526 Background: CX-2009 is a PROBODY drug conjugate (PDC) directed against CD166 (ALCAM) and conjugated to DM4, a potent microtubule inhibitor (MTI). CD166 is overexpressed in carcinomas but is also ubiquitously expressed in normal epithelium and thus has not been previously considered a viable target for a traditional antibody drug conjugate. PDCs have a peptide mask that blocks normal tissue binding and can be removed by tumor-associated proteases, thereby limiting off-tumor/on-target binding. CX-2009 demonstrated preclinical activity in multiple solid tumor models. Here we report results of the first in human study in patients with advanced cancer. Methods: In this phase I multi-part dose-escalation study, pts with advanced solid tumors received CX-2009 0.25–10 mpk IV every 14 or 21 days (Q2W or Q3W). Tumor types were selected based on expected high CD166 expression and MTI sensitivity. Results: The dose-escalation phase of the trial enrolled 43 pts; 49 additional pts were subsequently enrolled between 4–10 mpk to collect biomarker data and define the recommended phase II dose (RP2D), for a total of 92 pts as of 30 Nov 2019 (39 pts with breast cancer [BC], 22 ovarian [OC], 12 non-small cell lung [NSCLC], 9 head/neck squamous cell [HNSCC], 10 other) with a median of 6 (range 1–19) prior therapies. Median number of CX-2009 doses was 2 (range, 1–15). For Q3W dosing, one dose limiting toxicity (DLT; grade 3 vomiting) was observed at 8 mpk; MTD was not reached up to 10 mpk. The RP2D for Q3W schedule was 7 mpk based on safety, dose-response, and population pharmacokinetic simulations. Q2W dosing continues; DLTs were observed at 6 mpk. Common treatment-related adverse events (TRAEs) at 7 mpk (n=9) were nausea (44%), fatigue, infusion-related reactions (both 33%), vomiting and arthralgias (both 22%). Grade 3 TRAEs occurred in 2 pts (nausea/vomiting; peripheral neuropathy). No pts discontinued at 7 mpk due to TRAEs. Ocular toxicity was dose dependent; mild to moderate reversible keratitis/blurred vision was seen in 3 pts at 7 mpk and mitigated by ocular prophylaxis. Partial responses were seen in 8 pts (2 confirmed, both HR+/HER2- BC) treated between 4–10 mpk, including BC (n=5), OC (n=2), and HNSCC (n=1). SD (≥1 on-study scan) was observed in 21 pts, 5 had SD ≥3 mos. Conclusions: CX-2009 at 7 mpk is the RP2D on Q3W schedule. Phase II expansion has begun in pts with HR+/HER2- BC. The Q2W schedule will continue to enroll pts to define the RP2D. CX-2009 will also be studied in combination with CX-072, a PD-L1 PROBODY therapeutic ( NCT03149549 ) Clinical trial information: NCT03149549 .
A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer
