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Open Access Research article

Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study

Dusan Kotasek1*, Niall Tebbutt2, Jayesh Desai3, Stephen Welch4, Lillian L Siu4, Sheryl McCoy5, Yu-Nien Sun5, Jessica Johnson5, Adeboye H Adewoye5 and Timothy Price6

Author Affiliations

1 Adelaide Cancer Center, Level 1, Tennyson Centre, 520 South Road, Kurralta Park, SA 5037, Australia

2 Medical Oncology Unit, Level 6, Harold Stokes Building, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia

3 Department of Medical Oncology, The Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia

4 The Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada

5 Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA

6 Department of Medical Oncology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA 5011, Australia

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BMC Cancer 2011, 11:313  doi:10.1186/1471-2407-11-313

Published: 26 July 2011

Abstract

Background

This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors.

Methods

Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6).

Results

Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease.

Conclusions

Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.

Trial Registration

ClinicalTrials.gov NCT01235416