Background. Secreted clusterin (sCLU) promotes survival and stimulates epithelial to mesenchymal transition (EMT) in cancer cells, leading to tumor invasion, metastasis and chemoresistance. AB-16B5 is a humanized IgG2 mAb specific for the EMT-inducing region in some isoforms of sCLU produced by tumor cells, with much less affinity for sCLU found in healthy individuals. Pre-clinical models showed that AB-16B5 inhibits EMT and displays synergy with chemotherapeutic agents. We performed a first-in-human phase I trial to assess safety and tolerability of AB-16B5 and to determine a recommended dose for phase II studies.

Methods. Patients (pts) with evaluable and refractory advanced solid malignancies were eligible with adequate organ and bone marrow functions and an ECOG of 0-2. AB-16B5 was administered as a 60-min IV weekly infusion (21-day cycles). Dose escalation followed an accelerated scheme for the 1.5 and 3 mg/kg dose levels and a standard 3 + 3 design for subsequent levels (6, 9 and 12 mg/kg). All pts underwent collection of blood samples for PK analysis. Pre-treatment and post-treatment (end of cycle 2) tumor biopsies were collected if feasible in pts dosed at 9 and 12 mg/kg. Biopsies were used to evaluate EMT status and to investigate the presence of AB-16B5. Radiological imaging was performed every 6 weeks for the first 8 cycles, then every 9 weeks thereafter.

Results. 15 pts (13 carcinomas of various origins, 1 melanoma and 1 sarcoma) were enrolled from May 2015 to October 2016. Pts received between 1 and 53 weekly doses (median: 9 doses). The most frequently reported adverse events (AEs, all causalities) were nausea, abdominal pain, constipation, vomiting, back pain, pruritus and dyspnea. Most of the AEs were of Grade 1 or 2. Among the AEs ≥ Grade 3, only 2 (Grade 3 infusion related reaction and rash) were judged related to AB-16B5. No dose-limiting toxicities were identified during the first cycle of treatment for any pt. 5 serious AEs were reported (sepsis, pyrexia, dyspnea, intra-abdominal hemorrhage and main stem bronchus obstruction), none of which were judged related to the study treatment. PK analysis across all dose levels confirmed that systemic exposure to AB-16B5 increased in a dose proportional manner. The presence of AB-16B5 at the tumor site was confirmed in all 5 pts where a post-treatment tumor lysate could be generated. Biomarker analysis in paired tumor biopsies provided some evidence for EMT inhibition as seen by increased E-cadherin expression after treatment with AB-16B5 in 2 pts. In one of these 2 pts with advanced gastric cancer, this was also accompanied by a loss of vimentin expression. This pt had stable disease (SD) with clinical benefit and remained on treatment for 24 weeks. Another pt with follicular thyroid cancer had SD for almost 1 year.

Conclusion. Weekly infusions of AB-16B5 are well tolerated up to 12 mg/kg. This dose level is the recommended phase II dose for future trials. Early correlative studies on tumor tissue provide evidence of molecular modulation of the tumor environment in humans. Clinical trial registry number: NCT02412462

Citation Format: Cristiano Ferrario, Julie Laurin, Leon Van Kempen, Caroline Lambert, Alan Spatz, Oksana Markova, Gerald Batist, Adrian Langleben, Mario Filion, Jacques Jolivet. Phase 1 first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT098. doi:10.1158/1538-7445.AM2017-CT098