American Society of Clinical Oncology, 2010.

  20. Philip PA, Mooney M, Jaffe D, Eckhardt G, Moore M, Meropol N, Emens L, O'Reilly E, Korc M, Ellis L, Benedetti J, Rothenberg M, Willett C, Tempero M, Lowy A, Abbruzzese J, Simeone D, Hingorani S, Berlin J, Tepper J (2009) Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol 27(33):5660–5669. doi:10.1200/JCO.2009.21.9022

    Article  PubMed  Google Scholar 

  21. Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V (1995) Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22(4 Suppl 11):3–10

    PubMed  CAS  Google Scholar 

  22. Rosell R, Scagliotti G, Danenberg KD, Lord RV, Bepler G, Novello S, Cooc J, Crino L, Sanchez JJ, Taron M, Boni C, De Marinis F, Tonato M, Marangolo M, Gozzelino F, Di Costanzo F, Rinaldi M, Salonga D, Stephens C (2003) Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 22(23):3548–3553. doi:10.1038/sj.onc.1206419

    Article  PubMed  CAS  Google Scholar 

  23. Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, Provencio M, Isla D, Taron M, Diz P, Artal A (2004) Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 10(4):1318–1325

    Article  PubMed  CAS  Google Scholar 

  24. Nakahira S, Nakamori S, Tsujie M, Takahashi Y, Okami J, Yoshioka S, Yamasaki M, Marubashi S, Takemasa I, Miyamoto A, Takeda Y, Nagano H, Dono K, Umeshita K, Sakon M, Monden M (2007) Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int J Cancer 120(6):1355–1363. doi:10.1002/ijc.22390

    Article  PubMed  CAS  Google Scholar 

  25. Kwon WS, Rha SY, Choi YH, Lee JO, Park KH, Jung JJ, Kim TS, Jeung HC, Chung HC (2006) Ribonucleotide reductase M1 (RRM1) 2464 G > A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines. Pharmacogenet Genomics 16(6):429–438. doi:10.1097/01.fpc.0000204999.29924.da

    Article  PubMed  CAS  Google Scholar 

  26. Bepler G, Zheng Z, Gautam A, Sharma S, Cantor A, Sharma A, Cress WD, Kim YC, Rosell R, McBride C, Robinson L, Sommers E, Haura E (2005) Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. Lung Cancer 47(2):183–192. doi:10.1016/j.lungcan.2004.07.043

    Article  PubMed  Google Scholar 

  27. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, Laurent GJ (2002) Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 22(10):1631–1636

    Article  PubMed  CAS  Google Scholar 

  28. Szczeklik W, Sanak M, Szczeklik A (2004) Functional effects and gender association of COX-2 gene polymorphism G-765 C in bronchial asthma. J Allergy Clin Immunol 114(2):248–253. doi:10.1016/j.jaci.2004.05.030

    Article  PubMed  CAS  Google Scholar 

  29. Hu Z, Miao X, Ma H, Wang X, Tan W, Wei Q, Lin D, Shen H (2005) A common polymorphism in the 3'UTR of cyclooxygenase 2/prostaglandin synthase 2 gene and risk of lung cancer in a Chinese population. Lung Cancer 48(1):11–17. doi:10.1016/j.lungcan.2004.09.004

    Article  PubMed  CAS  Google Scholar 

  30. Zhang W, Lee J, Schiller JH, Carbone DP, Chung CH, H. L Use of germline polymorphisms in VEGF to predict tumor response and progression-free survival in non-small cell lung cancer (NSCLC) patients treated with sorafenib: Subset pharmacogenetic analysis of Eastern Cooperative Oncology Group (ECOG) trial E2501. Abstract # 7607. In: Proceedings of The American Society of Clinical Oncology, 2010.

Download references

Funding

Supported in part by Grants No. NO1 CM-62209, P30CA033572 and P30CA14089 from the National Institutes of Health.

Disclosures

Dr. Heinz-Josef Lenz receives clinical trial funding from Bayer Phrmaceuticals. Dr. Anthony El-Khoueiry is on the speaker’s bureau for Bayer Pharmaceuticals. No other authors have conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 3440, Los Angeles, CA, 90033, USA

    A. B. El-Khoueiry, W. Zhang & H. J. Lenz

  2. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    R. K. Ramanathan

  3. Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    D. Y. Yang & H. J. Lenz

  4. City of Hope Cancer Center, Medical Oncology, Duarte, CA, USA

    S. Shibata

  5. Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MA, USA

    J. J. Wright

  6. UC Davis Cancer Center, Internal Medicine—Hematology/Oncology, Sacramento, CA, USA

    D. Gandara

Authors
  1. A. B. El-Khoueiry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. K. Ramanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Y. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. J. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Gandara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. J. Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. B. El-Khoueiry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

El-Khoueiry, A.B., Ramanathan, R.K., Yang, D.Y. et al. A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. Invest New Drugs 30, 1175–1183 (2012). https://doi.org/10.1007/s10637-011-9658-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-011-9658-9

Keywords

Search

Navigation