Endpoints and assessments
death, DLTs, Pain, toxicities, Prostate Cancer, pain, tumour
BLOOD, PROSTATE CANCER, ADVERSE EVENT, TUMOUR
In the Phase Ib escalation, the primary endpoint was the MTD of xentuzumab based on occurrence of dose-limiting toxicities (DLTs). MTD was defined as the dose level at which ≤1 DLT was observed in six patients during the first 28-day cycle of treatment. DLTs were defined as per the criteria in the Supplementary Methods.In the Phase Ib expansion, the primary endpoint was PSA response (defined as a decline in PSA value >50% compared with baseline and confirmed by the next available value at least 3 weeks later). Secondary endpoints were investigator-assessed progression-free survival (PFS) and circulating tumour cell (CTC) response. PFS was defined as time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 [PCWG2] criteria) or soft tissue (based on modified RECIST v1.1), whichever occurred earlier, or death from any cause. CTC response was defined as a CTC reduction from ≥5 to <5 cells per 7.5 ml blood for at least one post-baseline timepointThe primary endpoint in Phase II was investigator-assessed PFS. Secondary endpoints were centrally-assessed PFS, overall survival (OS; defined as the time from randomisation to death from any cause), time to PSA progression (defined as time from first treatment until a ≥25% increase in PSA and an absolute increase of >2 ng/ml from the nadir, in cases where there had been a PSA decline from baseline before increasing, or from the baseline if there had been no PSA decline from baseline), maximum decline in PSA, percentage change in PSA at Week 12, PSA response (as defined above) and CTC response assessed by three criteria: CTC reduction (decline from ≥5 to <5 cells per 7.5 ml blood for at least one post-baseline timepoint), maximum decline in CTC counts from baseline, and CTC status at Week 12 (≥5 to <5 cells per 7.5 ml blood).Tumours were assessed at screening by computed tomography or magnetic resonance imaging of the chest, abdomen and pelvis, and a bone scan. The same radiographic procedure had to be used throughout the study. In the Phase Ib escalation, imaging was performed every 12 weeks. In the Phase Ib expansion and Phase II parts, imaging was performed at baseline, every 2 cycles (8 weeks) up to Week 24 and every 3 cycles (12 weeks) thereafter. All imaging data collected in the Phase II part were sent to a central imaging unit to obtain an independent blinded confirmation of tumour response assessment.PSA assessments were performed locally. Blood samples were taken at screening, baseline, at the start of cycle 3, and every cycle thereafter. Upon PSA progression, patients were to be kept on trial treatment until radiological or symptomatic progression was documented. Blood samples for CTC assessment were taken at baseline, at the beginning of cycles 1–3, 5 and 7, and every 12 weeks thereafter. CTCs were analysed by cell counting at an authorised Contract Research Organisation (Veridex CellSearch technology).Safety was assessed by incidence and severity of AEs which were graded according to Common Terminology Criteria for Adverse Events version 4.03. The Brief Pain Inventory short form was used in all parts of the trial to assess pain at the start of each cycle [Evaluation of biomarkers was conducted as an exploratory objective of the trial. Blood samples were taken for quantification of free and total IGF-1 and IGF-2, total IGF binding protein (IGFBP)-3 and IGF bioactivity. IGF-1, IGF-2 and IGFBP-3 were quantified using validated immunoassays. IGF bioactivity was analysed in plasma by the quantification of IGF-1R-phosphorylation in cells expressing human IGF-1R. PTEN expression was assessed by immunohistochemistry (IHC) in archival formalin-fixed, paraffin-embedded (FFPE) tumour samples and was undertaken centrally by Discovery Life Sciences (Kassel, Germany) using the antibody clone 138G6 (cat #9559, Cell Signaling Technology) and the fully automated Ventana Benchmark Ultra platform following the Ultra View DAB procedure (cat #760-500, Ventana Medical Systems/Roche Diagnostics).RNA and DNA were extracted from archival FFPE tumour tissue, to determine gene expression profiles and mutational status (FoundationOne Assay, bait set T7; Foundation Medicine, Cambridge, MA [