Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheochromocytoma/Paraganglioma Previously Treated With Systemic Targeted Radioligand Therapy

Last updated: April 4, 2025
Sponsor: National Cancer Institute (NCI)
Overall Status: Active - Recruiting

Phase

1/2

Condition

Carcinoid Syndrome And Carcinoid Tumours

Digestive System Neoplasms

Gastric Cancer

Treatment

68Ga-DOTATATE

[203Pb]VMT-alpha-NET

[212Pb]VMT-alpha-NET

Clinical Study ID

NCT06427798
10001711
001711-C
  • Ages 18-120
  • All Genders

Study Summary

Background:

Gastrointestinal neuroendocrine tumors (GI NET) are a type of cancer that affects the stomach and intestines; pheochromocytoma/paragangliomas (PPGL) are tumors that grow in or near the adrenal glands. Both of these types of tumor have high levels of a protein called somatostatin receptors (SSTR) on their surfaces. Researchers want to test a treatment that targets SSTR.

Objective:

To test a drug ([212Pb]VMT-alpha-NET) in people with GI NET or PPGL. The drug has 2 components: a protein to bind to SSTR and a radioactive agent to kill the cancer cells.

Eligibility:

Adults aged 18 years or older with GI NET or PPGL tumors that have spread and cannot be removed with surgery.

Design:

Participants will be screened. They will have a physical exam, with imaging scans, blood tests, and tests of their heart function.

[212Pb]VMT-alpha-NET is given through a tube attached to a needle inserted into a vein (infusion). Treatment will be given in four 8 week cycles. Participants will receive the drug on the first day of each cycle. They will remain in the clinic at least 4 hours after each infusion and may nee to stay in th hospital for up to 48 hour for monitoring and testing. They will have blood tests every week of each cycle.

Some participants will also get a related study drug ([203Pb]VMT-alpha-NET). They will receive this drug a few days before the first 2 cycles. At 4, 24, and 48 hours after each infusion, they will have whole body scans. These scans will show where the study drug went in their body.

Follow-up visits will continue for 10 years....

Eligibility Criteria

Inclusion

  • INCLUSION CRITERIA:

  • Participants must have histopathologically confirmed gastrointestinal neuroendocrinetumors (GI NET) or pheochromocytoma/paraganglioma (PPGL) cancers that are metastaticor inoperable per Standard of Care.

  • Have received at least 1 prior systemic radioligand therapy for definitivetherapeutic purposes. Note: Participants with prior external beam radiationtreatment (EBRT) will also be eligible as long as they have had at least 1 prioradministration of a systemic radioligand therapy.

  • Must have at least 1 measurable lesion by RECIST 1.1 (phase II only).

  • History of progression by imaging (e.g., RECIST 1.1) or clinically (defined asincrease in severity or frequency of symptoms related to disease) within the past 36months prior to the first dose of [203Pb]VMT-alpha-NET.

  • Evidence of somatostatin receptors (SSTR) expression on at least 50% of theradiographically identifiable (i.e., visible on an anatomic scan such as CT ormagnetic resonance imaging [MRI]) tumor, as indicated by a positive (uptakequalitatively identifiable as above the local background) on SSTR PET scan.

  • Age >= 18 years.

  • ECOG performance status <= 1.

  • Participants must have adequate organ and marrow function as defined below:

  • Leukocytes: 3,000/microliter

  • Absolute Neutrophil Count: 1,500/microliter

  • Platelets: 100,000/miroliter

  • Hemoglobin: >= 9.0 g/dL

  • Total bilirubin: within normal institutional limits. Note: <= 5 X institutionalupper limit of normal (ULN) if bilirubin elevation is due to a benign processsuch as Gilbert syndrome

  • AST: <= 2.5 X institutional ULN

  • ALT: <= 2.5 X institutional ULN

  • Creatinine: within normal institutional limits

OR

  • Calculated creatinine clearance (glomerular filtration rate (eGFR): >= 60mL/min/1.73 m^2 for participants with creatinine levels above institutional normal

  • Participants with treated brain metastases are eligible if follow-up brainimaging after central nervous system (CNS)-directed therapy shows no evidenceof progression at screening.

  • Participants with new or progressive brain metastases or leptomeningeal diseaseare eligible as long as the participant is asymptomatic and not requiringmedication for symptom control from the brain lesions at screening.

  • Participants seropositive for human immunodeficiency virus (HIV) must:

  • be on effective anti-retroviral therapy; and

  • have an undetectable viral load at screening.

  • Participants seropositive for hepatitis B virus (HBV), must have HBV viral loadundetectable at screening.

-Participants seropositive for hepatitis C virus (HCV) must:

  • received curative treatment; and

  • have an undetectable HCV viral load at screening.

  • Participants may enroll in this study while on another therapeutic trial inorder to start the screening process. However, all other investigational agentsshould be stopped at least 28 days prior to receiving [203Pb]VMT-alpha-NET.

  • Individuals of child-bearing potential (IOCBP) and individuals who can fatherchildren must agree to use an effective method of contraception (barrier,hormonal, intrauterine device [IUD], surgical sterilization, abstinence) atstudy entry and up to 6 months after the last dose of the study agent(s).

