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A phase Ib study of sonidegib (LDE225), an oral small molecule inhibitor of smoothened or Hedgehog pathway, in combination with docetaxel in triple negative advanced breast cancer patients: GEICAM/2012–12 (EDALINE) study

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Summary

Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination’s maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard “3 + 3” design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29–155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013–001750-96. Study GEICAM/2012–12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376

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Acknowledgments

Authors thank all participating patients and their families, as well as the whole network of investigators, research nurses, study coordinators, central labs and GEICAM staff, with special mention to Mª José Escudero, Ruth Caro, Ana Blach and Cristina del Monte from the GEICAM staff.

Funding

Novartis Farmacéutica, S.A. provided financial support and the study drug.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    Manuel Ruiz-Borrego & Jesús Corral

  2. Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, Málaga, Spain

    Begoña Jimenez & José Trigo

  3. Department of Medical Oncology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain

    Silvia Antolín

  4. Department of Medical Oncology, IdISSC, CIBERONC-ISCIII, Hospital Clínico San Carlos, Madrid, Spain

    Jose A. García-Saenz

  5. Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    Yolanda Jerez

  6. Department of Medical Oncology, Fundación Onkologikoa, San Sebastián, Spain

    Ander Urruticoechea

  7. Department of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Barcelona, Barcelona, Spain

    Helena Colom

  8. Department of Pharmacy, IDIBELL, Catalan Institute of Oncology, Hospital Duran i Reynals, L’Hospitalet de Llobregat, Barcelona, Spain

    Nuria Gonzalo & Carmen Muñoz

  9. GEICAM, Spanish Breast Cancer Group, San Sebastián de los Reyes, Madrid, Spain

    Sara Benito, Rosalía Caballero, Susana Bezares & Eva Carrasco

  10. Department of Pathology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain

    Federico Rojo

  11. Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, C/Dr. Esquerdo 46, 28009, Madrid, Spain

    Miguel Martín

Authors
  1. Manuel Ruiz-Borrego
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  2. Begoña Jimenez
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  3. Silvia Antolín
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  4. Jose A. García-Saenz
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  5. Jesús Corral
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  6. Yolanda Jerez
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  8. Ander Urruticoechea
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  9. Helena Colom
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  10. Nuria Gonzalo
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  11. Carmen Muñoz
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  12. Sara Benito
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  13. Rosalía Caballero
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  14. Susana Bezares
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  15. Eva Carrasco
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  16. Federico Rojo
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  17. Miguel Martín
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Corresponding author

Correspondence to Miguel Martín.

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Conflict of interest

Federico Rojo: AES Program, grant PI15/00934 and grant PT17/0015/0006, ISCIII. Eva Carrasco’s husband is Novartis advisor for onco-hematology products. Rest of the authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.

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Ruiz-Borrego, M., Jimenez, B., Antolín, S. et al. A phase Ib study of sonidegib (LDE225), an oral small molecule inhibitor of smoothened or Hedgehog pathway, in combination with docetaxel in triple negative advanced breast cancer patients: GEICAM/2012–12 (EDALINE) study. Invest New Drugs 37, 98–108 (2019). https://doi.org/10.1007/s10637-018-0614-9

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  • DOI: https://doi.org/10.1007/s10637-018-0614-9

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