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
- Conditions
- Somatostatin Receptor PositiveGastrointestinal Neuroendocrine TumorsParagangliomasPheochromocytoma
- Interventions
- Registration Number
- NCT06427798
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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....
- Detailed 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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 66
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Dosimetry Arm 1 [212Pb]VMT-alpha-NET Escalating doses of \[212Pb\]VMT-alpha-NET, imaging with \[203Pb\]VMT-alpha-NET. 2/Arm 2 [212Pb]VMT-alpha-NET Escalating doses of \[212Pb\]VMT-alpha-NET. 3/Arm 3 68Ga-DOTATATE \[212Pb\]VMT-alpha-NET at MTD. 1/Dosimetry Arm 1 [203Pb]VMT-alpha-NET Escalating doses of \[212Pb\]VMT-alpha-NET, imaging with \[203Pb\]VMT-alpha-NET. 1/Dosimetry Arm 1 68Ga-DOTATATE Escalating doses of \[212Pb\]VMT-alpha-NET, imaging with \[203Pb\]VMT-alpha-NET. 3/Arm 3 [212Pb]VMT-alpha-NET \[212Pb\]VMT-alpha-NET at MTD. 2/Arm 2 68Ga-DOTATATE Escalating doses of \[212Pb\]VMT-alpha-NET.
- Primary Outcome Measures
Name Time Method Phase I: MTD of [212Pb]VMT-alpha-NET using a 3+3 dose escalation design in GI NET and PPGL in a re-treatment setting DLT period (through 12 weeks after initial 212Pb]VMT-alpha-NET administration). The MTD will be presented as a recommended dose to be used as the recommended phase II dose (RP2D) for the combined participant population, as well as for each disease group being studied (GI-NET, PPGL).
Phase II: ORR by 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 Baseline until progression or 6 years after receiving the first infusion of study drug. The overall response rate will be presented as a percentage along with 95% confidence intervals. Only evaluable participants will be included.
- Secondary Outcome Measures
Name Time Method Progression Free Survival Baseline until progression or 10 years after receiving the first infusion of study drug PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Kaplan-Meier curves of PFS will be constructed. Median PFS will be reported with 95% confidence intervals.
Safety of [203Pb]VMT-alpha-NET and [212Pb]VMT-alpha-NET Study duration Descriptive tabulations of toxicity will be provided, along with the agent attribution determination and CTCAE grade for each toxicity event. The data will be presented as an absolute count of the event at a participant level as well as a percentage of total evaluable participants.
Overall Survival Baseline until progression or 10 years after receiving the first infusion of study drug Kaplan-Meier curves of OS, will be constructed. Median OS will be reported with 95% confidence intervals.
PK properties of [212Pb]VMT-alpha-NET via blood and urine sampling After every infusion of [212Pb]VMT-alpha-NET PK data will be represented as a scatter plot graphing time vs. the amount of radioactivity found in blood and urine samples.
Dosimetry properties of [212Pb]VMT-alpha-NET via SPECT/CT, using [203Pb]VMT-alpha-NET as a surrogate with and without the administration of amino acids (Dosimetry Arm 1 only) In Dosimetry Arm 1 after every [203Pb]VMT-alpha-NET infusion Biodistribution and dosimetry data will be represented in a tabular format which indicates the percentage of the injected dose calculated to be in each of the major organs using gamma scan results. Radiation dose calculations will be performed using OLINDA/EXM software. Absorbed doses in organs and the whole body will be determined using the appropriate adult phantom (e.g., adult male, adult female). Tumor lesion absorbed doses will be determined using the sphere model in OLINDA.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States