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 À2 ) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m À2 ) 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 À2 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 À2 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 450% 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 À2 and 420 mg pertuzumab following a loading dose of 840 mg.

Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9

“…At this age, all mice were diagnosed with mammary neoplasia, presenting anechoic and/or hypoechoic neoplastic structures in the mammary glands, as revealed by ultrasound imaging evaluation (33). Plasmid DNA vaccine was administered by electroporation intramuscularly at weeks 13,15,20,22,30,32,40, and 42 ( Fig. 2).…”

Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy

“…Pertuzumab binds domain II of the HER2 ECD, preventing ligand-dependent association of HER2 with other HER family members (24) and demonstrated clinical activity as a single agent and in combination with chemotherapy in ovarian, non-small cell lung and prostate cancer (25)(26)(27)(28)(29). Pertuzumab combined with trastuzumab has antitumor activity in cell culture (30) and animal models of HER2-amplified cancer (23,31) and in patients with HER2-positive mBC (32,33).…”

A modern paradigm for treating HER2-positive advanced breast cancer: Dual HER2 blockade and antibody-drug conjugates

“…Исследования I фазы показали, что пертузумаб от-личается хорошей переносимостью -максимально пере-носимая доза не была достигнута. Учитывая этот факт, а также длительный (почти 3 нед) период полувыведения, было рекомендовано назначение фиксированной дозы препарата: 840 мг в качестве нагрузочной дозы и 420 мг каждые 3 нед в качестве поддерживающей [11].…”