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A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas

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Abstract

Purpose

A multi-cohort phase II study of fostamatinib, an oral multi-kinase inhibitor, was conducted to determine the response rate in patients with advanced colorectal (CRC), thyroid, non-small cell lung, head and neck, and renal cell carcinomas, and pheochromocytomas.

Methods

Patients received 200 mg fostamatinib BID in 4-week cycles with response assessed every 2 cycles. Blood was collected for pharmacokinetic analysis and measurements of circulating tumor cells and circulating endothelial (progenitor) cells (CE(P)Cs).

Results

A total of 37 patients (22 CRC), median of 4 prior therapies, were enrolled. Due to toxicities in four of the first five patients, the study was amended to incorporate a dose escalation phase for each histology. The maximum-tolerated dose was established at 50 mg BID in CRC but was not established for the other cancers. Common grade 3/4 toxicities included transaminitis, hyperbilirubinemia, and hypertension. Pharmacokinetic profile was similar to previous reports. Seventy-three percent of CRC patients had liver involvement and 91 % had prior anti-angiogenic therapy. Patients with abnormal liver tests at baseline were more likely to experience grade ≥2 hepatotoxicity than those with normal tests (44 vs. 0 %). No responses were observed; disease stabilization rate was 27 % in CRC. Reduction in CECs following treatment was associated with a better disease stabilization rate (75 vs. 0 %) in CRC.

Conclusion

Fostamatinib had limited anti-tumor activity in this first clinical trial in patients with advanced refractory solid tumors; reduction in CECs and CEPs was indicative of anti-angiogenic effects. Abnormal liver testing at baseline appeared to influence drug tolerability.

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References

  1. Sweeny DJ, Li W, Clough J, Bhamidipati S, Singh R, Park G, Baluom M, Grossbard E, Lau DT (2010) Metabolism of fostamatinib, the oral methylene phosphate prodrug of the spleen tyrosine kinase inhibitor R406 in humans: contribution of hepatic and gut bacterial processes to the overall biotransformation. Drug Metab Dispos Biol Fate Chem 38:1166–1176

    Article  PubMed  CAS  Google Scholar 

  2. Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C, Wong BR, Lovell S, Sun T, Park G, Argade A, Jurcevic S, Pine P, Singh R, Grossbard EB, Payan DG, Masuda ES (2006) R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 319:998–1008

    Article  PubMed  CAS  Google Scholar 

  3. Clemens GR, Schroeder RE, Magness SH, Weaver EV, Lech JW, Taylor VC, Masuda ES, Baluom M, Grossbard EB (2009) Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing. Birth Defects Res A Clin Mol Teratol 85:130–136

    Article  PubMed  CAS  Google Scholar 

  4. Wang X, Mychajlowycz M, Lau C, Gutierrez C, Scott JA, Chow CW (2012) Spleen tyrosine kinase mediates BEAS-2B cell migration and proliferation and human rhinovirus-induced expression of vascular endothelial growth factor and interleukin-8. J Pharmacol Exp Ther 340:277–285

    Article  PubMed  CAS  Google Scholar 

  5. Fruchon S, Kheirallah S, Al Saati T, Ysebaert L, Laurent C, Leseux L, Fournie JJ, Laurent G, Bezombes C (2012) Involvement of the Syk-mTOR pathway in follicular lymphoma cell invasion and angiogenesis. Leukemia 26:795–805

    Article  PubMed  CAS  Google Scholar 

  6. Alley M, Hollingshead M, Pacula-Cox C, Carter J, Jacob W, Pine P (2008) Preclinical pharmacologic evaluations of R406/R788, a multi-kinase inhibitor which exhibits unique, differential in vitro anticancer activity as well as in vivo antitumor efficacy following oral adminstration. In: American Association for Cancer Research Meeting. April 12–16, 2008, San Diego, Abstract 4889

  7. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA (2010) Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115:2578–2585

    Article  PubMed  CAS  Google Scholar 

  8. Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB (2009) Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 113:3154–3160

    Article  PubMed  CAS  Google Scholar 

  9. Weinblatt ME, Kavanaugh A, Burgos-Vargas R, Dikranian AH, Medrano-Ramirez G, Morales-Torres JL, Murphy FT, Musser TK, Straniero N, Vicente-Gonzales AV, Grossbard E (2008) Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthr Rheum 58:3309–3318

    Article  CAS  Google Scholar 

  10. Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB (2010) An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med 363:1303–1312

