Phase 1 study of OBT076, a first-in-class anti-DEC205 ADC, in patients with advanced/metastatic solid tumors: Safety, efficacy, and PK/PD results.
Authors: Rixe Olivier , Tang Shou-Ching , Sahebjam Solmaz , Mita Monica M. , Mita Alain C. , Rosen Lee S. , Bisht Arnima , Fandi Abderrahim , Rohlff Christian , Mehta Rutika 
Published: June 2022

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Background: OBT076, an Antibody Drug Conjugate (ADC) consisting of a fully human IgG1 antibody conjugated via a cleavable linker to the derivative microtubule inhibitor DM4. It has specificity for the CD205/Ly75 target antigen which is an endocytic receptor overexpressed on the cell surface and immunosuppressive dendritic cells. This phase 1 study evaluates safety, tolerability, PK/PD and preliminary efficacy of OBT076 in solid tumor patients with high expression of target protein CD205 (CAP-CLIA validated centralized IHC test). Methods: Open label, two parts trial in patients with metastatic CD205+ve solid tumors who progressed on standard therapy. Part 1 of the study consisted in dose escalation from 1.6 mg/kg to 3.5 mg/kg. An mTPI design is used to guide to determine the maximum tolerated dose (MTD) Treatment was given on day 1 every 3 weeks followed by GCSF on day 8. Blood samples and flow cytometry were used to assess PK/PD. Tumor response was assessed every three cycles. Part 2 of trial is an expansion basket trial enriched in indications where preliminary efficacy has been shown. Results: The study completed Part 1 dose escalation. Part 2 expansion phase is ongoing. Between Dec 2019 and January 2022, 20 patients were enrolled (18 patients in the dose escalation and 2 in the ongoing expansion). The median age 61, 9 patients were males and 9 had ECOG PS 0. All patients had at least one metastatic site and 90% received at least 2 lines of chemotherapy in the metastatic setting. Recommended dose for the expansion phase is 3.0 mg/kg. No other significant side effects have been observed. PK data showed that Cmax of 40.000-90.000 ng/ml was achieved between 2.5 and 3.5mg/kg dose and is comparable to the therapeutic dose in mouse models. In part 1 of the study, 7 patients derived clinical benefit despite being in disease progression at trial entry. One patient with gastric cancer with linitis plastica experienced major improvement with complete disappearance of ascites and metastatic adenopathy after cycle 3. The six other patients had lasting stable disease and received between 5-14+ cycles with median of 5 cycles. Two patients with low PD-L-1 expression received checkpoint inhibitor treatment with pembrolizumab after 2 and 5 cycles of OBT076, both patients experienced near complete response after only one to two cycles. Conclusions: OBT076 at 3.0mg/kg has shown favorable safety profile with manageable neutropenia. The preliminary efficacy has shown preliminary antitumoral single agent activity in gastric, ovarian and lung cancer. The two patients who received a sequential administration of pembrolizumab after OBT076 showed major tumor activity. Sequential administration of OBT076 followed by a PD-1 inhibitor was also supported by PD markers and warrants further evaluation. Clinical trial information: NCT04064359. [Table: see text]