title: A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours.
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.
authors.affiliation: Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.
authors.forename: G
authors.initials: G
authors.lastname: Attard
authors.forename: J
authors.initials: J
authors.lastname: Kitzen
authors.forename: S P
authors.initials: SP
authors.lastname: Blagden
authors.forename: P C
authors.initials: PC
authors.lastname: Fong
authors.forename: L C
authors.initials: LC
authors.lastname: Pronk
authors.forename: J
authors.initials: J
authors.lastname: Zhi
authors.forename: G
authors.initials: G
authors.lastname: Zugmaier
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.forename: M
authors.initials: M
authors.lastname: de Jonge
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D018450:Disease Progression; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D043823:Taxoids; C485206:pertuzumab