Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

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

Detailed Description
-----------------
This is a prospective, multi-center open-label dose escalation, dose expansion study of [212Pb]VMT01 in up to 52 adult subjects with unresectable or metastatic SSTR2-expressing neuroendocrine tumors (NETs) who have not received prior peptide receptor radionuclide therapy (PRRT). The radioactivity dose escalation period (phase I) tests up to 4 escalating radioactivity dose cohorts of up to 8 subjects (administered at approximately 8-week intervals) at the assigned cohort radioactivity dose. Pre-specified dose adjustments and individual stopping rules for repeat treatment cycles are based on observed dose-limiting toxicities (DLTs) and adverse events (AEs). The Maximum Tolerated Dose (MTD) will be determined based on observed DLTs within 42 days of the first treatment cycle. The recommended expansion dose(s) will be determined following a holistic analysis of observed DLTs, AEs, estimated cumulative organ radiation exposure, and efficacy signals over the course of all treatment cycles for all dose cohorts. If MTD can not be identified within the 4 radioactivity dose cohorts, a Maximum Feasible Dose (MFD), incorporating manufacturing and logistical considerations for [212Pb]VMT-α-NET production, may be determined. Reno-protective amino acids will be co-administered in a separate IV line prior to each [212Pb]VMT-α-NET dose in all subjects. Escalation will be based on a modified toxicity probability interval design [mTPI-2] until MTD is identified or the pre-specified rules are met. A lead-in dosimetry sub-study will be conducted during the dose escalation period in which all subjects in the first two dose cohorts will undergo dosimetric evaluation prior to receiving the therapeutic agent.

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

Conditions
-----------------
Neuroendocrine Tumors, Neuroendocrine Tumor of the Lung, Neuroendocrine Tumor of Pancreas, Neuroendocrine Carcinoma Metastatic, Neuroendocrine Tumor Carcinoid, Carcinoid Tumor of GI System, Carcinoid Tumor, Paraganglioma, Pheochromocytoma

Intervention / Treatment
-----------------
* Drug: [212Pb]VMT-α-NET
* Drug: [212Pb]VMT-α-NET


Participation Criteria
=================
Eligibility Criteria
-----------------
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 AST/ALT ≥ 3.0 x ULN

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A Phase I/IIa First-in-Human Study of [212Pb]VMT-α-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose Escalation to determine MTD/MFD in 32 patients receiving up to 4 administrations of [212Pb]VMT-α-NET approximately 8 weeks apart. A dosimetry sub-study utilizing [203Pb]VMT-α-NET has been incorporated into the study. | Drug: [212Pb]VMT-α-NET<br>* Patients with positive uptake on FDA approved SSTR2 PET/CT will receive a fixed dose of [212Pb]VMT-α-NET IV administered every 8 weeks for a maximum of four doses<br>|
| Experimental: Dose Expansion with RPh2D<br>Up to 20 patients with NET | Drug: [212Pb]VMT-α-NET<br>* Patients with positive uptake on FDA approved SSTR2 PET/CT will receive a fixed dose of [212Pb]VMT-α-NET IV administered at the RPh2D and schedule determined in Phase I dose escalation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years] | Any untoward medical occurrence in a clinical investigational participant administered [212Pb]VMT-α-NET and which does not necessarily have a causal relationship with this treatment | 42 days; up to 3 years | 
| Number of patients with laboratory abnormalities [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years] |  | 42 days; up to 3 years | 
| Number of participants with dose-limiting toxicities (DLTs) [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years] |  | 42 days; up to 3 years | 
| Area under the concentration-time curve (AUC) [Time Frame: 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years | Pharmacokinetic (PK) endpoint | 42 days; up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor efficacy of in terms of tumor response | Determination of the overall response rate (ORR) by RECIST v1.1 in subjects with neuroendocrine tumors | up to approximately 3 yrs | 
| Determine the duration of response (DOR) receiving [212Pb]VMT-α-NET. | RECIST v1.1 | up to approximately 3 yrs | 
| Progression-free survival (PFS) and Overall survival (OS) | RECIST v1.1 | up to approximately 3 yrs | 
| Biodistribution of [212Pb]VMT-α-NET using a microdose of the therapeutic surrogate, [203Pb]VMT-α-NET | Biodistribution will be calculated by utilizing SPECT/CT scans. | 1 hour, 4 hours and 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SSTR, Pb-212, Carcinoid Tumor, Radiopharmaceuticals, Neuroendocrine Tumors, Metastatic Neuroendocrine Tumors, Lead-212, Theranostics, Alpha Particle Therapy