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

Overseen By Joy 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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the treatment [212Pb]VMT-Alpha-NET for neuroendocrine tumors?

Research shows that similar treatments using lead-212 (212Pb) for neuroendocrine tumors have shown promising results, with high tumor uptake and effectiveness in targeting cancer cells. Additionally, studies on related therapies have demonstrated improved outcomes when combined with other treatments, suggesting potential benefits for [212Pb]VMT-Alpha-NET. ^{1 2 3 4 5}

Is [212Pb]VMT-Alpha-NET safe for humans?

There is limited safety data available specifically for [212Pb]VMT-Alpha-NET in humans. However, related treatments like [203Pb]Pb-eSOMA-01 have shown promising results in preclinical studies with high tumor uptake and low kidney absorption in mice, suggesting potential safety. Further investigations are needed to confirm its safety in humans. ^{1 3 5 6 7}

How is the drug [212Pb]VMT-Alpha-NET different from other treatments for neuroendocrine tumors?

[212Pb]VMT-Alpha-NET is unique because it uses targeted alpha therapy (TAT) with lead-212, which may offer more precise targeting of tumor cells compared to traditional treatments. This approach aims to improve outcomes by delivering a high dose of radiation directly to the tumor while minimizing damage to surrounding healthy tissues. ^{1 3 5 8 9}

Research Team

Frank I Lin, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

[212Pb]Pb-eSOMA-01: A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors. [2023]

2. Germany 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

203 Pb-VMT-α-NET Scintigraphy of a Patient With Neuroendocrine Tumor. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Molecular imaging Theranostics of Neuroendocrine Tumors. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors. [2023]

6. United States 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. [2023]

7. Turkey pubmed.ncbi.nlm.nih.gov

Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study. [2022]

9. United States 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. [2023]