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.
- 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.
