1037P - Phase I dose-escalation trial with tumor-targeted interleukin-12 (IL12-L19L19) in patients with solid tumors

Background

Interleukin-12 (IL12) is a potent immunostimulatory cytokine that enhances T- and NK-cell-mediated anti-tumor immunity. The targeted delivery of IL12, by conjugation to the tumor-targeting antibody L19, increased the therapeutic index and showed a potent anti-tumor effect in mouse models. The L19 antibody binds to the alternatively spliced extra domain B (EDB) of fibronectin, an abundant component of the stroma of most solid tumors, which is undetectable in most healthy adult tissues. The promising preclinical results with EDB-targeted IL12 provided the motivation to study IL12-L19L19 in a phase I clinical trial.

Methods

Eligible patients (pts) have progressive metastatic solid cancers and transiently benefited from prior immune checkpoint inhibitors. The treatment consists of weekly intravenous administrations of IL12-L19L19 up to a maximum of eight infusions, followed by bi-weekly maintenance until disease progression, unacceptable toxicity, withdrawal of consent, or the investigator’s decision. During the Dose Escalation part, patients are sequentially assigned to 9 dose levels (0.1 μg/kg to 32 μg/kg). The Dose Escalation continues until the Dose Limiting Toxicity (DLT) rate reaches 33% in a cohort of 2 – 6 pts. Once the Recommended Dose (RD) is defined, 40 additional pts will be treated in the Dose Expansion part.

Results

A total of 14 pts (median age 62 years [37-72], 9 male, 5 female) have completed the DLT observation window in cohorts 1 – 5. The most common tumor types are NSCLC (4 pts) and melanoma (3 pts). One patient in cohort 3 (0.5 μg/kg) developed a DLT (G3 transient AST/ALT increase). None of the pts in cohorts 1 (0.1 μg/kg), 2 (0.25 μg/kg), 4 (1 μg/kg), and 5 (2 μg/kg) developed a DLT. The most common treatment-related adverse events (TRAEs) of any grade were fever (88%), fatigue (41%), and lymphocyte count decrease (41%). The most common CTCAE G3 TRAE was pyrexia (12%). 8 of 14 pts had Stable Disease, and one patient suffering from metastatic TNBC achieved a Partial Response at week 8. The Dose Escalation part of the trial is still ongoing.

Conclusions

Intravenous infusion with IL12-L19L19 treatment has been tolerated up to 2 μg/kg. The RD of IL12-L19L19 is still to be defined. Initial signs of activity have been observed.

Clinical trial identification

EudraCT 2019-000613-36, NCT04471987.

Editorial acknowledgement

Legal entity responsible for the study

Philogen S.p.A.

Funding

Philogen S.p.A.

Disclosure

W. Alsdorf: Financial Interests, Personal, Other, fees for congress participation: Janssen, Biontech; Financial Interests, Personal, Other, assistance in medical writing: Biontech. I. Colombo: Financial Interests, Personal, Expert Testimony: AstraZeneca, GSK; Financial Interests, Personal, Other, Travel grants: Tesaro, GSK; Financial Interests, Institutional, Expert Testimony: AstraZeneca; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Travel Grants: AstraZeneca; Financial Interests, Personal, Other, travel grants: Janssen; Financial Interests, Personal, Full or part-time Employment, My husband was a Medtronic employee until 04.2020: Medtronic; Financial Interests, Personal, Full or part-time Employment, My husband is an employee since 02.2022: Medtronic; Financial Interests, Personal, Stocks/Shares: Medtronic; Financial Interests, Institutional, Invited Speaker: MSD, Bayer, Vivesto, Incyte, AstraZeneca; Non-Financial Interests, Leadership Role: Swiss Group for Clinical Cancer Research (SAKK). S. Dakhel: Financial Interests, Personal, Full or part-time Employment: Philochem AG. T. Hemmerle: Financial Interests, Personal, Full or part-time Employment: Philochem AG, Philogen S.p.A.. E. Puca: Financial Interests, Personal, Full or part-time Employment: Philochem AG; Financial Interests, Personal, Member of the Board of Directors: Philogen S.p.A.. C. Libbra: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A.. S. Mulatto: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A.. J.C. Mock: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A., Philochem AG. K. Lorizzo: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A.. D. Neri: Financial Interests, Personal, Member of the Board of Directors: Philochem AG, Philogen S.p.A.; Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A., Philochem AG. A. Covelli: Financial Interests, Personal, Full or part-time Employment, CMO: Philogen S.p.A.; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Cellestia Biotech, Italfarmaco, Peptomyc. U. Lauer: Financial Interests, Personal, Other, Consultant: Boehringer Ingelheim, ViraTherapeutics; Financial Interests, Personal, Advisory Role: Novartis, Amgen, Bayer, Asgard Therapeutic. J.C. Hassel: Financial Interests, Personal, Invited Speaker: BMS, Novartis, sanofi, MSD, Sunpharma, Almirall, Roche, Amgen, GSK, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, Pierre Fabre, Sunpharma, GSK; Financial Interests, Institutional, Advisory Board: Novartis, BMS, Immunocore, Nektar, Philogen; Financial Interests, Institutional, Research Grant: BMS, Sunpharma; Financial Interests, Institutional, Invited Speaker: Philogen, BMS, Genentech, Immunocore, Immunocore, 4SC, Novartis, BioNTech, Idera, Iovance, Nektar, Pierre Fabre, Regeneraon, Sanofi; Non-Financial Interests, Leadership Role: DeCOG; Non-Financial Interests, Member: ASCO. A. Stathis: Financial Interests, Institutional, Expert Testimony: Bayer, Eli Lilly; Financial Interests, Institutional, Advisory Board: Janssen, Roche; Financial Interests, Institutional, Other, Travel grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Pfizer, Merck MSD, Roche, Novartis, ADC Therapeutics, AbbVie, Bayer, Philogen, Cellestia, AstraZeneca, Incyte, Amgen, Loxo Oncology. W.M. Fiedler: Financial Interests, Other, Personal fees and non-financial support: AbbVie; Financial Interests, Research Grant: Amgen, Apis, Pfizer; Financial Interests, Other, personal fees and non-financial support: Amgen, Apis, Pfizer; Financial Interests, Other, personal fees: Jazz Pharmaceuticals, Celgene, Morphosys, Incyte, Stemline Therapeutics, Daiichi Sankyo, Servier; Financial Interests, Other, patent: Amgen; Financial Interests, Other, support for medical writing: Amgen, Pfizer, AbbVie. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. All other authors have declared no conflicts of interest.