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All Drugs and Chemicals

Somatostatin

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

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

68Ga-DOTATATE PET/CT whole-body scanning will be done at target dose of 5 mCi. The whole-body PET/CT scan will be started approximately 60 minutes after the tracer injection and will take up to 2 hours.

68Ga-DOTATATE

\[203Pb\]VMT-alpha-NET (6 mCi) will be given IV at 7 days prior.

[203Pb]VMT-alpha-NET

\[212Pb\]VMT-alpha-NET will be given IV on Day 1 of every cycle for 4 cycles total at escalating doses in Phase I and at MTD during Phase II. One cycle is 8 weeks.

[212Pb]VMT-alpha-NET

Joy Zou, R.N.

Frank I Lin, M.D.

National Cancer Institute Referral Office

Background:

Gastrointestinal neuroendocrine tumors (GI NET) are a type of cancer that affects the stomach and intestines; pheochromocytoma/paragangliomas (PPGL) are tumors that grow in or near the adrenal glands. Both of these types of tumor have high levels of a protein called somatostatin receptors (SSTR) on their surfaces. Researchers want to test a treatment that targets SSTR.

Objective:

To test a drug (\[212Pb\]VMT-alpha-NET) in people with GI NET or PPGL. The drug has 2 components: a protein to bind to SSTR and a radioactive agent to kill the cancer cells.

Eligibility:

Adults aged 18 years or older with GI NET or PPGL tumors that have spread and cannot be removed with surgery.

Design:

Participants will be screened. They will have a physical exam, with imaging scans, blood tests, and tests of their heart function.

\[212Pb\]VMT-alpha-NET is given through a tube attached to a needle inserted into a vein (infusion). Treatment will be given in four 8 week cycles. Participants will receive the drug on the first day of each cycle. They will remain in the clinic at least 4 hours after each infusion and may nee to stay in th hospital for up to 48 hour for monitoring and testing. They will have blood tests every week of 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 for 10 years....

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 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 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 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
* The overall study accrual ceiling will be set to 53 participants

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

Phase I/II Trial of Systemic Targeted Radioligand Therapy (TRT) With Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR Positive (SSTR+) Gastrointestinal (GI) Neuroendocrine Tumors (NET) and Pheochromocytoma/ Paragangliomas Previously Treated With Systemic Radiolig and Therapy

.All IPD recorded in the medical record will be shared with intramural investigators upon request. This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review.

The MTD will be presented as a recommended dose to be used as the recommended phase II dose (RP2D) for the combined participant population, as well as for each disease group being studied (GI-NET, PPGL).

The overall response rate will be presented as a percentage along with 95% confidence intervals. Only evaluable participants will be included.

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 will be reported with 95% confidence intervals.

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.

Kaplan-Meier curves of OS, will be constructed. Median OS will be reported with 95% confidence intervals.

PK data will be represented as a scatter plot graphing time vs. the amount of radioactivity found in blood and urine samples.

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.

National Cancer Institute (NCI)

Nervous System Diseases

Thyroid Diseases

Carcinoma

Pituitary Diseases

Thyroid Neoplasms

Carcinoma, Medullary

Carcinoma, Neuroendocrine

Neoplasms, Glandular and Epithelial

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Adenocarcinoma

Head and Neck Neoplasms

Thyroid Cancer, Medullary

Parathyroid Carcinoma

Pituitary Cancer

Lutetium Lu 177 dotatate

Radiopharmaceuticals

Parathyroid Hormone

Patients receive 177Lu-DOTATATE IV over 30 minutes every 8-16 weeks. Treatment continues for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

Lutetium Lu 177 Dotatate

Camilo Jimenez

This phase II trial studies how well 177Lu-DOTATATE works in treating patients with rare endocrine cancers that have spread from where they started to nearby tissue or lymph nodes (locally advanced), spread to other places in the body (metastatic), or cannot be removed by surgery (unresectable). Radioactive drugs, such as 177Lu-DOTATATE, may carry radiation directly to cancer cells and not harm normal cells. 177Lu-DOTATATE may help to control endocrine cancers compared to standard treatment.

PRIMARY OBJECTIVE:

I. Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 determined by Ia. Computed tomography (CT) or Ib. Magnetic resonance imaging (MRI).

