The Anti-CD19 Bispecific T-Cell Engager (BiTE) MT103 (MEDI-538), Induces Dose-Dependent Complete and Partial Responses in Relapsed Non-Hodgkin Lymphoma (NHL): Phase I Study MT103-104.

MT103 (MEDI-538), a bispecific, single chain construct specific for CD19 and CD3, is a member of a novel class of highly active antibody derivatives that direct T-cells to target cells. The primary objective of this study is to evaluate the safety and tolerability of a 4- to 8-week continuous intravenous infusion at increasing dose levels in patients with relapsed NHL, starting at dose level 1 (DL1) of 0.5μg/m²/24h. Dose-limiting toxicities (DLTs) were assessed during the first 2 weeks of infusion. To date, 31 patients have been included up to a dose level of 30μg/m²/24h. No DLTs were observed from DL1 to DL3 (5μg/m²/24h. At DL4 (5μg/m²/24h on day 1, followed by 15 μg/m²/24h maintenance dose), 7 patients (pts) were treated. One of the 7 pts had elevated liver enzymes up to CTC grade 3 after 2 weeks, and another patient showed reversible confusion, assessed as a DLT on the 2^nd treatment day. For further optimization of safety and convenience of the initiation phase, the stepwise increase was modified to a constant infusion rate. This regimen was well tolerated and showed a favorable safety profile. Due to these modifications a total of 13 pts were treated at 15μg/m²/24h. At 30μg/m²/24h, 6 pts were treated; one DLT (metabolic acidosis, grade 4) was recorded. Confounding factors for this event were pre-existing renal insufficiency, fever and increasing anemia. The adverse events (AEs) were transient and the most common ones observed so far in all cohorts, regardless of causality, were (overall/grade 3 or 4) leucopenia (63%/37%), lymphopenia (59%/59%), pyrexia (55%/7%) elevated liver enzymes (44%/4%). At the dose level of 15μg/ m²/24h, MT103 induced 1 complete (CR) and 2 partial responses (PRs) in indolent lymphoma, which had not been observed at the previous dose levels. A total of 5 pts including the responders at this dose level had bone marrow involvement by indolent lymphoma. MT103 induced complete disappearance of lymphoma cells from the bone marrow in 3 and partial reduction in 2 of the 5 cases. One of these 5 patients had lymphoplasmocytoid lymphoma pre-treated with fludarabine. MT103 induced a 60% reduction of paraprotein. At the dose level of 30μg/m2/24h, clinical benefit was observed in mantle cell lymphoma (MCL), which had not been noted at the previous dose levels. One out of 3 evaluable pts with MCL enrolled at this dose level experienced a CR and one showed complete disappearance of lymphoma cells from the bone marrow. Best responses in the 26 evaluable pts overall were 2 CRs, 2 PRs, 2 minimal responses (MRs) and 13 SDs. Best responses in 14 evaluable patients starting at the dose level of 15μg/m²/24h were 2 CRs, 2 PRs, 2 MRs and 5 SDs.Conclusions: The current data suggest a favorable safety profile of MT103 administered as continuous 4 to 8 week infusion. MT103 induces CRs and PRs in relapsed indolent lymphoma and MCL in an apparently dose dependent fashion. Pronounced effects on lymphoma bone marrow infiltration have further demonstrated the clinical activity of MT103. Determination of the optimal biological dose is ongoing.