109O - Phase I study of MEDI9253, a recombinant Newcastle Disease Virus encoding interleukin-12, in combination with durvalumab in participants with select advanced/metastatic solid tumors

Background

MEDI9253 is a Newcastle Disease Virus (rNDV) that incorporates a IL-12 transgene. It replicates in tumor cells resulting in lysis, local expression of IL-12, and activation of T and NK lymphocytes. Thus, it might leverage immune checkpoint inhibitors (ICI) by priming antitumor responses. We report interim results of the first time in human study.

Methods

This is an open-label, phase I study of MEDI9253 as a single-agent or in combination with durvalumab in patients (pts) with selected advanced/metastatic solid tumors. Dose escalation evaluated MEDI9253 as a single dose (SD) of monotherapy and as multiple doses together with durvalumab (10⁸, 10⁹ and 10¹⁰ Focus-Forming Units or FFU). Primary endpoints were safety and tolerability; key secondary endpoints included preliminary activity, PK and PD.

Results

Forty pts (17 F/23 M) were included (median age: 57.5 yo; range 22-80 years). Thirty-four pts received multiple doses: 4 pts at 10⁹ with sequential durvalumab (SD1), 20 pts at 10¹⁰ with sequential durvalumab (SD2) and 10 pts at 10¹⁰ with concurrent durvalumab (SD3, RP2D). Twenty-nine Grade 3-4 toxicities were observed in 13 patients. Cmax was 6.3 Log10 copies/mL in the SD2 cohort following infusion. The levels of plasma IL-12 reached mean Cmax of 143.79 and 168.93 pg/mL for SD1 and SD2, respectively, within 12 hours after infusion. NDV genome copies were detected in the tumors of 4/13 (31%) pts using RT-PCR. MEDI9253 promoted a ≥2-fold increase in tumoral CD8 T cell frequency in 15% patients, and increased PD-L1 expression. Eight out of 10 patients dosed at RP2D in combination with durvalumab were evaluable, including one partial response in a pre-treated melanoma patient, and four prolonged SD.

Conclusions

MEDI9253 in combination with durvalumab elicited modest clinical efficacy in the studied population. Administration RP2D of 10¹⁰ with durvalumab was feasible and safe. MEDI9253 infected patients' tumors, and increased CD8 infiltration and PD-L1 expression.

Clinical trial identification

NCT04613492.

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca, PLC.

Funding

AstraZeneca, PLC.

Disclosure

S. Postel-Vinay: Financial Interests, Institutional, Advisory Board, Steering Committee: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, As part of the Drug Development Department (DITEP) SPV is Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus: Various drug companies; Financial Interests, Institutional, Research Grant, Translational research funding: IMCore Hoffman LaRoche; Financial Interests, Institutional, Research Grant, Preclinical Research Funding: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator of phase I/II clinical trials: AstraZeneca, GSK, PEP Therapy, BMS, Novartis; Amgen, Oxford Biotherapeutics, Clovis, Roche. J. Cosaert: Financial Interests, Personal, Full or part-time Employment: AstraZeneca, PLC. M. Hattersley, M. Phillips, E. Tu, N. Durham, S. Agrawal, P.L. Martin, P. Chandrasekar, F.I. Arnaldez: Financial Interests, Personal, Full or part-time Employment: AstraZeneca, PLC. K. Ouali: Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP), KO is principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, AstraZeneca Ab, AstraZeneca, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Cato Research, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, EverImmune, Exelixis, Faron Pharmaceuticals Ltd, Foghorn Therapeutics Inc, Forma Tharapeutics, Gamamabs, Genentech, Genmab, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, IGM Biosciences, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D Llc, K-Group Beta, Kinnate Biopharma, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France: Various drug companies.