Background: MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1. The SLT-I A1 forces MT-3724 internalization and irreversibly inactivates ribosomes triggering cell death. We present interim results from a Phase I study in patients (pts) with B-cell NHL who relapsed after prior response to anti-CD20 Mab and chemotherapy (NCT02361346). Methods: 24 pts were treated by 13FEB2018: 21 pts (12 DLBCL) at 5-100 µg/kg/dose in 6 dose escalation cohorts and 3 pts (all DLBCL) at 75 µg/kg/dose in MTD expansion cohort. MT-3724 was given as six 2-hr IV infusions on Days 1-12 of each cycle (C) for up to 5 cycles. Investigator assessed tumor response after C2, C4 and C5 using Cheson criteria. Results: Demographics in 24 evaluable pts were: 54% female, mean age 66 yrs (range 34-78); ≥4 prior NHL therapies in 67%; ECOG status 0 in 42%, 1 in 46%, 2 in 4% and unknown in 8%. All pts had ≥1 AE (59 G≥3; 13 related), and 15 pts (63%) had 33 SAEs (23 G≥3; 4 related). The most common AEs were peripheral edema (67%), fatigue (43%), diarrhea (38%), myalgia (38%) and cough (33%). MT-3724 was not tolerated at 100 µg/kg/dose (2 pts had 1 DLT each: G2 pneumonia and G2 ileus). In dose escalation, no pts had DLT at doses ≤MTD of 75 µg/kg/dose. In the MTD expansion, 2 of 3 pts had G2 capillary leak syndrome (CLS) leading to dose delay and reduction. The CLS events occurred in obese pts (96 and 154 kg = high total of 7208 and 11572 µg/dose) and were reversible, but MTD was reduced to 50 µg/kg/dose and capped at 6000 µg/dose. Five pts (all DLBCL) had clinical benefit at 5-75 µg/kg/dose [1 CR and 2 PR (ORR 12.5%)’ 2 SD with large tumor reduction (48% and 49%; DCR 21%)]. All pts with benefit had undetectable serum rituximab (RTX) level at screening. No pts with detectable screening RTX level had benefit, likely due to competitive inhibition of CD20 binding by prior RTX. Conclusions: MT-3724 showed clinical anti-tumor activity in heavily pre-treated pts with R/R B-cell NHL. Consistent with mechanism of action, MT-3724 had the best activity in rapidly growing DLBCL. Safety and efficacy assessment is ongoing at the adjusted MTD of 50 µg/kg/dose in DLBCL pts with undetectable screening RTX level. Clinical trial information: NCT02361346