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Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors

  • PHASE I STUDIES
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Summary

Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m2 with two chemotherapy doublets; OCD, 75 mg/m2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m2 docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m2 (cohort 3) or 200 mg/m2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3–4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m2 ombrabulin with 75 mg/m2 cisplatin/75 mg/m2 docetaxel or 200 mg/m2 paclitaxel/AUC6 carboplatin, every 3 weeks.

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Acknowledgments

We thank Florent Mazuir (Sanofi, France) for pharmacokinetics analyses, Essediq El-Yandouzi (Sanofi, France) for study management support, Jean-Christophe Quirot (Sanofi, France) for programming support, and Sarah MacKenzie (Medi-Axe, France, funded by Sanofi) for assistance writing the manuscript.

Funding

This study was supported by Sanofi.

Disclosure

The institutes of CS, LG, and JCS received a study grant from Sanofi. CO, BD and MH are employees of Sanofi. All other authors have no conflicts of interest.

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Authors and Affiliations

  1. Drug Development Department (DITEP), University Paris Sud, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif, France

    Rastislav Bahleda, Andrea Varga & Jean-Charles Soria

  2. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    Cristiana Sessa

  3. Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy

    Gianluca Del Conte & Luca Gianni

  4. National Cancer Institute, Milan, Italy

    Giuseppe Capri

  5. Oncology Division, Sanofi, Vitry-sur-Seine, France

    Corina Oprea

  6. Operational Unit, Sanofi, Vitry-sur-Seine, France

    Byzance Daglish

  7. Biostatistics & Programming, Sanofi, Vitry-Sur-Seine, France

    Marie Hospitel

  8. San Raffaele Hospital, Milan, Italy

    Gianluca Del Conte

Authors
  1. Rastislav Bahleda
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  2. Cristiana Sessa
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  3. Gianluca Del Conte
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  4. Luca Gianni
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  9. Marie Hospitel
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  10. Jean-Charles Soria
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Correspondence to Jean-Charles Soria.

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Bahleda, R., Sessa, C., Del Conte, G. et al. Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors. Invest New Drugs 32, 1188–1196 (2014). https://doi.org/10.1007/s10637-014-0119-0

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  • DOI: https://doi.org/10.1007/s10637-014-0119-0

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