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

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 each cycle.
* 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.