[212Pb]VMT-Alpha-NET for Neuroendocrine Tumors

Overseen By Joy H Zou, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Antiretrovirals

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Secondary malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 32 weeks

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, [212Pb]VMT-Alpha-NET, which targets specific proteins found in some tumors. These proteins, known as somatostatin receptors (SSTRs), often appear in cancers affecting the lungs, kidneys, digestive tract, and more. The primary goal is to determine if the drug can shrink these tumors, particularly when they have spread and cannot be surgically removed. Individuals with SSTR-positive tumors in the specified areas, which have spread and are inoperable, may qualify. Participants will receive the drug through an IV and undergo regular scans and tests to monitor its effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

Yes, you will need to stop any investigational agents and systemic therapies at least 28 days before starting the trial drug, except for small cell lung cancer patients, who need to stop systemic therapy at least 14 days prior.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that [212Pb]VMT-Alpha-NET has generally been well-tolerated in studies so far. Previous findings indicate that patients experienced some side effects, mostly mild to moderate, with nausea and tiredness being common.

As this treatment is in an early testing phase, the main goal is to understand its safety and any possible side effects. Although the data appears promising, more research is needed to fully assess its safety. Researchers will closely monitor participants to ensure their well-being throughout the trial.

Overall, early results suggest the treatment might be safe for humans, but careful observation remains important.

Why do researchers think this study treatment might be promising?

Researchers are excited about [212Pb]VMT-Alpha-NET because it offers a new approach for treating neuroendocrine tumors. Unlike standard treatments such as somatostatin analogs or targeted therapies, [212Pb]VMT-Alpha-NET uses a radiopharmaceutical approach, targeting tumor cells with precision. This treatment combines [212Pb], a radioactive isotope, with VMT-alpha-NET, potentially delivering radiation directly to cancer cells while sparing healthy tissue. Additionally, the trial explores both escalating doses and the maximum tolerated dose, aiming to find the optimal balance between effectiveness and safety. This innovative approach could potentially offer better outcomes for patients with fewer side effects than current therapies.

What evidence suggests that [212Pb]VMT-Alpha-NET might be an effective treatment for neuroendocrine tumors?

Research has shown that [212Pb]VMT-Alpha-NET targets tumors with high levels of somatostatin receptors (SSTRs), common in many neuroendocrine tumors. These tumors often appear in the lungs, head and neck, and digestive tract. [212Pb]VMT-Alpha-NET is designed to attach to these receptors and deliver radioactive particles directly to the tumor cells, potentially shrinking them. Early results from similar treatments have been promising in reducing tumor size by focusing on these receptors. This trial will explore different dosages of [212Pb]VMT-Alpha-NET across its various treatment arms, aiming to concentrate the treatment on cancer cells while limiting harm to healthy cells. Although research in humans is ongoing, this targeted treatment offers hope for those with SSTR-positive tumors.

Who Is on the Research Team?

Frank I Lin, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with certain advanced cancers (lung, kidney, head and neck, digestive tract, adrenal glands) that have somatostatin receptors and can't be surgically removed. Participants must be over 18 years old with tumors that have spread to other organs.

Inclusion Criteria

Required prior therapies: GI NET, PPGL, H&N: no specific prior therapy is needed. SCLC: At least one prior line of standard of care systemic treatment such as chemotherapy and/or immunotherapy. KC: Renal cell carcinoma (RCC) participants should have received at least one line of prior therapy in the metastatic setting and should have received at least one Programmed cell death protein 1 (PD1) / Programmed death-ligand 1 (PDL1)-targeted immune checkpoint inhibitor as well as one agent targeting the VEGF pathway. Participants with fumarate hydratase (FH) deficient RCC should have received at least one prior line of systemic therapy (such as bevacizumab plus erlotinib). No prior therapy is needed for participants with other histologic subtypes.

My cancer has worsened in the last 3 years, either by scans or symptoms.

My cancer is one of the specified types and cannot be removed by surgery or has spread.

Exclusion Criteria

Any investigational agents should be stopped at least 28 days prior to the first dose of [203Pb]VMT-Alpha-NET, Systemic therapy should be stopped at least 28 days prior to the first dose of [203Pb]VMT-Alpha-NET (participants with prior systemic therapies for their malignancy only, except participants with SCLC), Systemic therapy should be stopped at least 14 days prior to the first dose of [203Pb]VMT-Alpha-NET (participants with SCLC only), 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 females of childbearing potential 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, Uncontrolled intercurrent illness, factors, evaluated by medical history and physical exam which would potentially increase in the risk of the participant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive [212Pb]VMT-Alpha-NET intravenously every 8 weeks for a total of 4 cycles, with hospital stays and weekly blood tests during each cycle

32 weeks

4 cycles with multiple visits per cycle

Dosimetry

A subset of participants receive [203Pb]VMT-Alpha-NET for imaging and dosimetry studies, with whole-body scans and blood/urine collection

16 weeks

Multiple visits for imaging and sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits every 12 weeks for 3 years, then annually up to 6 years

6 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• [212Pb]VMT-Alpha-NET

Trial Overview [212Pb]VMT-Alpha-NET is being tested for its effectiveness on shrinking tumors with somatostatin receptors. The drug is administered intravenously in four 8-week cycles. Some may also receive [203Pb]VMT-Alpha-NET to track the drug's distribution.

How Is the Trial Designed?

