Yap, T. A., Vidal, L., Adam, J., Stephens, P., Spicer, J., Shaw, H., Ang, J., Temple, G., Bell, S., Shahidi, M., Uttenreuther-Fischer, M., Stopfer, P., Futreal, A., Calvert, H., de Bono, J. S., Plummer, R. (2010) Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors. JOURNAL OF CLINICAL ONCOLOGY, 28 (25). pp. 3965-3972. ISSN 0732-183X

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Abstract

Purpose Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. Patients and Methods Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. Results Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting >= 6 months. Conclusion Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

Item Type:	Article
Authors (ICR Faculty only):	De-Bono, Johann
All Authors:	Yap, T. A., Vidal, L., Adam, J., Stephens, P., Spicer, J., Shaw, H., Ang, J., Temple, G., Bell, S., Shahidi, M., Uttenreuther-Fischer, M., Stopfer, P., Futreal, A., Calvert, H., de Bono, J. S., Plummer, R.
Uncontrolled Keywords:	GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE; DOSE-ESCALATION; CLINICAL-TRIALS; DUAL INHIBITOR; GEFITINIB; GUIDELINES; RESISTANCE; ERLOTINIB
Funding Acknowledgement:	Boehringer Ingelheim ; Drug Development Unit of the Royal Marsden NHS Foundation Trust ; Cancer Research UK ; Experimental Cancer Medicine Centre ; National Institute for Health Research Biomedical Research Centre
Funding Text:	Supported by Boehringer Ingelheim; the Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research UK. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). Northern Institute for Cancer Research, Newcastle University is supported by programmatic grant funding from Cancer Research UK and is an Experimental Cancer Medicine Centre.
Research teams:	ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers ICR divisions > Clinical Studies > Prostate Cancer Targeted Therapy Group
Depositing User:	Users 10 not found.
Date Deposited:	29 Sep 2010 10:30
Last Modified:	11 Jul 2017 10:06
URI:	http://publications.icr.ac.uk/id/eprint/9859

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