[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Paragangliomas, Small Cell Lung, Renal Cell, and Head and Neck Cancers
- Conditions
- Head and Neck TumorsSomatostatin Receptor PositiveKidney CancersSmall Cell Lung CancersPheochromocytoma/ParagangliomasGastrointestinal Neuroendocrine Tumors
- Interventions
- Registration Number
- NCT06479811
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Some cancers have high levels of proteins called somatostatin receptors (SSTRs) on the surface of the tumors. These tumors can be in the lung, head and neck, digestive tract, kidneys, and in or near the adrenal glands. Researchers want to know if drug treatments that target SSTRs can help shrink these types of tumors.
Objective:
To test a study drug (\[212Pb\]VMT-Alpha-NET) in people with tumors that have SSTRs.
Eligibility:
People aged 18 years and older with tumors of the lung, kidneys, head and neck, digestive tract, or adrenal glands that have SSTRs. Their tumors must have spread to other organs and cannot be removed with surgery.
Design:
Participants will be screened. They will have a physical exam with blood and urine tests. They will have imaging scans and a test of their heart function. A sample of tumor tissue may be collected if one is not already available.
\[212Pb\]VMT-Alpha-NET is given through a tube attached to a needle inserted into a vein. The drug will be given on the first day of four 8-week cycles. Participants will stay in the hospital for a few nights after each dose. They will have blood tests once a week during 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 up to 6 years after the last treatment.
- 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), pheochromocytoma/paragangliomas (PPGL), small cell lung cancers (SCLC), kidney cancers (KC), and some head and neck (H\&N) cancers.
* 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.
* 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 than beta-emitting TRTs.
* 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.
Objective:
-To determine the maximum tolerated dose (MTD) of \[212Pb\]VMT-Alpha-NET (dose escalation cohort) and assess the safety of \[212Pb\]VMT-Alpha-NET at the MTD (dose expansions cohorts).
Eligibility:
* Age \>= 18 years.
* Histopathologically confirmed GI NET, PPGL, SCLC, KC, or H\&N (nasopharyngeal carcinoma \[NPC\], olfactory neuroblastoma \[ONB\], sinonasal neuroendocrine carcinoma \[SNEC\]) cancers that are metastatic or inoperable.
* No prior systemic radioligand therapy.
* Eastern Cooperative Oncology Group (ECOG) Performance Status \<= 1.
Design:
* This is an open-label, single-arm, single-center, phase I study evaluating the safety, preliminary efficacy, and pharmacokinetic properties of \[212Pb\]VMT-Alpha-NET in GI NET, PPGL, SCLC, KC, or H\&N cancers.
* First, participants will be accrued in Dose Escalation Part with 4 dose levels to estimate MTD of \[212Pb\]VMT-Alpha-NET. Once MTD is estimated, the following participants with GI NET, PPGL, SCLC, KC, or H\&N cancers 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 3 years after that for safety and efficacy assessments. Beyond 3 years, participants will be contacted annually through any NIH-approved platform to assess for overall survival and health status.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 120
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Dosimetry Arm 1 68Ga-DOTATATE Escalating doses of \[212Pb\]VMT-alpha-NET, imaging with \[203Pb\]VMT-alpha-NET 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 [212Pb]VMT-alpha-NET Escalating doses of \[212Pb\]VMT-alpha-NET, imaging with \[203Pb\]VMT-alpha-NET 2/Arm 2 68Ga-DOTATATE Escalating doses of \[212Pb\]VMT-alpha-NET 3/Arm 3 68Ga-DOTATATE \[212Pb\]VMT-alpha-NET at MTD 3/Arm 3 [212Pb]VMT-alpha-NET \[212Pb\]VMT-alpha-NET at MTD 2/Arm 2 [212Pb]VMT-alpha-NET Escalating doses of \[212Pb\]VMT-alpha-NET
- Primary Outcome Measures
Name Time Method MTD of [212Pb]VMT-alpha-NET (dose escalation cohort) and safety of [212Pb]VMT-alpha-NET at the MTD (dose expansions cohorts) DLTs through 12 weeks after initial 212Pb]VMT-alpha-NET administration (dose escalation) and all toxicities from day 1 up through 3 years (dose expansion). The MTD will be presented as a recommended dose to be used in Dose Expansion Part for each disease group being studied.Descriptive tabulations of toxicity will be provided in Dose Expansion Part, 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.
- Secondary Outcome Measures
Name Time Method Overall Response Rate Baseline, weeks 12 and 32 during treatment, every 12 weeks after that until progression or 3 years after the first [203Pb]VMT-alpha-NET infusion. The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The overall response rate will be presented as a percentage along with 95% confidence intervals. Only evaluable participants will be included.
Progression Free Survival Baseline until progression or 6 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 and OS will be reported with 95% confidence intervals.
Safety of [203Pb]VMT-alpha-NET (dose escalation cohort) 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 6 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) After each SPECT/CT and gamma planar imaging and after every [203Pb]VMT-alpha-NET infusion (in Dosimetry Arm 1 only) 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