Melissa L. Johnson, MD Director, Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology speaks about A phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE®) immuno-oncology therapy against DLL3, in SCLC.
Link to Article:
https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.TPS8577
Conceptual –
TPS8577 77
Context:
SCLC is an active neuroendocrine tumor; recurrence, rapid growth, and resistance to current therapies are frequently accompanied by a response to initial chemotherapy and radiotherapy. Delta-like ligand 3 (DLL3) is a Notch receptor inhibitory ligand that is expressed but minimally expressed in normal tissues in most SCLC tumors. For T cell-redirecting immunotherapy, DLL3 may therefore be a promising target. AMG 757 is an extended half-life BiTE antibody construct designed to bind DLL3-positive cells to CD3-positive T cells temporarily and induce T cell-mediated cell lysis and proliferation of T cells concomitantly. In the SHP-77 human SCLC xenograft model in vivo, AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth. In a preclinical multi-dose toxicology analysis in cynomolgus monkeys, AMG 757 was well tolerated with no signs of tissue harm at weekly doses of up to 4.5 mg/kg.
Methodology:
An open-label, ascending, multiple-dose, phase 1 analysis evaluating AMG 757 is NCT03319940. The research will initially recruit adult patients who have progressed after at least 1 platinum-based chemotherapy regimen with relapsed/refractory SCLC. ECOG output status 0"“2, at least 2 detectable lesions per changed RECIST 1.1, no untreated or symptomatic brain metastases, and sufficient organ function are additional inclusion requirements. The main objectives are to assess safety and tolerability and to determine the maximum tolerated dose (MTD) or the recommended dose for phase 2. (RP2D). Pharmacokinetics (PK) characterization and preliminary antitumor activity assessment are secondary objectives. During the dose discovery process, patients will be monitored during the first 28 days for dose-limiting toxicities. To inform decisions on dose escalation/de-escalation, a Bayesian logistic regression model will be used. The expansion step of the dose will confirm the MTD or RP2D and gather additional data on safety and efficacy. AMG 757 will be given once every 2 weeks as a short-term intravenous infusion. Based on evolving PK and safety data, alternative dosing schedules could be explored. Data on clinical trials: NCT03319940.