Group I: 3/Arm 3 Experimental Treatment 2 Interventions

\[212Pb\]VMT-alpha-NET at MTD

Group II: 2/Arm 2 Experimental Treatment 2 Interventions

Escalating doses of \[212Pb\]VMT-alpha-NET

Group III: 1/Dosimetry Arm 1 Experimental Treatment 3 Interventions

Escalating doses of \[212Pb\]VMT-alpha-NET, imaging with \[203Pb\]VMT-alpha-NET

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Targeted alpha therapy (TAT) using lead-212 (212Pb) shows promise for treating neuroendocrine tumors (NETs), with the study identifying [212Pb]Pb-eSOMA-01 as a leading candidate based on its high tumor uptake and low kidney absorption in tests with tumor-bearing mice.

The ligands developed for this therapy demonstrated high radiochemical yields and stability, with [212Pb]Pb-eSOMA-01 achieving the highest absorbed dose in tumors (35.49 Gy/MBq) while minimizing exposure to healthy tissues, indicating a potential for safer and more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[212Pb]Pb-eSOMA-01: A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors. Chapeau, D., Koustoulidou, S., Handula, M., et al.[2023]

In a patient with advanced midgut neuroendocrine tumor and carcinoid heart disease, the use of 203 Pb-VMT-α-NET showed high uptake in liver metastases, indicating its potential effectiveness for targeted therapy.

The imaging results from 203 Pb-VMT-α-NET were comparable to those from 68 Ga-HA-DOTATATE PET/CT, suggesting that 203 Pb-VMT-α-NET could be a feasible option for therapy in patients who are refractory to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

203 Pb-VMT-α-NET Scintigraphy of a Patient With Neuroendocrine Tumor. Müller, D., Herrmann, H., Schultz, MK., et al.[2023]

In a study of 11 patients with grade 1/2 metastatic neuroendocrine tumors treated with [225Ac]Ac-DOTATATE, the therapy demonstrated a high disease control rate of 89%, with 44.4% of patients showing a partial response and 44.4% having stable disease.

The treatment was found to be stable and safe, with only mild toxicities reported (grade 2 renal and hematotoxicity), and a median progression-free survival of 12 months, indicating its potential effectiveness for patients who were refractory to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors. Demirci, E., Alan Selçuk, N., Beydağı, G., et al.[2023]

Neuroendocrine neoplasms (NEN), particularly well-differentiated types, can be effectively diagnosed and treated using peptide receptor radionuclide therapy (PRRT) with somatostatin receptor analogues, which have been shown to be a safe and effective treatment option following FDA and EMA approval of 177Lu-DOTATATE.

Current research is focused on enhancing the efficacy of PRRT and minimizing its toxicity through personalized treatment approaches, improved patient selection, and the development of new radiopharmaceuticals, indicating a promising future for NEN management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular imaging Theranostics of Neuroendocrine Tumors. Fortunati, E., Bonazzi, N., Zanoni, L., et al.[2023]

In a study of 32 patients with advanced metastatic GEP-NETs who were refractory to 177Lu-DOTATATE therapy, 225Ac-DOTATATE targeted alpha therapy showed promising efficacy, with 15 patients achieving partial remission and no documented disease progression during a median follow-up of 8 months.

The therapy also resulted in a significant decrease in plasma chromogranin levels, indicating a biochemical response, and suggests that 225Ac-DOTATATE could be a valuable treatment option for patients who have exhausted other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Broadening horizons with 225Ac-DOTATATE targeted alpha therapy for gastroenteropancreatic neuroendocrine tumour patients stable or refractory to 177Lu-DOTATATE PRRT: first clinical experience on the efficacy and safety. Ballal, S., Yadav, MP., Bal, C., et al.[2022]

A 46-year-old man with rectal neuroendocrine tumors and extensive skeletal metastases was treated with 6 cycles of 225Ac-DOTATATE, showing excellent symptomatic, biochemical, and radiological responses without severe adverse events.

The use of 225Ac-DOTATATE as a first-line treatment offers a promising new strategy for patients with metastatic neuroendocrine tumors who have a high burden of skeletal disease, potentially overcoming the limitations of traditional β-emitter therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha Before Beta: Exceptional Response to First-Line 225Ac-DOTATATE in a Patient of Metastatic Neuroendocrine Tumor With Extensive Skeletal Involvement. Satapathy, S., Sood, A., Das, CK., et al.[2023]

Combining peptide receptor radionuclide therapy (PRRT) with anti-PD1 immunotherapy significantly enhances treatment response in neuroendocrine tumors (NETs), with the most effective approach being to administer PRRT before anti-PD1 therapy.

In a study involving 96 mice with human NET cells, the early PRRT regimen led to the greatest reduction in tumor size and increased T-cell activation, indicating a robust inflammatory response compared to other treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors. Esfahani, SA., De Aguiar Ferreira, C., Summer, P., et al.[2023]

In a study of 43 patients with advanced gastrointestinal neuroendocrine tumors, (177)Lu-Dotatate peptide receptor radionuclide therapy (Lu-PRRT) demonstrated an 84% disease control rate, with a median response duration of 25 months and a median progression-free survival of 36 months.

Both standard and reduced dosages of Lu-PRRT were found to be safe, as none of the patients experienced side effects, even those at higher risk for kidney or bone marrow toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study. Paganelli, G., Sansovini, M., Ambrosetti, A., et al.[2022]

In a study involving 35 patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with Lutathera (177Lu-DOTATATE), the treatment was well tolerated, with most adverse events being low grade.

Among patients who completed all 4 cycles of Lutathera, 22% showed a partial response, 44% had stable disease, and 13% experienced disease progression, indicating Lutathera's potential efficacy in managing GEP-NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peptide receptor radionuclide therapy implementation and results in a predominantly gastrointestinal neuroendocrine tumor population: A two-year experience in a nonuniversity setting. Mejia, A., Vivian, E., Nwogu, C., et al.[2023]

Citations