1. ¹Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK
2. ²Erasmus MC, Department of Medical Oncology, Rotterdam, The Netherlands
3. ³F. Hoffmann-La Roche Ltd., Division Pharma Oncology, Basel, Switzerland

Correspondence: Dr JS de Bono, Centre for Cancer Therapeutics, Institute for Cancer Research, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, England. E-mail: jdebono@icr.ac.uk

Received 18 June 2007; Revised 3 September 2007; Accepted 26 September 2007.

Abstract

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m^-2) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m^-2) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m^-2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m^-2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug–drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m^-2 and 420 mg pertuzumab following a loading dose of 840 mg.