Clinical trial NCT05636618: Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
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
Small-cell Lung Cancer
Keywords: Radiopharmaceuticals
SSTR
Neuroendocrine Tumors
Carcinoid Tumor
Metastatic Neuroendocrine Tumors
Lead-212
Pb-212
Theranostics
Alpha Particle Therapy
Lead sponsor: Perspective Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-12-05
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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
Primary purpose: TREATMENT

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 \[212Pb\]VMT-α-NET in up to 160 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).

Additionally, up to 40 subjects may be enrolled in each of the cohorts.

The Maximum Tolerated Dose (MTD) will be determined based on observed DLTs within 42 days of the first treatment cycle.

The recommended expansion (Phase IIa) 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.

Up to 120 subjects will be considered for enrollment in the dose-expansion phase (Phase IIa) with approximately 100 subjects with GEP-NETs, approximately 10 subjects with bronchial NETs \[small cell lung cancer\], and approximately 10 subjects with pheochromocytoma or paragangliomas)

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.

Eligibility 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

Primary outcomes:
measure: Number of participants with adverse events (AEs) [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years]
timeFrame: 42 days; up to 3 years
measure: Number of patients with laboratory abnormalities [Time Frame: Through 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years]
timeFrame: 42 days; up to 3 years
measure: 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]
timeFrame: 42 days; up to 3 years
measure: Area under the concentration-time curve (AUC) [Time Frame: 42 days following last dose of [212Pb]VMT-α-NET; up to 3 years
timeFrame: 42 days; up to 3 years
Secondary outcomes:
measure: Anti-tumor efficacy of in terms of tumor response
timeFrame: up to approximately 3 yrs
measure: Determine the duration of response (DOR) receiving [212Pb]VMT-α-NET.
timeFrame: up to approximately 3 yrs
measure: Progression-free survival (PFS) and Overall survival (OS)
timeFrame: up to approximately 3 yrs
measure: Biodistribution of [212Pb]VMT-α-NET using a microdose of the therapeutic surrogate, [203Pb]VMT-α-NET
timeFrame: 1 hour, 4 hours and 24 hours
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Miami
country: United States
facility: Biogenix Molecular
state: Florida
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Grand Rapids
country: United States
facility: BAMF Health
state: Michigan
city: Troy
country: United States
facility: Michigan Health Professionals
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
Study officials:
References: