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A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer

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Abstract

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.

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References

  1. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;3829893:709–19.

    Article  Google Scholar 

  2. Scagliotti GV, Novello S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev. 2012;384:292–302.

    Article  Google Scholar 

  3. Zhang Q, Pan J, Lubet RA, Wang Y, You M. Targeting the insulin-like growth factor-1 receptor by picropodophyllin for lung cancer chemoprevention. Mol Carcinog. 2014. doi:10.1002/mc.22206.

    Google Scholar 

  4. Tabernero J, Chawla SP, Kindler H, et al. Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab. Target Oncol. 2015;10(1):65–76.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Tran TN, Selinger CI, Yu B, et al. Alterations of insulin-like growth factor-1 receptor gene copy number and protein expression are common in non-small cell lung cancer. J Clin Pathol. 2014;67(11):985–91.

    Article  CAS  PubMed  Google Scholar 

  6. Agullo-Ortuno MT, Diaz-Garcia CV, Agudo-Lopez A, et al. Relevance of insulin-like growth factor 1 receptor gene expression as a prognostic factor in non-small-cell lung cancer. J Cancer Res Clin Oncol. 2015;141(1):43–53.

    Article  CAS  PubMed  Google Scholar 

  7. Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 2004;641:236–42.

    Article  Google Scholar 

  8. Johnson EA, Marks RS, Mandrekar SJ, et al. Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Lung Cancer. 2008;602:200–7.

    Article  Google Scholar 

  9. Ekman S, Frodin JE, Harmenberg J, et al. Clinical phase I study with an insulin-like growth factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma. Acta Oncol. 2011;503:441–7.

    Article  Google Scholar 

  10. Gascoigne KE, Taylor SS. How do anti-mitotic drugs kill cancer cells? J Cell Sci. 2009;122Pt(15):2579–85.

    Article  Google Scholar 

  11. Treat J, Scagliotti GV, Peng G, Monberg MJ, Obasaju CK, Socinski MA. Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): a combined analysis of three phase 3 trials. Lung Cancer. 2012;762:222–7.

    Article  Google Scholar 

  12. Sederholm C, Hillerdal G, Lamberg K, et al. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005;2333:8380–8.

    Article  Google Scholar 

  13. Yang JJ, Zhou Q, Liao RQ, et al. Nedaplatin/Gemcitabine versus carboplatin/gemcitabine in treatment of advanced non-small cell lung cancer: a randomized clinical trial. Chin J Cancer Res. 2012;242:97–102.

    Article  Google Scholar 

  14. McNeil C. New NSCLC staging raises treatment issues. J Natl Cancer Inst. 2007;9923:1748–9.

    Article  Google Scholar 

Download references

Acknowledgments

This work has been supported by Axelar AB.

Conflicts of interest

Johan Harmenberg reports receiving consulting fees from Axelar and holding shares in Axelar. Maria Klockare and Markus Jerling report receiving consulting fees from Axelar. Olle Larsson reports holding shares in Axelar.

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Authors and Affiliations

  1. Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden

    Georg Holgersson, Stefan Bergström & Simon Ekman

  2. Department of Oncology, Gävle Hospital, 801 87, Gävle, Sweden

    Georg Holgersson, Stefan Bergström & Michael Bergqvist

  3. Axelar AB, Karolinska Institutet Science Park, Nobels väg 3, 171 65, Solna, Sweden

    Johan Harmenberg, Maria Klockare, Markus Jerling & Olle Larsson

  4. UCR, Dag Hammarskjöldsv 50 A, Uppsala Science Park, 751 83, Uppsala, Sweden

    Magnus Ringbom

  5. Department of Medical Sciences: Respiratory Medicine, Uppsala University, 751 85, Uppsala, Sweden

    Kristina Lamberg Lundström

  6. Department of Respiratory Medicine, Gävle Hospital, 801 87, Gävle, Sweden

    Hirsh Koyi & Eva Brandén

  7. Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

    Michael Bergqvist

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  1. Georg Holgersson
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  2. Stefan Bergström
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  3. Johan Harmenberg
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  7. Simon Ekman
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Correspondence to Georg Holgersson.

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Holgersson, G., Bergström, S., Harmenberg, J. et al. A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer. Med Oncol 32, 129 (2015). https://doi.org/10.1007/s12032-015-0578-y

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  • DOI: https://doi.org/10.1007/s12032-015-0578-y

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