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 need to stay in the 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....
Participants must have histopathologically confirmed gastrointestinal neuroendocrine tumors (GI NET) or pheochromocytoma/paraganglioma (PPGL) cancers that are metastatic or inoperable per Standard of Care.
Have received at least 1 prior systemic radioligand therapy for definitive therapeutic purposes. Note: Participants with prior external beam radiation treatment (EBRT) will also be eligible as long as they have had at least 1 prior administration of a systemic radioligand therapy.
Must have at least 1 measurable lesion by RECIST 1.1 (phase II only).
History of progression by imaging per RECIST 1.1 or clinically (defined as increase in severity or frequency of symptoms related to disease) within the past 36 months prior to the first dose of [203Pb]VMT-alpha-NET.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to VMT-alpha-NET.
Positive Beta human chorionic gonadotropin (Beta-HCG) serum or urine pregnancy test performed in i IOCBP at screening.
QTc > 450 ms on electrocardiogram (EKG) at screening. Note: Framingham correction for QTc will be used.
History of or detection at screening of active/untreated secondary malignancy except nonmelanoma skin cancer and carcinoma in situ of the uterine cervix.
Sequential
68Ga-DOTATATE
Drug68Ga-DOTATATE PET/CT whole-body scanning will be done at target dose of 5 mCi. The whole-body PET/CT scan will be started approximately 60 minutes after the tracer injection and will take up to 2 hours.
[203Pb]VMT-alpha-NET
Drug\[203Pb\]VMT-alpha-NET (6 mCi) will be given IV at 7 days prior.
[212Pb]VMT-alpha-NET
Drug\[212Pb\]VMT-alpha-NET will be given IV on Day 1 of every cycle for 4 cycles total at escalating doses in Phase I and at MTD during Phase II. One cycle is 8 weeks.
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
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
The overall response rate will be presented as a percentage along with 95% confidence intervals. Only evaluable participants will be included.
Progression Free Survival
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
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
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
PK data will be represented as a scatter plot graphing time vs. the amount of radioactivity found in blood and urine samples.
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