Phase I expansion study of P-cadherin-targeted 90Y-FF-21101 antibody in advanced chemorefractory colorectal and pancreatic-biliary cancers

78 Background: Overexpression of the cell-cell adhesion protein P-cadherin has been associated with a more aggressive cancer cell phenotype, cancer stem cell properties, tumor invasion and metastasis. We determined the safety and recommended Phase II dose of the yttrium-labeled P-cadherin-targeted 90Y-FF-21101 monoclonal antibody (mAb) in patients (pts) with advanced tumors, and focused our expansion study in advanced colorectal (CRC) and pancreatic-biliary cancers (non-CRC tumors). We report the safety, efficacy, and correlative pharmacokinetics (PK)/pharmacodynamics (PD) in this cohort. Methods: Pts enrolled must have progressed on all standard therapies. 25 mCi/m2 (8 mCi/mg mAb) 90Y-FF-21101 was administered intravenously every 12 weeks (wks) until disease progression or unacceptable toxicity. Disease response was assessed based on RECIST v1.1 every 8 wks (1 cycle = 28 days). Serum mAb PK, existence of anti-drug antibodies (ADA) and tumor P-cadherin expression were also evaluated. Results: 31 pts [mean age 63 (range, 39-89); 14F/17M; median number of prior therapies, 3 (range, 1-11)] with CRC (18) and non-CRC tumors [pancreatic (8), cholangiocarcinoma (3), duodenal (2)] received a median of 1 (range, 1-2) dose of 90Y-FF-21101. Median duration on study was 8.1 (3.9 – 27) wks (CRC) and 8 (1.1-17.1) wks (pancreatic-biliary). Myelosuppression was the most common treatment-related adverse event [thrombocytopenia (87%; Grade (Gr) 3/4 in 45%), lymphopenia (74%; Gr 3/4 in 61%), anemia (52%; Gr 3/4 in 13%), leukopenia (32%; Gr 3/4 in 16%)], in addition to fatigue (68%, 1 Gr 3) and nausea (39%, 1 Gr 3). Three pts required dose reduction to 20 mCi/m2 with subsequent infusion after Gr 3/4 thrombocytopenia [(pancreatic (2), CRC (1)]. The clinical benefit rate in pts with CRC based on stable disease (SD) for ≥8 wks is 43.8% (7/16 pts), with a median PFS of 8.1 wks and OS of 27 wks [median PFS, 7.9 wks; OS, 17.1 wks in non-CRC]. Longer-term SD was maintained in 2 pts with CRC for 17-24 wks; one continues on treatment. Enrollment is ongoing in the non-CRC cohort. FF-21101 has a mean t1/2 of approximately 65 hours, and post-treatment ADA titers have been observed in < 5% of pts. Tumor P-cadherin expression analysis by IHC demonstrated H-scores > 150 in 88% (14/16) of CRC pts, 75% (9/12) for non-CRC; 2 CRC pts with SD ≥17 wks had H-scores ≥190. Conclusions: 90Y-FF-21101 administered every 12 wks demonstrated expected toxicities and has been generally well-tolerated, with preliminary evidence of benefit demonstrated in heavily pre-treated pts with advanced CRC. The optimal dose and schedule for this radioimmunotherapeutic will continue to be explored, along with pre-treatment P-cadherin expression as a predictive biomarker for disease response. Clinical trial information: NCT02454010.