Study design and patients
malignancy, fracture, adenocarcinoma of the prostate, Tumors, PD, mCRPC
UNCONTROLLED HYPERTENSION, NEUROENDOCRINE TUMOURS, DISEASE, LYTIC LESION, ADENOCARCINOMA OF THE PROSTATE, METASTATIC DISEASE, BASAL CELL CARCINOMA, TUMORS, MALIGNANCIES, LEPTOMENINGEAL METASTASES, REMISSION, ONCOLOGY, TRANSITIONAL CELL CARCINOMA
This multicentre, open-label, Phase Ib/II trial was conducted in 27 centres in eight countries. The trial comprised: a Phase Ib 3 + 3 escalation phase to determine the MTD and/or recommended Phase II dose (RP2D) of xentuzumab plus enzalutamide in patients with mCRPC after docetaxel and abiraterone; a Phase Ib exploratory expansion phase in patients with mCRPC and PSA progression on enzalutamide; and a Phase II phase, where patients with mCRPC were randomised (1:1) to xentuzumab plus enzalutamide or enzalutamide alone. Randomisation was performed centrally via an Interactive Voice/Web Response system.Eligible patients were adults with histologically or cytologically confirmed adenocarcinoma of the prostate and radiographic evidence of metastatic disease (stage M1 or D2). Other eligibility criteria were: PSA ≥20 ng/ml (later amended to ≥5 ng/ml) and prior surgical or chemical castration with a serum testosterone of <50 ng/ml; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 (ECOG PS 2 was permitted in the dose escalation part); and adequate organ function.For the Phase Ib escalation and Phase II parts, patients had experienced progressive disease (PD) while, or after, receiving docetaxel and abiraterone. They were required to have received ≥12 weeks of docetaxel and were intolerant to, or unlikely to derive benefit from, further docetaxel-based therapy. PD was defined as progressive measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, bone scan progression (at least two new lesions plus rising PSA values), or an increasing PSA level (at least two consecutive rising values taken at least 1 week apart). Patients must not have received more than two prior non-docetaxel-containing cytotoxic chemotherapy regimens for mCRPC, a taxane-based treatment or abiraterone within 4 weeks prior to study treatment start, or prior enzalutamide in any setting. For the exploratory expansion cohort, patients had to be receiving enzalutamide and had PSA progression with at least two consecutive rising values at least 1 week apart. Patients must not have received prior taxane-based chemotherapy or abiraterone in any setting.Other exclusion criteria were prior therapy with agents targeting the IGF pathway; prior chemotherapy, immunotherapy, biological therapies, molecular targeted therapy, hormone therapy (except luteinizing hormone-releasing hormone agonists/antagonists), radiotherapy (except localised therapy for analgesic purposes or for lytic lesions at risk of fracture) within 4 weeks of starting trial treatment; small cell or neuroendocrine tumours; known or suspected leptomeningeal metastases; uncontrolled or poorly controlled hypertension; previous or concomitant malignancies at any other site (except for benign basal cell carcinoma, benign low grade transitional cell carcinoma of the bladder, or an effectively treated malignancy that had been in remission for >5 years and was considered cured).The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was approved by the independent ethics committees (IECs) and institutional review boards of the participating centres The IEC (National Research Ethics Service Committee London – Chelsea Research Ethics Committee Bristol Centre, Bristol, United Kingdom) of the Coordinating Investigator gave a favourable opinion for the study on 14 August 2014. All patients provided written informed consent.