26O - Phase I dose-escalation trial with tumor-targeted interleukin-12 (IL12-L19L19) in patients with solid tumors

Background

Interleukin-12 (IL12) is a potent cytokine that promotes 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 murine models of cancer. The promising preclinical results with IL12-L19L19 provided the motivation to initiate a multicenter phase I clinical trial.

Methods

Eligible patients (pts) have progressive metastatic solid cancers and were free from progression for at least three months during prior immune checkpoint inhibitor treatment. The treatment consists of eight weekly intravenous administrations of IL12-L19L19, 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 (ranging from 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

As of the cutoff date (30.10.2023), 20 DLT-evaluable pts (median age 62 years [37-76], 12 male, 8 female) have been treated in cohorts 1 – 7. The most common tumor types are melanoma (6 pts) and NSCLC (5 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) and 4 (1 μg/kg) to 7 (8 μg/kg) developed a DLT. The most common CTCAE v. 5 G3 treatment-related adverse events (TRAEs) were lymphocyte count decrease (25%) and fever (13%). No G4 or G5 TRAEs have been recorded so far. Ten of 20 pts had Stable Disease, and one patient suffering from metastatic TNBC achieved a Partial Response at week 8. Cohort 8 (16 μg/kg) of the Dose Escalation part of the trial is currently ongoing. Pharmacokinetics analysis reveals a dose dependent increase in exposure and serum biomarkers reveal activation of the immune system following administration of the IMP.

Conclusions

Intravenous infusion with IL12-L19L19 has been tolerated up to 8 μg/kg and the RD is still to be defined. Initial signs of activity with limited toxicity 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

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, Advisory Board, Advisory Board: Menarini, Gilead; 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, Personal, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Personal, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Personal, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Personal, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Personal, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Personal, Officer, ESMO Clinical Practice Guidelines Chair: ESMO; Non-Financial Interests, Personal, Member of Board of Directors, Chair of Clinical Practice Guidelines Committee: ESMO. 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, Institutional, Invited Speaker: AstraZeneca, MSD, Bayer, Vivesto, Incyte; Financial Interests, Personal, Stocks/Shares: Medtronic; Non-Financial Interests, Personal, Leadership Role: Swiss Group for Clinical Cancer Research (SAKK). S. Dakhel, T. Hemmerle: Financial Interests, Personal, Full or part-time Employment: Philochem AG. E. Puca: Financial Interests, Personal, Full or part-time Employment: Philochem AG; Financial Interests, Personal, Member of Board of Directors: Philogen S.p.A. S. Mulatto, K. Lorizzo: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A. J.C. Mock: Financial Interests, Personal, Full or part-time Employment: Philochem AG, Philogen S.p.A. D. Neri: Financial Interests, Personal, Leadership Role: Philochem AG, Philogen S.p.A.; Financial Interests, Personal, Stocks/Shares: Philogen S.p.A.; Financial Interests, Personal, Member of Board of Directors: Philogen S.p.A. A. Covelli: Financial Interests, Personal, Member of Board of Directors, CMO: Philogen S.p.A.; Financial Interests, Personal, Advisory Role: Cellestia Biotech, Italfarmaco, Peptomyc. J. Simon: Financial Interests, Personal, Advisory Role: Philogen S.p.A. U. Lauer: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Abalos Therapeutics; Financial Interests, Personal, Advisory Board: Asgard Therapeutics. H. Läubli: Financial Interests, Institutional, Expert Testimony: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Palleon Pharmaceuticals, GlycoEra; Financial Interests, Institutional, Invited Speaker: Novartis. J.C. Hassel: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Sanofi, MSD, Sunpharma, Amgen, GSK, Pierre Fabre, Immunocore, IO Biotech; Financial Interests, Personal, Advisory Board: MSD, Pierre Fabre, Sunpharma, GSK, Onkowissen; Financial Interests, Institutional, Advisory Board: Novartis, BMS, Immunocore, Philogen, Sanofi; Financial Interests, Institutional, Research Grant: BMS, Sunpharma; Financial Interests, Institutional, Invited Speaker: Philogen, BMS, Genentech, Immunocore, 4SC, Novartis, BioNTech, Idera, Iovance, Nektar, Pierre Fabre, Regeneron, Sanofi, Genmab, Replimune; Non-Financial Interests, Personal, Member: ASCO; Non-Financial Interests, Personal, Leadership Role: DeCOG. A. Stathis: Financial Interests, Institutional, Expert Testimony: Bayer, Eli Lilly; Financial Interests, Institutional, Advisory Board: Janssen, Roche; Financial Interests, Institutional, Other, Travel grant: AstraZeneca, Incyte; 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, Personal, Other, Personal fees and non-financial support: AbbVie; Financial Interests, Personal, Research Grant: Amgen, Apis, Pfizer; Financial Interests, Personal, Other, personal fees: Jazz Pharmaceuticals, Morphosys, Incyte, Stemline Therapeutics, Daiichi Sankyo, Servier; Financial Interests, Personal, Other, patent: Amgen; Financial Interests, Personal, Writing Engagements: Amgen, Pfizer, AbbVie. N. Mach: Financial Interests, Personal, Member of Board of Directors: Release Therapeutics. All other authors have declared no conflicts of interest.