SECONDARY OBJECTIVES:

I. To estimate progression-free survival at 1-year. II. To correlate blood pressure control and change/discontinuation of antihypertensive medications with tumor responses in patients with pheochromocytomas and paragangliomas (PHPGs).

III. To correlate plasma metanephrines and chromogranin A with tumor responses in patients with PHPGs.

IV. To correlate calcitonin, carcinoembryonic antigen, and chromogranin A with tumor responses in patients with medullary thyroid carcinoma (MTCs).

V. To correlate pituitary hormones (depending on particular tumor, e.g. prolactin for prolactinomas, insulin-like growth factor (IGF-1) for acromegaly, adrenocorticotropic hormone (ACTH) and 24-hour urine free cortisol for Cushing disease, and chromogranin A with tumor responses in patients with functional pituitary carcinomas).

VI. To correlate calcium, intact parathyroid hormone (iPTH), and chromogranin A with tumor responses in patients with parathyroid carcinoma.

VII. Toxicity assessment by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0).

VIII. To correlate tumor responses with tumor uptake score in somatostatin receptor scintigraphy, overall prognosis and responsiveness to lutetium Lu 177 dotatate (177Lu-DOTATATE).

IX. To determine the percentage of tumors that demonstrate uptake on diagnostic 68Gallium-DOTATATE positron emission tomography (PET)/CT that would make treatment with 177Lu-DOTATATE feasible.

EXPLORATORY OBJECTIVES:

I. To evaluate pituitary function in all patients to look for possible radiation late effects on the pituitary gland.

II. To estimate best biochemical response for specific tumor markers in patients with non-measurable disease.

III. To correlate biochemical response in patients with non-measurable disease with RECIST 1.1 tumor response criteria for patients with non-measurable disease.

OUTLINE:

Patients receive 177Lu-DOTATATE intravenously (IV) over 30 minutes every 8-16 weeks. Treatment continues for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at week 72 and then every 24 weeks for up to 5 years.

Radioactive Drug (177Lu-DOTATATE) for the Treatment of Locally Advanced, Metastatic, or Unresectable Rare Endocrine Cancers

A Phase II Study to Evaluate the Effects of 177Lu-DOTATATE in Patients With Unresectable and Progressive Rare Metastatic Endocrine Carcinomas: Medullary Thyroid Cancer, Parathyroid Carcinoma, Pituitary Carcinoma, and Malignant Pheochromocytoma/Paraganglioma

Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 determined by computed tomography (CT) or magnetic resonance imaging (MRI). Will be calculated as the proportion of patients with complete responses (CR), partial responses (PR), or stable disease (SD) at the CT/MRI assessment time point.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT06427798	Somatostatin Re... Gastrointestina... Pheochromocytom... Paragangliomas	68Ga-DOTATATE [203Pb]VMT-alph... [212Pb]VMT-alph...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
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	NCT06427798	Somatostatin Re... Gastrointestina... Pheochromocytom... Paragangliomas	68Ga-DOTATATE [203Pb]VMT-alph... [212Pb]VMT-alph...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Radioactive Drug (177Lu-DOTATATE) for the Treatment of Locally Advanced, Metastatic, or Unresectable Rare Endocrine Cancers	NCT04106843	Locally Advance... Locally Advance... Metastatic Adre... Metastatic Para... Metastatic Para... Pituitary Gland... Somatostatin Re... Stage III Thyro... Stage IV Thyroi... Stage IVA Thyro... Stage IVB Thyro... Stage IVC Thyro... Unresectable Ad... Unresectable Pa...	Lutetium Lu 177...	18 Years -	M.D. Anderson Cancer Center
Radioactive Drug (177Lu-DOTATATE) for the Treatment of Locally Advanced, Metastatic, or Unresectable Rare Endocrine Cancers	NCT04106843	Locally Advance... Locally Advance... Metastatic Adre... Metastatic Para... Metastatic Para... Pituitary Gland... Somatostatin Re... Stage III Thyro... Stage IV Thyroi... Stage IVA Thyro... Stage IVB Thyro... Stage IVC Thyro... Unresectable Ad... Unresectable Pa...	Lutetium Lu 177...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for somatostatin receptor positive