This study is Phase I/IIa First-in-Human Study of [212Pb]VMT-α-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Tumors

This is a prospective, multi-center, open-label, radioactivity dose-finding/ dose expansion study of [212Pb]VMT-α-NET in up to approximately 300 adult subjects with unresectable or metastatic SSTR2-expressing tumors who have not received prior peptide receptor radionuclide therapy (PRRT).

Somatostatin Receptor type 2 (SSTR2) is highly expressed on various tumors including Neuroendocrine tumors (NETs), meningioma and therefore is an attractive therapeutic target. Lead-212 ([212Pb]-) based peptide-radiopharmaceuticals are an emerging class of targeted alpha-particle cancer therapies that have potential to improve delivery of a highly effective form of radiation.

[212Pb] VMT-a-NET is a targeted alpha therapy agent designed to enhance the precision and effectiveness of cancer treatment by delivering a highly potent form of radiation directly to cancer cells. This approach aims to maximize radiation delivery to tumors while minimizing exposure to healthy tissues.

The study will be conducted in 2 parts:

Part 1: Phase I Dose-Finding: Subjects will receive radioactive doses of [212Pb]VMT-α-NET for dose-limiting toxicity (DLT) observation, determining Optimal Biological Dose (OBD) and potential Recommended Phase 2 Dose (RP2D) for Part 2 (Dose Expansion). Dose changes or adjustments will be made by the safety monitoring committee (SMC) and Sponsor.

The RP2D will be determined following a holistic analysis of observed DLTs, Adverse Events (AEs), estimated cumulative organ radiation exposure, and efficacy signals over the course of all treatment cycles for all dose cohorts.

Part 2: Phase IIa Dose-Expansion: This part will enroll subjects with gastroenteropancreatic NETS, bronchial NETS, pheochromocytoma or paragangliomas, and meningioma. Subjects will receive RP2D identified in Part 1 for further assessment of safety and preliminary efficacy.

Reno-protective amino acids will be co-administered prior to each [212Pb]VMT-α-NET dose in all subjects. Dose-finding will be based on an adaptive design until optimal biologic dose is identified or the pre-specified rules are met.

A dosimetry sub-study using [203Pb]VMT-α-NET will be conducted. The subjects will undergo dosimetric evaluation prior to receiving the therapeutic agent.

Inclusion Criteria:

1. Adult (ages ≥18) PRRT-naïve subjects with NETs or meningioma by local pathology.
2. Disease described clinically as: (a) Locally advanced/unresectable or metastatic NETs for dose-finding part of the study (b) Locally advanced/unresectable or metastatic GEP-NETs, bronchial NETs, pheochromocytoma, or paragangliomas for the dose-expansion part of the study (c) Requiring at least 1 prior surgery (resection/biopsy) and a maximum of 1 line of EBRT, if technically feasible, for meningioma.
3. For meningioma: histologically confirmed diagnosis of meningioma, i.e., all grades (1 to 3) per World Health Organization Classification of Tumors of the Central Nervous System (5th edition; WHO-CNS5)
4. Radiological evidence of measurable disease by: (a) For NETs: RECIST v1.1 criteria on CT with contrast or MRI of the areas of tumor involvement within 60 days of enrollment.
5. Lesions must have shown radiological evidence of disease progression in the 12 months prior to enrollment. (b) For meningioma: RANO meningioma criteria on contrast-enhanced skull MRI for meningioma within 3 weeks prior to enrollment.
6. Demonstration of lesional SSTR expression: (a) For NETs: using an FDA-approved somatostatin receptor PET imaging agent, e.g. [68Ga]DOTATATE, [64Cu]DOTATATE, or [68Ga]DOTATOC (b) For meningioma: using a standard-of-care SSTR PET imaging agent within 45 days of enrollment
7. ECOG Performance Status ≤ 1.
8. Subjects with HIV positivity are allowed if CD4 Count > 350 cells/μL.
9. Concurrent Somatostatin Analog (SSA) Therapy use while on protocol therapy is allowed provided that the subject must be able to tolerate withholding long-acting SSA therapy for a minimum of 28 days and short-acting SSA therapy for a minimum of 24 hours before the first and subsequent administrations of [203Pb]VMT-α-NET or [212Pb]VMT-α-NET
10. For NETs: Progressive Disease on approved therapies other than radionuclide therapy.
11. For subjects with meningioma who are receiving corticosteroid treatment, the dose must be ≤ 4 mg/day dexamethasone (or other corticosteroid equivalent dose) for a minimum of 7 days before the initiation of study treatment.
12. Must have clinically demonstrated adequate catecholamine blockade if catecholamine-secreting pheochromocytoma/paraganglioma tumors are present.
13. Able to understand and sign informed consent and comply with all study requirements.
14. Life expectancy > 3 months.
15. Satisfactory organ function as determined by laboratory testing.
16. For females of reproductive potential: agree to use of highly effective contraception and refrain from donating eggs (ova, oocytes) for the purpose of reproduction starting from screening, during treatment, and for at least 6 months after the last dose of [212Pb]VMT-α-NET
17. For males of reproductive potential: agree to use of condoms or other methods to ensure effective contraception with partner and refrain from donating sperm starting from screening, during treatment, and for at least 6 months after the last dose of [212Pb]VMT-α-NET

Exclusion Criteria:

1. Known hypersensitivity to SSA, SSTR imaging agents or any of the excipients of [212Pb]VMT-α-NET.
2. Known additional malignancy that is progressing or requires active treatment.
3. Pregnancy or breastfeeding a child.
4. Febrile illness within 48 hours of any scheduled [212Pb]VMT-α-NET administration should be rescheduled > 48 hours after resolution of fever].
5. Treatment with another investigational medicinal product within 30 days of anticipated treatment.
6. Prior treatment with systemic PRRT based therapies (i.e., [90Y] DOTATATE/DOTATOC or [177Lu] DOTATATE)
7. Prior treatment with 90-Yttrium radioembolization must be completed at least 6 months prior to enrollment.
8. External beam radiation therapy (EBRT) must be completed at least 30 days prior to enrollment.
9. Subjects who have received prior treatment with 90Y radioembolization or EBRT should have radiation absorbed dose to critical organs documented.
10. Prior treatment with systemic anticancer therapy must be completed at least 30 days prior to enrollment (except for SSAs in subjects with functional tumors).
11. Major surgery must be completed at least 30 days prior to enrollment.
12. For Subjects with NETs: Known brain metastases; unless these metastases have been treated and stabilized 6 months prior to enrollment and the subject has been off steroid support for at least 14 days prior to enrollment.
13. Recently diagnosed and active infections requiring a time-limited course of antifungals or antibiotics in the 3 days prior to enrollment.
14. Receipt of live attenuated vaccines in the 7 days prior to enrollment.
15. Grade 3 nausea/vomiting or diarrhea within 72 hours before the of first scheduled dose of [212Pb]VMT-α-NET despite adequate antiemetic and other supportive care
16. Known medical condition which would make this protocol unreasonably hazardous for the subject.
17. Medical history of a condition resulting in a severe allergic reaction such as anaphylaxis or angioedema to known components of the Investigational Medicinal Product or excipients.
18. Current abuse of alcohol or illicit drugs (exclusive of use of medically prescribed cannabinoids).
19. Existence of any medical or social issues likely to interfere with study conduct or that may cause increased risk to the subject or to others, e.g., lack of ability to follow radiation safety precautions.
20. QTc > 450 milliseconds for males and females.

Protocol, CSR