Phase 1 study of FF-21101(90Y), a radioimmunotherapeutic targeting P-cadherin, in advanced solid tumors

Background: CDH3 gene overexpression of P-cadherin correlates with increased tumor cell invasiveness and is observed in breast, colon, lung, and pancreatic tumors. FF-21101 is a humanmouse chimeric monoclonal antibody directed against P-cadherin, conjugated with 111In for dosimetry and 90Y for therapy. This first-in-human study assesses dosimetry (biodistribution) and therapeutic outcome of FF-21101(90Y). Methods: For dosimetry, patients (pts) received 5 mCi/5mg FF-21101(111In) 1 week before the FF-21101(90Y) therapeutic dose to assess biodistribution and ensure 90Y radiation dose estimates did not exceed the recommended allowable limit for each organ. Single therapeutic dose cohorts were planned for FF-21101(90Y) (8 mCi/mg) at 5, 10, 15, 20 or 25 mCi/m2 (3+3 dose escalation schema), with repeat doses allowed every 4 cycles. Disease assessments were based on RECIST V1.1. Pre-treatment tumor samples were assessed for P-cadherin expression by immunohistochemistry (IHC). Pharmacokinetics (PK) of FF-21101 also were assessed. Results: Seven pts (3M, 4F) with advanced primary solid tumors and loco-regional metastases were treated with FF-21101(90Y) in the first 3 dose cohorts. Median (range) values: age 55 years (31-69), number of prior treatments, including surgery, radiation and/or chemotherapy 5 (2-8); tumor types: ovarian carcinoma (CA) (2 pts), vaginal CA, pancreatic neuroendocrine tumor (PNET), desmoplastic small round cell (DSRC) tumor, colorectal CA (CRC), recurrent liposarcoma (1 pt each). Primary and/or metastatic tumors from 4 of 7 pts (57.1%) demonstrated positive uptake of FF-21101(111In). Highest uptake was seen in epithelial tumors, consistent with P-cadherin targeting. Median (range) time on study following the FF-21101(90Y) dose was 8 (4-40) weeks. The vaginal CA pt demonstrated an 18.5% decrease as best response through 16 weeks following a single therapeutic dose. A viable pre-study tumor sample was not available for IHC staining. Pre-treatment tumor samples available from 6 of 7 patients demonstrated high H scores (≥ 100) in 3 pts (50%); 2 ovarian and 1 PNET; all remain on study through 4, 12 and 40 weeks, respectively, thus demonstrating the potential predictive utility of pre-treatment tumor P-cadherin expression. FF-21101(90Y) has been well-tolerated. Drug-related adverse events (AEs) include Gr 1 rash (1 pt) and increased AST (Gr 1/2, 2 pts) at 5 mCi/m2, and lymphopenia (1 Gr 3 in 3 pts at 10 mCi/m2), all reversible. There have been no drug-related serious AEs. Mean FF-21101 Cmax and AUC0-t increased with dose, suggesting linear PK. Conclusions: Tumor P-cadherin overexpression provides an attractive target for radioimmunotherapy. FF-21101(111In/90Y) exhibits favorable dosimetry, good tolerability and preliminary evidence of reduction in tumor burden. Pre-treatment tumor P-cadherin expression may be an important biomarker for patient selection.