Abstract
Purpose
To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.
Methods
Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs.
Results
In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.
Conclusions
For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.
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References
Seto T, Kato T, Nishio M et al (2014) Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15:1236–1244
Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134
Larsen AK, Ouaret D, El Ouadrani K, Petitprez A (2011) Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 131:80–90
Tabernero J (2007) The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5:203–220
Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK (2012) Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 16:15–31
Grothey A, Galanis E (2009) Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 6:507–518
Naumov GN, Nilsson MB, Cascone T et al (2009) Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res 15:3484–3494
BIBW 2992 Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation. ClinicalTrialsgov [Website] 2009. http://www.clinicaltrials.gov/ct2/show/NCT00617656
Hu-Lowe DD, Zou HY, Grazzini ML et al (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283
Balak MN, Gong Y, Riely GJ et al (2006) Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501
Kobayashi S, Boggon TJ, Dayaram T et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792
Pao W, Miller VA, Politi KA et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS medicine 2:e73
Oxnard GR, Arcila ME, Sima CS et al (2011) Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 17:1616–1622
Gendreau SB, Ventura R, Keast P et al (2007) Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res 13:3713–3723
Pietanza MC, Gadgeel SM, Dowlati A et al (2012) Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. J Thorac Oncol 7:856–865
Pietanza MC, Lynch TJ Jr, Lara PN Jr et al (2012) XL647—a multitargeted tyrosine kinase inhibitor: results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib. J Thorac Oncol 7:219–226
Acknowledgements
We thank the nurses and other personnel of the clinical research centers at Stanford and at the Mayo Clinic for their work in support of this study.
Funding
This research was funded by Exelixis, Inc. via a contract to Stanford University with Dr. Branimir Sikic as the Principal Investigator.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Das, M., Padda, S.K., Frymoyer, A. et al. A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies. Cancer Chemother Pharmacol 82, 541–550 (2018). https://doi.org/10.1007/s00280-018-3646-0
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DOI: https://doi.org/10.1007/s00280-018-3646-0