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Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: Results of a Phase II, randomized, noncomparative study

  • PHASE II STUDIES
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Summary

Purpose Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. Methods Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg PO daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m2 IV Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. Results Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3–4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment. Conclusions OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

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Acknowledgements

We thank our patients, US Oncology physicians (see Appendix), site coordinators (especially Mariel Sumner in Spokane, WA), project managers Staci Bell, Tamika Austin, and Debra Bailey, data reviewer Tracy Locke, and biostatistician Jessica Donato-Jensen. This trial was supported by Lilly USA, LLC.

Author information

Authors and Affiliations

  1. US Oncology Research, Inc., The Woodlands, TX, USA

    Donald A. Richards, Paul R. Kuefler, Carlos Becerra, Lalan S. Wilfong, Robert H. Gersh, Kristi A. Boehm, Feng Zhan & Lina Asmar

  2. Texas Oncology Tyler, 910 E. Houston Street, Suite 100, Tyler, TX, 75702, USA

    Donald A. Richards

  3. Northern Arizona Hematology Oncology Associates, Flagstaff, AZ, USA

    Paul R. Kuefler

  4. Baylor-Sammons Cancer Center, Dallas, TX, USA

    Carlos Becerra

  5. Texas Oncology, Dallas, TX, USA

    Lalan S. Wilfong

  6. Cancer Care Northwest, Spokane, WA, USA

    Robert H. Gersh

  7. Eli Lilly and Company and/or any of its subsidiaries, Indianapolis, IN, USA

    Scott P. Myrand, Rebecca R. Hozak, Luping Zhao, John F. Gill, Brian P. Mullaney, Coleman K. Obasaju & Steven J. Nicol

Authors
  1. Donald A. Richards
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Corresponding author

Correspondence to Donald A. Richards.

Additional information

This research was supported, in part, by a research grant from Lilly USA, LLC; Indianapolis, IN.

Appendix

Appendix

The following oncologists from the USOR network also participated in this study: Harvey, Jimmie H, Birmingham, AL; McKenzie, Barry A, Springfield, OR; Schlegel, Peter J, Spokane, WA; Barrera, David, Fort Worth, TX; Cartwright, Thomas H, Ocala, FL; Esler, Vance William, Amarillo, TX; Flores, Maria Regina C, Winter Park, FL; Flynn, Thomas P, Minneapolis, MN; Hyman, William J, Tyler, TX; Kocs, Darren, Austin, TX; McKenney, Scott A, Beaumont, TX; McMahon, Richard T, Littleton, CO; Negron, Angel G, Fort Worth, TX; Nugent, Francis W, Albany, NY; Obara, Gregory, Las Vegas, NV; Orlowski, Richard, Hickory, NC; Sandbach, John, Austin, TX; Sienko, Mark, Spokane, WA; Tellez, Claudia, Chicago, IL; Acevedo, Patrick V, Ocala, FL; Alemany, Carlos A, Orlando, FL; Aly, Elsayed, Indianapolis, IN; Amare, Mammo, Dallas, TX; Balazs, Andrea, Spokane, WA; Barnett, John, Longmont, CO; Beganovic, Sead, Indianapolis, IN; Berger, Maury B, Ocala, FL; Brandt, Debra Schwab, Torrington, CT; Buchanan, Glenn S, Eugene, OR; Busby, Leslie, Boulder, CO; Chakmakjian, Carl G, Waco, TX; Cichon, Jolanta U, Denton, TX; Cline-Burkhardt, Mika, Las Vegas, NV; Connor, Charles, Plano, TX; Danso, Michael A, Winter Park, FL; DeRosa, William, Morristown, NJ; Di Bella, Nicholas J, Aurora, CO; DiMento, Johanna, Flagstaff, AZ; Encarnacion, Carlos, Waco, TX; Ferris, Linda L, Winfield, IL; Foote, Lawrence E, Sugarland, TX; Forero, Leonardo, Amarillo, TX; Gesme, Dean H, Minneapolis, MN; Goldschmidt, Jerome H Jr, Christiansburg, VA; Gore, Ira Jr, Birmingham, AL; Goslin, Robert H, Amsterdam, NY; Greenfield, Bruce, Santa Fe, NM; Hakimian, David, Niles, IL; Harth, Cheryl A, Dallas, TX; Hellerstedt, Beth, Austin, TX; Howe, Craig WS, St Paul, MN; Hwang, Alice, Portland, OR; Jain, Sharad K, Denton, TX; Jensen, Cynthia L, New Port Richey, FL; Kahn, Michael, Winfield, IL; Kirkpatrick, Haskell, Dallas, TX; Kolibaba, Kathryn S, Vancouver, WA; Kumar, Aparna R, Tyler, TX; Lakhanpal, Shailendra, Birmingham, AL; Lavelle, Joseph W, Dayton/Kettering, OH; Lee†, Gary L, Eugene, OR; Loesch, David M, Indianapolis, IN; Markowitz, Daniel, Edmonds, WA; McCollum, Andrew D, Dallas, TX; Newman, Steven B, Chicago, IL; Overmoyer, Beth A, New Milford, CT; Parikh, Rupesh J, Henderson, NV; Patel, Mrugesh P, Bedford, TX; Raju, Robert N, Dayton/Kettering, OH; Reddy, Chandra, Terre Haute, IN; Reznick, Douglas, Parker, CO; Rotche, Robert M, Christiansburg, VA; Saidman, Bruce, Kingston, PA; Sanatinia, Hamidreza, Las Vegas, NV; Sanchez, James D, Las Vegas, NV; Schlossberg, Howard R, Rexford, NY; Shaffer, David R, Hudson, NY; Snyder, David A, Santa Fe, NM; Solipuram, Praveena R, Thornton, CO; Tebcherany, Dina J, Austin, TX; Tin-U, Caesar K, Sugarland, TX; Tucker, Kent A, Birmingham, AL; Turner, James M, Bedford, TX; Vongkovit, Piyapong, Hickory, NC; Vukelja, Svetislava Judith, Tyler, TX; Wang, Chiyu, Dallas, TX; Wangsness, John A, Maplewood, MN; Ward, Jeffery C, Edmonds, WA; Weissman, Charles H, Latham, NY; Wu, Nini CY, Albany, NY; Zander, Paul J, Minneapolis, MN.

† deceased

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Richards, D.A., Kuefler, P.R., Becerra, C. et al. Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: Results of a Phase II, randomized, noncomparative study. Invest New Drugs 29, 144–153 (2011). https://doi.org/10.1007/s10637-009-9307-8

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