Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors (212-Pb-VMT)

• ClinicalTrials.gov Identifier: NCT05636618
• Recruitment Status: Recruiting
• First Posted: December 5, 2022
• Last Update Posted: April 3, 2024
• Sponsor: Perspective Therapeutics
• Information provided by (Responsible Party): Perspective Therapeutics

Study Description

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

Condition or disease	Intervention/treatment	Phase
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	Drug: [212Pb]VMT-α-NET	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention 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)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 27, 2023
• Estimated Primary Completion Date: September 30, 2026
• Estimated Study Completion Date: January 31, 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Escalation; 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; 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
Experimental: Dose Expansion with RPh2D; Up to 20 patients with NET	Drug: [212Pb]VMT-α-NET; 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

Outcome Measures

Primary Outcome Measures :

1. Number of participants with adverse events (AEs) [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years] [ Time Frame: 42 days; 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
2. Number of patients with laboratory abnormalities [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years] [ Time Frame: 42 days; up to 3 years ]
3. 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] [ Time Frame: 42 days; up to 3 years ]
4. Area under the concentration-time curve (AUC) [Time Frame: 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years [ Time Frame: 42 days; up to 3 years ]
   Pharmacokinetic (PK) endpoint

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult (ages ≥18) subjects with NETs by local pathology.
2. Locally advanced/unresectable or metastatic NETs.
3. 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.
4. Lesions must have shown radiological evidence of disease progression in the 12 months prior to enrollment.
5. 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.
6. ECOG Performance Status 0-2.
7. Subjects with HIV positivity are allowed if CD4 Count > 500 cells/μL.
8. 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.
9. 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.
10. Progressive Disease on approved therapies other than radionuclide therapy.
11. Must have clinically demonstrated adequate catecholamine blockade if catecholamine-secreting pheochromocytoma/paraganglioma tumors are present.
12. Able to sign informed consent and comply with all study requirements.
13. Life expectancy > 3 months.

Exclusion Criteria:

1. Known hypersensitivity to Octreotate, DOTATATE, or any of the excipients of [212Pb]VMT-α-NET.
2. Active secondary malignancy.
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 drug product (therapeutic IND agents) 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-Ytrium radioembolization must be completed at least 6 months prior to enrollment.
8. External beam radiation therapy must be completed at least 30 days prior to enrollment.
9. Prior treatment with systemic anticancer therapy must be completed at least 30 days prior to enrollment (except for SSAs in subjects with functional tumors).
10. Major surgery must be completed at least 30 days prior to enrollment.
11. 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.
12. Recently diagnosed and active infections requiring a time-limited course of antifungals or antibiotics in the 3 days prior to enrollment.
13. Receipt of live attenuated vaccines in the 7 days prior to enrollment.
14. Grade 3 nausea/vomiting or diarrhea within 72 hours of first scheduled dose despite adequate antiemetic and other supportive care
15. Known medical condition which would make this protocol unreasonably hazardous for the subject.
16. 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.
17. Current abuse of alcohol or illicit drugs (exclusive of use of medically prescribed cannabinoids).
18. 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.
19. QTc > 450 milliseconds for males and females.

20. 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

Contacts and Locations

Contacts

Contact: Markus Puhlmann, MD, MBA; (319) 665-2150; mpuhlmann@perspectivetherapeutics.com

Locations

United States, Florida

Mayo Clinic; Recruiting

Jacksonville, Florida, United States, 32224

Principal Investigator: Jason Starr, MD

United States, Illinois

The University of Chicago; Recruiting

Chicago, Illinois, United States, 60637

Principal Investigator: Chih-Yi Liao, MD

United States, Iowa

University of Iowa; Not yet recruiting

Iowa City, Iowa, United States, 52242

Principal Investigator: Yusuf Menda, MD

United States, Kentucky

University of Kentucky; Recruiting

Lexington, Kentucky, United States, 40536

Contact: Yvonne Taul 859-323-2354 yvonne.taul@uky.edu

Principal Investigator: Lowell Anthony, MD, FACP

United States, Maryland

Johns Hopkins; Recruiting

Baltimore, Maryland, United States, 21287

Principal Investigator: Lilja Solnes, MD

United States, Minnesota

Mayo Clinic; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Neda Tehrani 507-538-5714 tehrani.neda@mayo.edu

Principal Investigator: Thorvardur R Halfdanarson, MD

United States, Missouri

Washington University; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: John Crandall 314-747-5561 jcrandall@wustl.edu

Principal Investigator: Richard Wahl, MD

United States, Nebraska

Nebraska Cancer Specialists; Recruiting

Omaha, Nebraska, United States, 68130

Principal Investigator: Samuel Mehr, MD

Sponsors and Collaborators

Perspective Therapeutics

More Information

• Responsible Party: Perspective Therapeutics
• ClinicalTrials.gov Identifier: NCT05636618
• Other Study ID Numbers: VMT-α-NET-T101
• First Posted: December 5, 2022
• Last Update Posted: April 3, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Protocol, CSR

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Perspective Therapeutics:

Radiopharmaceuticals; SSTR; Neuroendocrine Tumors; Carcinoid Tumor; Metastatic Neuroendocrine Tumors; Lead-212; Pb-212; Theranostics; Alpha Particle Therapy

Additional relevant MeSH terms:

Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Carcinoma, Neuroendocrine; Pheochromocytoma; Paraganglioma; Pancreatic Neoplasms; Lung Neoplasms; Digestive System Neoplasms; Gastrointestinal Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Gastrointestinal Diseases