  • Nursing participants must be willing to discontinue nursing from studytreatment initiation through 6 months after the last dose of the study agents.

  • The ability of the participant to understand and the willingness to sign awritten informed consent document.

Exclusion

EXCLUSION CRITERIA:

  • History of allergic reactions attributed to compounds of similar chemical orbiologic composition to VMT-alpha-NET.

  • Positive Beta human chorionic gonadotropin (Beta-HCG) serum or urine pregnancy testperformed in IOCBP at screening.

  • QTc > 450 ms on electrocardiogram (EKG) at screening. Note: Framingham correctionfor QTc will be used

  • History of or detection at screening of active/untreated secondary malignancy exceptnonmelanoma skin cancer and carcinoma in situ of the uterine cervix.

  • Uncontrolled intercurrent illness, factors, evaluated by medical history andphysical exam which would potentially increase in the risk of the participant.

Study Design

Total Participants: 66
Treatment Group(s): 3
Primary Treatment: 68Ga-DOTATATE
Phase: 1/2
Study Start date:
February 07, 2025
Estimated Completion Date:
July 01, 2039

Study Description

Background:

  • Somatostatin receptors (SSTR) have been shown to be over-expressed in a number of human tumors, including gastrointestinal (GI) neuroendocrine tumors (NET) and pheochromocytoma/paragangliomas (PPGL)

  • Targeted radioligand therapy (TRT) is a class of cancer therapeutic agents formed by attaching a radioactive isotope to a ligand that can target specific surface receptors such as SSTR on a tumor cell membrane. Efficacy is typically determined by the radiation dose deposited onto a tumor, which is determined by the radioactive isotope being used as well as the binding characteristics of the ligand-receptor/transporter pair

  • While there have been clinical successes with treating gastrointestinal neuroendocrine tumors (GI NET) and PPGL with SSTR-targeting beta-emitting TRTs, tumors will invariably start to progress after some time. Re-treatment using the same beta-emitting agents at the time of progression can be done but has decreased efficacy compared to the TRT-naive setting

  • Alpha emitters such as 212Pb emit alpha particles that are more damaging to tumor cells than beta emitters such as 177Lu. Therefore, TRT agents using alpha emitters are considered to be more potent and could be better than betas in the re-treatment setting

  • VMT-alpha-NET is a peptide that binds to SSTR, which when attached to 212Pb becomes an alpha particle-emitting TRT that can be used to treat tumors that have SSTR surface expression

  • [203Pb]VMT-alpha-NET is the chemically identical imaging surrogate for [212Pb]VMT-alpha-NET and has the same mechanism of action via binding to SSTR2. The nuclide 203Pb contained in [203Pb]VMT-alpha-NET emits gamma radiation suitable for single-photon emission computerized tomography (SPECT) imaging. These images can be used to assess drug product biodistribution throughout the body

Objectives:

  • Phase I: To determine the maximal tolerated dose (MTD) of [212Pb]VMT-alpha-NET using a 3+3 dose escalation design in GI NET and PPGL in a re-treatment setting

  • Phase II: To determine the Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of participants treated with [212Pb]VMT-alpha-NET at the MTD at the completion of 4 cycles of treatment, reported by disease groups

Eligibility:

  • Age >= 18 years

  • Histopathologically confirmed GI NET or PPGL that are metastatic or inoperable

  • At least 1 prior systemic radioligand therapy

  • Eastern Cooperative Oncology Group (ECOG) Performance Status <= 1

Design:

  • This is an open-label, single-arm, single-center, phase I/II study evaluating the safety, preliminary efficacy, and pharmacokinetic properties of [212Pb]VMT-alpha-NET in GI NET and PPGL in a re-treatment setting

  • Phase I participants will be accrued using a 3+3 dose escalation design with 3 dose levels to estimate MTD of [212Pb]VMT-alpha-NET. Once MTD is estimated, Phase II participants with GI NET and PPGL will be accrued in separate cohorts and treated at MTD of [212Pb]VMT-alpha-NET

  • [212Pb]VMT-alpha-NET will be given IV every 8 weeks for a total of 4 administrations

  • A subset of participants (Dosimetry Arm 1) will have [203Pb]VMT-alpha-NET administration followed by whole-body gamma scans combined with dosimetry SPECT/ Computed Tomography (CT) scans and collection of blood and urine samples prior to the first and the second doses of [212Pb]VMT-alpha-NET (Cycles 1-2)

  • All participants will undergo serial whole-body dose rate measurements after [203Pb]VMT-alpha-NET and/or [212Pb]VMT-alpha-NET administration

  • Participants will have timed clinical laboratory evaluations, imaging studies, and research blood, and urine samples while on the study therapy for safety and efficacy evaluations

  • Following completion of treatment, participants will be seen at the NIH Clinical Center approximately 30 days later, every 12 weeks for years 1-3, every 6 months for years 4-6 for safety and efficacy assessments. Beyond 6 years, participants will be contacted annually through any NIH-approved platform to assess for overall survival and health status

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Active - Recruiting

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