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Phase I dose-escalation trial of afatinib, an irreversible ErbB family blocker, in combination with gemcitabine or docetaxel in patients with relapsed or refractory solid tumors

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Summary

Background Afatinib, an irreversible ErbB family blocker, has shown synergistic antitumor activity and manageable tolerability in combination with chemotherapy. This phase I study assessed oral afatinib plus intravenous gemcitabine or docetaxel in patients with relapsed/refractory solid tumors. Methods Patients received afatinib (30, 40, or 50 mg) plus gemcitabine (1000 or 1250 mg/m2) or docetaxel (60 or 75 mg/m2). Dose escalation proceeded via a 3 + 3 design until the maximum tolerated dose (MTD) was reached. Adverse events (AEs), pharmacokinetics and antitumor activity were also assessed. Results Dose-limiting toxicities during Cycle 1 were reported in 6/39 patients receiving afatinib/gemcitabine (most commonly diarrhea, thrombocytopenia and vomiting) and 16/54 patients receiving afatinib/docetaxel (most commonly febrile neutropenia and stomatitis). The MTDs were established as afatinib 40 mg/gemcitabine 1000 mg/m2 and afatinib 30 mg/docetaxel 60 mg/m2. The most common drug-related AEs were diarrhea, asthenia and rash with afatinib/gemcitabine, and diarrhea, asthenia and stomatitis with afatinib/docetaxel. No relevant pharmacokinetic interactions were observed for either combination. Both combinations demonstrated clinical activity and durable disease control at the MTDs. Compared with the MTD, higher response rates were achieved with afatinib 30 mg/docetaxel 75 mg/m2 (28% vs 6%); however, this regimen was associated with problematic febrile neutropenia, an expected AE with docetaxel, that is often managed with growth factor support. Conclusions Afatinib/gemcitabine and afatinib/docetaxel demonstrated manageable safety profiles, with evidence of clinical efficacy at the MTDs. For afatinib/docetaxel, a dose level of afatinib 30 mg/docetaxel 75 mg/m2 produced higher response rates. Trial registration: NCT01251653 (ClinicalTrials.gov).

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Acknowledgments

The authors would like to thank the patients, their families, and the investigators and staff at all clinical sites for their valuable contributions to this study. This trial was sponsored by Boehringer Ingelheim. The sponsor was involved in the study design, data collection, data analysis, reporting of the results, and preparation of the manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version for submission. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Fiona Scott of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.

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Authors and Affiliations

  1. Institut de Cancérologie de l’Ouest, Site René Gauducheau, Boulevard Jacques Monod, 44805, Saint-Herblain Cedex, France

    Sandrine Hiret

  2. Centre Georges-François Leclerc, 1 rue professeur Marion, BP 77980, 21079, Dijon, France

    Nicolas Isambert

  3. Institut Universitaire du Cancer de Toulouse-Oncopole and Institut Claudius Regaud, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France

    Carlos Gomez-Roca & Jean-Pierre Delord

  4. Department of Pneumology, Thoracic Oncology, CHU Nantes, Boulevard Jacques Monod, 44805, Saint-Herblain Cedex, France

    Jaafar Bennouna

  5. Boehringer Ingelheim France S.A.S, 12 Rue André Huet, 51100, Reims, France

    Mouna Sassi & Hélène de Mont-Serrat

  6. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd, Ridgefield, CT, 06877, USA

    Jean Fan

  7. Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach an der Riß, Germany

    David Schnell

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  1. Sandrine Hiret
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Correspondence to Sandrine Hiret.

Ethics declarations

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and Good Clinical Practice as defined by the International Conference on Harmonization. The study was approved by the relevant local Institutional Review Boards and/or Independent Ethics Committees, and informed consent was obtained from all individual participants included in the study.

Conflicts of interest

CG-R has participated in advisory boards for Astra-Zeneca, BMS and Novartis. JB has participated in advisory boards for BMS, Boehringer Ingelheim, Astra Zeneca and Roche. JF and MS were employees of Boehringer Ingelheim at the time of study conduct. HdM-S and DS are current employees of Boehringer Ingelheim.

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Hiret, S., Isambert, N., Gomez-Roca, C. et al. Phase I dose-escalation trial of afatinib, an irreversible ErbB family blocker, in combination with gemcitabine or docetaxel in patients with relapsed or refractory solid tumors. Invest New Drugs 36, 1044–1059 (2018). https://doi.org/10.1007/s10637-018-0601-1

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