Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

Neuroendocrine Tumors Clinical Trial

— 212-Pb-VMT  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05636618
• Other study ID #: VMT-a-NET-T101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 27, 2023
• Est. completion date: January 31, 2028

Study information

• Verified date: March 2024
• Source: Perspective Therapeutics
• Contact: Markus Puhlmann, MD, MBA
• Phone: (319) 665-2150
• Email: mpuhlmann[@]perspectivetherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: January 31, 2028
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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-a-NET.

2. Active secondary malignancy.

3. Pregnancy or breastfeeding a child.

4. Febrile illness within 48 hours of any scheduled [212Pb]VMT-a-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

Related Conditions & MeSH terms

• Carcinoid Tumor
• Carcinoid Tumor of GI System
• Carcinoma, Neuroendocrine
• Digestive System Neoplasms
• Gastrointestinal Neoplasms
• Lung Neoplasms
• Neoplasms
• Neuroendocrine Carcinoma Metastatic
• Neuroendocrine Tumors
• Pancreatic Neoplasms
• Paraganglioma
• Pheochromocytoma

Intervention

Drug:
• [212Pb]VMT-a-NET
Patients with positive uptake on FDA approved SSTR2 PET/CT will receive a fixed dose of [212Pb]VMT-a-NET IV administered every 8 weeks for a maximum of four doses
• [212Pb]VMT-a-NET
Patients with positive uptake on FDA approved SSTR2 PET/CT will receive a fixed dose of [212Pb]VMT-a-NET IV administered at the RPh2D and schedule determined in Phase I dose escalation

Locations

Country	Name	City	State
United States	Johns Hopkins	Baltimore	Maryland
United States	The University of Chicago	Chicago	Illinois
United States	University of Iowa	Iowa City	Iowa
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Kentucky	Lexington	Kentucky
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Perspective Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events (AEs) [Time Frame: Through 42 days following last dose of [212Pb]VMT-a-NET; up to 3 years]	Any untoward medical occurrence in a clinical investigational participant administered [212Pb]VMT-a-NET and which does not necessarily have a causal relationship with this treatment	42 days; up to 3 years
Primary	Number of patients with laboratory abnormalities [Time Frame: Through 42 days following last dose of [212Pb]VMT-a-NET; up to 3 years]		42 days; up to 3 years
Primary	Number of participants with dose-limiting toxicities (DLTs) [Time Frame: Through 42 days following last dose of [212Pb]VMT-a-NET; up to 3 years]		42 days; up to 3 years
Primary	Area under the concentration-time curve (AUC) [Time Frame: 42 days following last dose of [212Pb]VMT-a-NET; up to 3 years	Pharmacokinetic (PK) endpoint	42 days; up to 3 years
Secondary	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
Secondary	Determine the duration of response (DOR) receiving [212Pb]VMT-a-NET.	RECIST v1.1	up to approximately 3 yrs
Secondary	Progression-free survival (PFS) and Overall survival (OS)	RECIST v1.1	up to approximately 3 yrs
Secondary	Biodistribution of [212Pb]VMT-a-NET using a microdose of the therapeutic surrogate, [203Pb]VMT-a-NET	Biodistribution will be calculated by utilizing SPECT/CT scans.	1 hour, 4 hours and 24 hours