Clinical activity, safety, and PK/PD from a phase I study of RO6874281, a fibroblast activation protein (FAP) targeted interleukin-2 variant (IL-2v)

Abstract

Background: CD44v6 is an isoform of the CD44 family of transmembrane glycopro-teins. High CD44v6 expression in epithelial cancer correlates with tumor growth, invasion , metastasis, and recurrence. CD44v6 is a co-receptor of the receptor tyrosine kinases c-Met, RON and VEGFR-2. Inhibition of CD44v6 blocks RTK activation and intracellular signaling processes. AMC303 is a highly selective inhibitor of CD44v6 with strong in vivo and in vitro anti-tumor activity. Methods: This is a Phase I/Ib open label, non-randomized, multi-center study for patients with resistant advanced cancer (NCT03009214) with dose escalation based on a 3 þ 3 design for all-comers (Part 1) and tumor type specific expansion cohorts at the Recommended Phase 2 Dose (RP2D) (Part 2). AMC303 was given IV, 0.1-20 mg/kg, in 30-60min. Tumor assessment (RECIST1.1) was performed every 6 weeks. A comprehensive biomarker program with paired tumor biopsies and plasma samples was established. Results: 26 patients with a total of 11 different cancer types were treated in 6 dose levels with colorectal cancer as most frequent type. AMC303 infusions were very well tolerated , most drug-related AEs were grade 1 and 2 (in 46% of patients). No related SAEs were reported. Most frequently reported related events were infusion related reactions and hypersensitivity (grade 1-2, in 22% of patients), followed by nausea, diarrhoe and fatigue. MTD was not achieved. PK analysis revealed a linear dose-exposure relationship , t 1/2 of 4-7h, CL of 40-60 mL/h/kg. 81% of patients received at least 6 weeks of therapy. No objective responses were observed in this unselected patient population during the dose escalation phase. More than 70% of tumors were CD44v6 positive by IHC, and 50% exhibited strong to moderate expression with no change after 3 weeks. Biomarker analyses by IHC (Ki67, S6, c-Met, Akt, MAPK), protein profiling of tumor lysates and plasma revealed up-and down-regulation of several biomarkers at 3 weeks. The optimal biological dose was established as 10 mg/kg based on PK/PD data. Conclusions: AMC303 was demonstrated to be well-tolerated with a favorable PK profile. Part 2 is designed to test anti-tumor activity, including patients with high expression of CD44v6 in specific tumor types. Background: Tumor cells harboring select genetic abnormalities (eg, BRD3/4-NUT) have shown sensitivity to BET inhibition. BMS-986158, a potent, selective and orally bioavailable BET inhibitor (BETi) was active in several established and pt-derived tumor xenograft models (Gavai AV, et al. AACR 2018; Wee S, et al. AACR 2018). Here we present initial data for BMS-986158 monotherapy from a phase 1/2a trial in previously treated pts with advanced cancer (NCT02419417). Methods: During dose escalation, pts received BMS-986158 (0.75, 1.25, 2.0, 3.0, or 4.5 mg) once daily across 3 schedules: A (5 days on/2 days off), B (14 days on/7 days off), or C (7 days on/14 days off). Pharmacokinetics (PK), pharmacodynamics, and safety were evaluated. Results: As of March 20, 2018, 68 pts (median age, 59) received BMS-986158 (A [n ¼ 31], B [n ¼ 8], or C [n ¼ 29]); 43% of pts had ! 4 prior therapies. Initial PK analysis of BMS-986158 showed dose-proportional and linear increase in exposure, with fast absorption (T max 2-4 h), long half-life (T 1/2 33-82 h), and dose-dependent AUC. Treatment(tx)-related AEs (TRAEs) occurred in 63% of pts (Gr 3-4, 22%). TRAEs (any Gr; Gr 3-4) reported in ! 15% of pts were mild diarrhea (34%; 0%), thrombocytopenia (28%; 15%), and fatigue (16%; 1.5%). No tx-related deaths or dis-continuations due to a TRAE occurred. The dose-limiting toxicity (DLT) was Gr 3-4 thrombocytopenia. Effects of BMS-986158 on gene transcription for biomarkers of BET activity (eg, CCR2 and HEXIM1) in peripheral blood cells were dose dependent and reversible with the 4.5-mg dose resulting in the highest change in gene expression. Of 4 pts with NUT midline carcinoma, an aggressive and fatal disease, 1 pt with a BRD3-NUT fusion received BMS-986158 (2.0 mg, schedule A) for 279 days, with best overall response of stable disease and 16% reduction in tumor burden, providing further evidence of target-mediated effects. Conclusions: BMS-986158 was well tolerated, with reversible thrombocytopenia as the only DLT. This safety profile together with initial PK findings and effect on target gene expression support the ongoing evaluation of BMS-986158 in pts with select advanced cancers. Background: High-dose IL-2 is approved for patients with metastatic melanoma and renal cell carcinoma but is associated with significant toxicity, frequently requiring intensive care. RO6874281 carries an engineered IL2v moiety with abolished binding to IL-2Ra. Affinity to IL-2Rbc is retained, resulting in activation of immune effector CD8 T and NK lymphocytes, but reduced activity on regulatory T cells (Tregs). The antibody part of RO6874281 binds with high affinity to FAP, which is strongly expressed on tumor-associated fibroblasts, and mediates retention and accumulation in malignant lesions. Methods: Study BP29842 investigates safety, PK/PD and anti-tumor activity of RO6874281, administered i.v. once per week in an outpatient setting to patients with metastatic solid tumors. The dose escalation part enrolled 28 patients with metastatic solid tumors and identified a recommended dose (RD) of 20mg, using one-step intra-patient escalation (15mg followed by 20mg). Patients with treatment refractory mela-noma and squamous cell carcinomas are enrolled to an extension cohort to confirm safety and further explore PK/PD and activity of the RD. So far, 16 patients were enrolled to this cohort including 6 with melanoma. Results: To date, most frequent adverse events (>30%) were pyrexia, infusion related reactions, fatigue/asthenia, nausea, diarrhea, decreased appetite and elevated aspartate and/or alanine transaminase. The majority of events were mild or moderate (Grade 1/ 2). At RD, RO6874281 rapidly expands CD8 and NK cells but not Tregs, both in peripheral blood and sequential tumor biopsies. Objective long-lasting (> 6 months) responses were observed in one patient each with head and neck cancer, penile squa-mous cell carcinoma and checkpoint inhibitor resistant malignant melanoma across