Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors

Sylvie Négrier, David Pérol, Rastislav Bahleda, Antoine Hollebecque, Etienne Chatelut, Helen Boyle, Philippe Cassier, Séverine Metzger, Ellen Blanc, Jean-Charles Soria, Bernard Escudier, Sylvie Négrier, David Pérol, Rastislav Bahleda, Antoine Hollebecque, Etienne Chatelut, Helen Boyle, Philippe Cassier, Séverine Metzger, Ellen Blanc, Jean-Charles Soria, Bernard Escudier

Abstract

Background: Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors.

Methods: In this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics.

Results: Twenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139-427) and 494 (227-761) μg.h/mL at Day 1, and 738 (487-989) and 1071 (678-1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion.

Conclusions: The combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination.

Trial registration: The study was retrospectively registered on ClinicalTrials.gov (number NCT01202032 ) on 2010, Sept 14th.

Keywords: Bevacizumab; Combination Angiogenesis; Pazopanib; Phase I trial; Renal carcinoma.

Conflict of interest statement

Ethics approval and consent to participate

The trial received local approval of the Ethic Committee of Lyon Sud-Est IV (n°10/008). Initial approval was obtained on 2010, Feb 1st. All patients provided written informed consent before enrolment.

The study was retrospectively registered on Consent for publication

Not applicable.

Competing interests

Reagents and funding were received from both Glaxo Smith Kline and Roche. S. Négrier received honoraria from Pfizer, Novartis, EUSA Pharma, IPSEN and Bristol-Meyer Squibb. D. Pérol received honoraria from Novartis, Lilly, Pierre Fabre, is a consultant/advisory board member for Celgene, Janssen and Roche, and received personal compensation for travel/accommodations from Roche. H. Boyle received honoraria for presentations and personal compensation for travel/accommodations from Pfizer, Sanofi, Janssen, Novartis, Amgen, and Astellas. P. Cassier received research support from Roche/Genentech, and honoraria from Roche. J.C. Soria declares personal compensation for travel/accommodations, and personal consultancy fees (<10,000 USD) from Roche. B. Escudier received honoraria from Pfizer, Novartis, Bristol-Myers Squibb Roche, and Exelixis. No potential competing interest were disclosed by the other authors.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study schedule (3 + 3 + 3 escalation steps)
Fig. 2
Fig. 2
Progression-free Survival

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