1128P - Preliminary results of first-in-human study of 225-Actinium MTI-201 (225Ac-MTI-201) in metastatic uveal melanoma

Background

Metastatic UM (mUM) has a poor prognosis with limited therapy options. The melanocortin-1 receptor (MC1R) receptor is highly expressed in UM. Actinium-225 (²²⁵Ac) is an alpha particle emitting radionuclide with high linear energy transfer & limited free path in tissue. We developed a novel MC1R targeted radiopharmaceutical, ²²⁵Ac-MTI-201 with high biostability, affinity, MC1R-specific cytotoxicity & defined dosimetry/pharmacokinetics (PK) in preclinical studies. Murine studies in UM showed significant tumor growth delay & improved survival with ²²⁵Ac-MTI-201. NCT05496686 is a first-in-human trial of ²²⁵Ac-MTI-201 in mUM.

Methods

Eligibility includes mUM patients (pts) with progressive disease after at least 1 prior systemic or liver-directed therapy. Pts receive 1 dose of intravenous ²²⁵Ac-MTI-201 with PK sampling. The one-compartment model was used to calculate blood and urine PK. There are 12 escalating dose levels (DL) from 4.7 μCi (0.17 MBq) to 1327 μCi (49.1 MBq). This follows a modified continual re-assessment method with cohort size of 1-2 based on dose limiting toxicity (DLT). Primary endpoint (EP) is safety with secondary EPs of PK, response rate & survival.

Results

Seven pts (3 female), median age 65 years (46-83), with median 2 (0-3) prior lines of systemic therapy, & three with prior liver directed therapy have been enrolled; six pts have received ²²⁵Ac-MTI-201 up to dose level 5 (76μCi). There has been no DLT or G4 toxicity so far. Toxicities include leucopenia (1 G3; 1 G2), lymphopenia (1 G3, 1G2), neutropenia (1 G3), ↓ platelets (1 G2), anemia (1 G1) & high AST (1 G1). Best response has been stable disease (n=2), both at DL 4 and 5; one response is ongoing at 16 weeks post-dose. Blood half-life ranged from 28 to 99 minutes with an elimination rate constant (k₁) of 0.007 to 0.025 min^-1, and a urinary excretion rate constant (k_e) of 1.1 to 4.2 min^-1.

Conclusions

In early assessment, ²²⁵Ac-MTI-201 single dose administration appears safe up to 76μCi with PK parameters as anticipated. The observation of disease stability is encouraging. Accrual & dose-escalation is ongoing & a multi-dose study of ²²⁵Ac-MTI-201 in mUM is planned. Supported by NIH/NCI SBIR Phase II Contract HHSN261201700035C & Modulation Therapeutics.

Clinical trial identification

NCT05496686.

Editorial acknowledgement

Legal entity responsible for the study

H. Lee Moffitt Cancer Center.

Funding

NIH/NCI SBIR Phase II Contract HHSN261201700035C & Modulation Therapeutics.

Disclosure

N.I. Khushalani: Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals, Merck, Iovance Biotherapeutics, Nektar, Castle Biosciences, Instil Bio, Novartis, Replimune, Immunocore; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Incyte, Astra-Zeneca; Financial Interests, Personal, Stocks/Shares: Asensus Surgical, Bellicum; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Merck, Novartis, HUYA, Regeneron, Replimune, Ideaya Biosciences; Financial Interests, Personal, Steering Committee Member: Bristol Myers Squibb, Regeneron, Replimune, Nektar; Financial Interests, Institutional, Coordinating PI: Celgene, Modulation Therapeutics; Non-Financial Interests, Principal Investigator, Global clinical trial: HUYA; Non-Financial Interests, Principal Investigator: Regeneron; Non-Financial Interests, Advisory Role, Scientific Advisory Board: T-knife Therapeutics; Other, Other, Travel support: Castle Biosciences, Regeneron. G. El-Haddad: Financial Interests, Personal, Advisory Board: NorthStar Medical Radioisotopes; Financial Interests, Personal, Speaker, Consultant, Advisor: Bayer Healthcare, Boston Scientific Corporation, Terumo Medical Corporation. K. Gage: Financial Interests, Personal, Full or part-time Employment, Immediate Family Member: Blueberry Pediatrics. Z. Eroglu: Financial Interests, Personal, Advisory Board: Pfizer, Regeneron, SunPharma, Incyte; Financial Interests, Institutional, Research Funding: Pfizer, Novartis, Boehringer Ingelheim-Ingelheim. J. Markowitz: Financial Interests, Institutional, Research Funding: Merck, Morphogenesis, Microba; Financial Interests, Personal and Institutional, Other, Patent: Moffitt Cancer Center. A. Tarhini: Financial Interests, Personal, Advisory Board: Bristol Myers Squib, Genentech/Roche, Easai, Instil Bio, Clinigen / Iovance, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, BioNTech, Merck; Financial Interests, Personal, Advisory Board, Scientific Consultant: ConcertAI; Financial Interests, Personal and Institutional, Steering Committee Member: Bristol Myers Squib; Financial Interests, Institutional, Steering Committee Member: Genentech-Roche; Financial Interests, Institutional, Research Grant: Regeneron, Sanofi-Genzyme, Clinigen, Acrotech, Pfizer, OncoSec; Financial Interests, Institutional, Local PI: Nektar, InflaRx, Scholar Rock, Agenus; Financial Interests, Institutional, Trial Chair: Checkmate. K. Hayes: Financial Interests, Institutional, Full or part-time Employment, I have been a full time employee for Modulation Therapeutics since 2018: Modulation Therapeutics, Inc; Non-Financial Interests, Member, I have been a member of AACR since 2006: American Association Cancer Research. L. Hazlehurst: Financial Interests, Personal, Member of Board of Directors, I am a board member and a president of MOdulation Therapeutics: Modulation Therapeutics; Financial Interests, Personal, Stocks/Shares: Modulation Therapeutics; Non-Financial Interests, Leadership Role: Modulation Therapeutics. M. McLaughlin: Financial Interests, Institutional, Officer, I am a co-founder and Executive Vice President of Modulation Therapeutics Inc that is developing the drug, MTI-201 which is in the Phase I clinical that we are presenting at ESMO: Modulation Therapeutics Inc; Financial Interests, Institutional, Ownership Interest, I own about 38% of the outstanding shares of Modulation Therapeutics Inc: Modulation Therapeutics Inc; Financial Interests, Institutional, Royalties, I am co-inventor of MTI-201: Moffitt Cancer Center. D. Morse: Financial Interests, Personal and Institutional, Licencing Fees or royalty for IP: H. Lee Moffitt Cancer Center. All other authors have declared no conflicts of interest.