    Article  PubMed  CAS  Google Scholar 

  11. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  12. Kummar S, Gutierrez ME, Chen A, Turkbey IB, Allen D, Horneffer YR, Juwara L, Cao L, Yu Y, Kim YS, Trepel J, Chen H, Choyke P, Melillo G, Murgo AJ, Collins J, Doroshow JH (2011) Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. Eur J Cancer 47:997–1005

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Baluom M, Samara E, Grossbard EB, Lau DT (2011) Fostamatinib, a Syk-kinase inhibitor, does not affect methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Clin Pharmacol 51:1310–1318

    Article  PubMed  CAS  Google Scholar 

  15. Geahlen RL (2009) Syk and pTyr’d: signaling through the B cell antigen receptor. Biochim Biophys Acta 1793:1115–1127

    Article  PubMed  CAS  Google Scholar 

  16. Ghosh D, Tsokos GC (2010) Spleen tyrosine kinase: an Src family of non-receptor kinase has multiple functions and represents a valuable therapeutic target in the treatment of autoimmune and inflammatory diseases. Autoimmunity 43:48–55

    Article  PubMed  CAS  Google Scholar 

  17. Dome B, Timar J, Ladanyi A, Paku S, Renyi-Vamos F, Klepetko W, Lang G, Dome P, Bogos K, Tovari J (2009) Circulating endothelial cells, bone marrow-derived endothelial progenitor cells and proangiogenic hematopoietic cells in cancer: from biology to therapy. Crit Rev Oncol Hematol 69:108–124

    Article  PubMed  Google Scholar 

  18. Ergun S, Hohn HP, Kilic N, Singer BB, Tilki D (2008) Endothelial and hematopoietic progenitor cells (EPCs and HPCs): hand in hand fate determining partners for cancer cells. Stem Cell Rev 4:169–177

    Article  PubMed  Google Scholar 

  19. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7:101–111

    PubMed  CAS  Google Scholar 

  20. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785–1787

    Article  PubMed  CAS  Google Scholar 

  21. Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26:4899–4905

    Article  PubMed  CAS  Google Scholar 

  22. Ronzoni M, Manzoni M, Mariucci S, Loupakis F, Brugnatelli S, Bencardino K, Rovati B, Tinelli C, Falcone A, Villa E, Danova M (2010) Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann Oncol 21:2382–2389

    Article  PubMed  CAS  Google Scholar 

  23. Torrisi R, Bagnardi V, Cardillo A, Bertolini F, Scarano E, Orlando L, Mancuso P, Luini A, Calleri A, Viale G, Goldhirsch A, Colleoni M (2008) Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity. Br J Cancer 99:1564–1571

    Article  PubMed  CAS  Google Scholar 

  24. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, Lahdenranta J, Chung DC, Fischman AJ, Lauwers GY, Shellito P, Czito BG, Wong TZ, Paulson E, Poleski M, Vujaskovic Z, Bentley R, Chen HX, Clark JW, Jain RK (2009) Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27:3020–3026

    Article  PubMed  CAS  Google Scholar 

  25. Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP, Jain RK (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27:3027–3035

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This project has been funded in whole or in part with federal funds from the National cancer institute, National institutes of health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the department of health and human services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, 3A44, Bethesda, MD, 20892, USA

    Sook Ryun Park, Giovanna Speranza, Richard Piekarz, John J. Wright, Jerry Collins, James H. Doroshow & Shivaani Kummar

  2. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Jane B. Trepel, Min-Jung Lee, Sylvia Alarcon, Seth M. Steinberg, James H. Doroshow & Shivaani Kummar

  3. Applied/Developmental Research Directorate, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Robert J. Kinders, Lihua Wang & Thomas Pfister

Authors
  1. Sook Ryun Park
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  2. Giovanna Speranza
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  3. Richard Piekarz
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  4. John J. Wright
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  7. Thomas Pfister
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  8. Jane B. Trepel
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  9. Min-Jung Lee
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  12. Jerry Collins
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  13. James H. Doroshow
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  14. Shivaani Kummar
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Corresponding author

Correspondence to Shivaani Kummar.

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Park, S.R., Speranza, G., Piekarz, R. et al. A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas. Cancer Chemother Pharmacol 71, 981–990 (2013). https://doi.org/10.1007/s00280-013-2091-3

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  • DOI: https://doi.org/10.1007/s00280-013-2091-3

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