Abstract
Purpose
The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug–drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI).
Methods
Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis.
Results
Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0–∞)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83–1.05) for AUC(0–∞) and 1.04 (90 % CI 0.97–1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88–1.04) for AUC(0–∞) and 0.97 (90 % CI 0.85–1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade ≥3 neutropenia was reported in 7 (24.1 %) patients.
Conclusions
There was no PK drug–drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns.
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References
Folkman J (2002) Role of angiogenesis in tumor growth and metastasis (review). Semin Oncol 29(6 Suppl 16):15–18
Zhu Z, Bohlen P, Witte L (2002) Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics. Curr Cancer Drug Targets 2:135–156
Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O’Bryant C, Chow LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, Eckhardt SG (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28:780–787
Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, Vernillet L, Risse ML, Boige V, Gouyette A, Vassal G (2000) Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 6:2012–2020
Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7:2182–2194
Chabot GG, Abigerges D, Catimel G, Culine S, de Forni M, Extra JM, Mahjoubi M, Hérait P, Armand JP, Bugat R, Clavel M, Marty ME (1995) Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6:141–151
Klein CE, Gupta E, Reid JM, Atherton PJ, Sloan JA, Pitot HC, Ratain MJ, Kastrissios H (2002) Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther 72:638–647
Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F, RAISE Study Investigators (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499–508
Chow LQ, Smith DC, Tan AR, Denlinger CS, Wang D, Shepard DR, Chaudhary A, Lin Y, Gao L (2016) Lack of pharmacokinetic drug–drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors. Cancer Chemother Pharmacol 78:433–441
Keizer RJ, Huitema AD, Schellens JH, Beijnen JH (2010) Clinical pharmacokinetics of therapeutic monoclonal antibodies (review). Clin Pharmacokinet 49:493–507
Mahmood I, Green MD (2007) Drug interaction studies of therapeutic proteins or monoclonal antibodies (review). J Clin Pharmacol 47:1540–1554
Denlinger CS, Blanchard R, Xu L, Bernaards C, Litwin S, Spittle C, Berg DJ, McLaughlin S, Redlinger M, Dorr A, Hambleton J, Holden S, Kearns A, Kenkare-Mitra S, Lum B, Meropol NJ, O’Dwyer PJ (2009) Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors. Cancer Chemother Pharmacol 65:97–105
Santoro A, Comandone A, Rimassa L, Granetti C, Lorusso V, Oliva C, Ronzoni M, Siena S, Zuradelli M, Mari E, Pressiani T, Carnaghi C (2008) A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer. Ann Oncol 19:1888–1893
Horita Y, Yamada Y, Kato K, Hirashima Y, Akiyoshi K, Nagashima K, Nakajima T, Hamaguchi T, Shimada Y (2012) Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial. Int J Clin Oncol 17:604–609
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This work was supported by Eli Lilly and Company. Eli Lilly and Company contracted with inVentiv Health Clinical for writing and editorial support, provided by Stacey E. Shehin, PhD, and Noelle Gasco, respectively.
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Ding Wang received funding from AbbVie, AstraZeneca, Bayer, Eli Lilly and Company, EMD Serono, Merck, and Novartis. Fadi Braiteh received remuneration from Ambry Genetics, Amgen, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Foundation Medicine, Heron Therapeutics, Genomic Health, Incyte, INSYS Therapeutics, Ipsen, Merck, Merrimack, Molecular Health, Novartis, Pfizer, Roche/Genentech, and Sanofi, and has a consultant advisory role with Amgen, BIND Therapeutics, BioTheranostics, Caris Life Sciences, Eli Lilly and Company, Foundation Medicine, Incyte, INSYS Therapeutics, Ipsen, Merrimack, Molecular Health, Novartis, Novocure, Pfizer, Roche/Genentech, and Sanofi. James J. Lee has no conflicts to disclose. Crystal S. Denlinger has a consultant/advisory role and received funding from Eli Lilly and Company. Dale R. Shepard has no conflicts to disclose. Archana Chaudhary, Yong Lin, Ling Gao, Christopher Asakiewicz, and Federico Nasroulah are employees of and may own stock in Eli Lilly and Company. Patricia LoRusso has a consultant/advisory role with Alexion, Astellas, Astex, Genentech, and Novartis and received funding from AbbVie, Genentech, and Pfizer.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the institutions’ ethics committee or institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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Wang, D., Braiteh, F., Lee, J.J. et al. Lack of pharmacokinetic drug–drug interaction between ramucirumab and irinotecan in patients with advanced solid tumors. Cancer Chemother Pharmacol 78, 727–733 (2016). https://doi.org/10.1007/s00280-016-3125-4
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DOI: https://doi.org/10.1007/s00280-016-3125-4