Significant anti-tumour activity has been reported with single-agent pertuzumab in refractory ovarian cancer (Gordon em et al /em , 2006) and due to renewed interest in the anti-tumour activity of docetaxel in this tumour type (Blagden and Kaye, 2005), further investigation of docetaxel in combination with pertuzumab in ovarian cancer patients is warranted. 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 SB 242084 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 drugCdrug 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. studies around the combination of pertuzumab with various cytotoxic brokers, including docetaxel, have demonstrated that there is at least an additive anti-tumour effect without compromising the toxicity profile. The potential improvement in anti-tumour activity to be gained by combining pertuzumab with docetaxel, and the minimal overlap in toxicity profiles, led to the conduct of this phase 1b study designed to determine the maximum-tolerated dose of pertuzumab and docetaxel when administered in combination every 21 days. The secondary objectives were to assess the safety and tolerability of this combination, to evaluate if there was any pharmacokinetic conversation between pertuzumab and docetaxel and to determine the objective responses in advanced solid tumours. PATIENTS AND METHODS Patients Patients with histologically confirmed advanced solid tumours that had progressed during or after standard therapy or for which no standard therapy was available were eligible for this study. A minimum of 4 weeks had to have exceeded from prior treatment with chemotherapy or radiotherapy. Patients were also required to have a life expectancy of at least 12 weeks and a Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1. SB 242084 Other eligibility criteria included adequate bone marrow (absolute neutrophil count ?1500?m?3, platelet count ?100?000?m?3, and haemoglobin (Hgb) ?9?g?dl?1), renal (creatinine ?upper normal limit or creatinine clearance of ?60?ml?min?1), hepatic (bilirubin ?upper normal limit and aspartate aminotransferase [AST], and alanine aminotransferase [ALT] ?2.5 times the upper limits of normal) and cardiac (baseline left ventricular ejection fraction [LVEF] of ?50%) function and a serum calcium within normal limits. Similarly, patients were excluded from the study if they had uncontrolled hypertension, symptomatic CNS metastasis or neuropathy ?grade 2 according to NCI-CTC version 3.0, or any prior malignancy, cardiac condition or serious medical illness that would affect their management according to the study protocol. Patients were also excluded if they had received a prior cumulative doxorubicin dose greater than 360?mg?m?2 or equivalent or had a prior history of severe hypersensitivity reactions to polysorbate 80. The institutional review boards at both participating sites approved the study protocol, and written informed consent was obtained before any study-related procedures. Study design and treatment This was a phase Ib, open-label, two-center study. Pertuzumab and docetaxel were administered as an intravenous (IV) infusion every 3 weeks. Pertuzumab was provided by F Hoffmann-La Roche (Basel, Switzerland). Each 10?ml single-use vial contained 175?mg of pertuzumab formulated in 10?mmol?l?1 L-histidine (pH6.0), 240?mmol?l?1 sucrose, and 0.02% polysorbate 20. The first dose of pertuzumab was given by intravenous infusion over 90?min. If the initial infusion was well tolerated, the infusion time was reduced to 30?min for subsequent infusions. Initially, the planned dose of pertuzumab was fixed dose at 1050?mg for each dose level. However, based Mouse monoclonal antibody to UHRF1. This gene encodes a member of a subfamily of RING-finger type E3 ubiquitin ligases. Theprotein binds to specific DNA sequences, and recruits a histone deacetylase to regulate geneexpression. Its expression peaks at late G1 phase and continues during G2 and M phases of thecell cycle. It plays a major role in the G1/S transition by regulating topoisomerase IIalpha andretinoblastoma gene expression, and functions in the p53-dependent DNA damage checkpoint.Multiple transcript variants encoding different isoforms have been found for this gene on results of phase II single-agent studies in metastatic breast cancer (unpublished data), ovarian cancer (Gordon em et al /em , 2006), and hormone refractory prostate cancer (HRPC) (De Bono em et al /em , 2007) which became available midway through this study and suggested no difference in toxicity or efficacy between the 420 SB 242084 and 1050?mg dose levels of pertuzumab, the protocol was amended.