A Phase I/IIa First-in-Human Study of [212Pb]VMT-a-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

Cancer Categories

Gastrointestinal (GI),Lung

Karmanos Trial ID

2025-004

NCT ID

NCT05636618

Age Group

Adult

Scope

National

Phase

Phase I/II

Principal Investigator

Anthony
Shields, M.D., Ph.D.
Oncology - Medical View Profile

Objective:

Primary Objectives:

To evaluate the safety by rate of DLTs and AEs of [212Pb]VMT-α-NET in subjects with NETs.
To determine the recommended phase 2 dose (RP2D) of [212Pb]VMT-α-NET in PRRT-naïve subjects with NETs.
To determine the PK properties of [212Pb]VMT-α-NET.
To determine the ORR by RECIST v1.1 in subjects with NETs receiving [212Pb]VMT-α-NET in the dose-expansion phase.

Secondary Objectives:

To determine the ORR by RECIST v1.1 in subjects with NETs receiving [212Pb]VMT-α-NET in the dose-escalation phase.
To determine the DOR by RECIST v1.1 in subjects with NETs receiving [212Pb]VMT-α-NET.
To determine the PFS by RECIST v1.1 in subjects with NETs receiving [212Pb]VMTα-NET.
To determine the OS in subjects with NETs receiving [212Pb]VMT-α-NET.

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Eligibility

Inclusion Criteria:

Adult (ages ≥18) subjects with NETs by local pathology.
Locally advanced/unresectable or metastatic NETs.
Radiological evidence of measurable disease by RECIST v1.1 criteria on CT with contrast or MRI of the areas of tumor involvement within 60 days of enrollment.
Lesions must have shown radiological evidence of disease progression in the 12 months prior to enrollment.
Demonstration of lesional SSTR2 expression using an FDA-approved somatostatin receptor PET imaging agent, i.e.[68Ga]DOTATATE, [64Cu]DOTATATE, or [68Ga]DOTATOC, (SSTR2 positivity defined as uptake > background liver) obtained and interpreted in accordance with product labeling and appropriate clinical use criteria within 12 months of enrollment.
ECOG Performance Status 0-2.
Subjects with HIV positivity are allowed if CD4 Count > 500 cells/μL.
Concurrent SSA use while on protocol therapy is allowed provided that the subject: 1) has a functional tumor and 2) has previously demonstrated radiographic disease progression while on SSA therapy.
Long-acting somatostatin analogues are allowed but should be withheld within 30 days prior to [68Ga]DOTATATE PET/CT (or another SSTR2-PET), if clinically possible. Short acting somatostatin analogues should be withheld for 24 hours.
Progressive Disease on approved therapies other than radionuclide therapy.
Must have clinically demonstrated adequate catecholamine blockade if catecholamine-secreting pheochromocytoma/paraganglioma tumors are present.
Able to sign informed consent and comply with all study requirements.
Life expectancy > 3 months.

Exclusion Criteria:

Known hypersensitivity to Octreotate, DOTATATE, or any of the excipients of [212Pb]VMT-α-NET.
Active secondary malignancy.
Pregnancy or breastfeeding a child.
Febrile illness within 48 hours of any scheduled [212Pb]VMT-α-NET administration should be rescheduled > 48 hours after resolution of fever].
Treatment with another investigational drug product (therapeutic IND agents) within 30 days of anticipated treatment.
Prior treatment with systemic PRRT based therapies (i.e., 90Y DOTATATE/DOTATOC or 177Lu DOTATATE)
Prior treatment with 90-Ytrium radioembolization must be completed at least 6 months prior to enrollment.
External beam radiation therapy must be completed at least 30 days prior to enrollment.
Prior treatment with systemic anticancer therapy must be completed at least 30 days prior to enrollment (except for SSAs in subjects with functional tumors).
Major surgery must be completed at least 30 days prior to enrollment.
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.
Recently diagnosed and active infections requiring a time-limited course of antifungals or antibiotics in the 3 days prior to enrollment.
Receipt of live attenuated vaccines in the 7 days prior to enrollment.
Grade 3 nausea/vomiting or diarrhea within 72 hours of first scheduled dose despite adequate antiemetic and other supportive care
Known medical condition which would make this protocol unreasonably hazardous for the subject.
Medical history of a condition resulting in a severe allergic reaction such as anaphylaxis or angioedema to known components of the Investigational Product or excipients.
Current abuse of alcohol or illicit drugs (exclusive of use of medically prescribed cannabinoids).
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.
QTc > 450 milliseconds for males and females.
Abnormal laboratory values:

Hemoglobin ≤ 9.0 g/dL
Platelet Count ≤ 60,000/mm3
Absolute Neutrophil Count (ANC) ≤ 1,250/mm3
Calculated Creatinine Clearance < 60 mL/min *OR Total Bilirubin ≥ 2.0 x ULN**
Albumin ≤ 2.8 g/dL

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