Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors

Isamu Okamoto, Toshio Shimizu, Masaki Miyazaki, Junji Tsurutani, Yasuko Ichikawa, Masaki Terashima, Masayuki Takeda, Soichi Fumita, Emiko Ohki, Nobuyuki Kimura, Junichi Hashimoto, Kazuhiko Nakagawa, Isamu Okamoto, Toshio Shimizu, Masaki Miyazaki, Junji Tsurutani, Yasuko Ichikawa, Masaki Terashima, Masayuki Takeda, Soichi Fumita, Emiko Ohki, Nobuyuki Kimura, Junichi Hashimoto, Kazuhiko Nakagawa

Abstract

Background: Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors.

Methods: Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m(2) on day 1 of repeated 21-day cycles.

Results: Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug-drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease.

Conclusions: Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m(2)) was well tolerated in previously treated patients with advanced solid tumors.

Trial registration: ClinicalTrials.gov NCT00732992.

Figures

Fig. 1
Fig. 1
Plasma concentration-time profiles for sunitinib, SU12662, total drug (sunitinib + SU12662), and pemetrexed on day 1 of cycle 2 for the CDD schedule. Data are means ± standard deviation (SD) for three patients
Fig. 2
Fig. 2
Tumor response. a maximum percentage change in the size of the target lesion in the eight evaluable patients. PD progressive disease, PR partial response, †stable disease due to a new bone lesion. b computed tomography of a solid tumor in the right lung of a patient indicated by † in part a at baseline (left panel) and on day 14 of cycle 2 for the CDD schedule. The tumor showed marked central cavitation after treatment

References

    1. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2:727–739. doi: 10.1038/nrc905.
    1. Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist. 2006;11:753–764. doi: 10.1634/theoncologist.11-7-753.
    1. Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 2009;6:569–579. doi: 10.1038/nrclinonc.2009.130.
    1. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884–896. doi: 10.1200/JCO.2006.06.3602.
    1. Papaetis GS, Syrigos KN. Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs. 2009;23:377–389. doi: 10.2165/11318860-000000000-00000.
    1. Heng DY, Kollmannsberger C. Sunitinib. Recent Results Cancer Res. 2010;184:71–82. doi: 10.1007/978-3-642-01222-8_6.
    1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–124. doi: 10.1056/NEJMoa065044.
    1. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–1338. doi: 10.1016/S0140-6736(06)69446-4.
    1. Christensen JG, Hall C, Hollister BA (2008) Antitumor efficacy of sunitinib malate in concurrent and sequential combinations with standard chemotherapeutic agents in non-small cell lung cancer (NSCLC) nonclinical models. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research; San Diego, CA. Abstract nr 1433.
    1. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–2644. doi: 10.1200/JCO.2003.11.136.
    1. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–1597. doi: 10.1200/JCO.2004.08.163.
    1. Walling J. From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates. Invest New Drugs. 2006;24:37–77.
    1. Chow LQM, Jonker DJ, Call JA, et al. A phase I dose-escalation study of sunitinib in combination with pemetrexed in patients with advanced solid malignancies. Ann Oncol. 2008;19(Suppl 8):480P.
    1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.
    1. Shirao K, Nishida T, Doi T et al. (2009) Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate. Invest New Drugs Sep 3 (Epub ahead of print)
    1. Uemura H, Shinohara N, Yuasa T, et al. A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol. 2010;40:194–202. doi: 10.1093/jjco/hyp146.
    1. Nakagawa K, Kudoh S, Matsui K, et al. A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours. Br J Cancer. 2006;95:677–682. doi: 10.1038/sj.bjc.6603321.
    1. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25–35. doi: 10.1200/JCO.2005.02.2194.
    1. Britten CD, Kabbinavar F, Hecht JR, et al. A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol. 2008;61:515–524. doi: 10.1007/s00280-007-0498-4.
    1. Abrams TJ, Murray LJ, Pesenti E, et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol Cancer Ther. 2003;2:1011–1021.
    1. Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26:1810–1816. doi: 10.1200/JCO.2007.14.5375.
    1. Novello S, Scagliotti GV, Rosell R, et al. Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. Br J Cancer. 2009;101:1543–1548. doi: 10.1038/sj.bjc.6605346.
    1. Escudier B, Roigas J, Gillessen S, et al. Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4068–4075. doi: 10.1200/JCO.2008.20.5476.
    1. George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959–1968. doi: 10.1016/j.ejca.2009.02.011.
    1. Rinaldi DA. Overview of phase I trials of multitargeted antifolate (MTA, LY231514) Semin Oncol. 1999;26:82–88.
    1. Rinaldi DA, Kuhn JG, Burris HA, et al. A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol. 1999;44:372–380. doi: 10.1007/s002800050992.
    1. Cullen MH, Zatloukal P, Sorenson S, et al. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008;19:939–945. doi: 10.1093/annonc/mdm592.
    1. Ohe Y, Ichinose Y, Nakagawa K, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res. 2008;14:4206–4212. doi: 10.1158/1078-0432.CCR-07-5143.
    1. Villela LR, Stanford BL, Shah SR. Pemetrexed, a novel antifolate therapeutic alternative for cancer chemotherapy. Pharmacotherapy. 2006;26:641–654. doi: 10.1592/phco.26.5.641.
    1. Tanai C, Yamamoto N, Ohe Y, et al. A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer. J Thorac Oncol. 2010;5:1068–1074.
    1. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009;14:253–263. doi: 10.1634/theoncologist.2008-0232.
    1. Socinski MA, Novello S, Brahmer JR, et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:650–656. doi: 10.1200/JCO.2007.13.9303.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj