## Protocol Section
### Identification Module
**NCT ID:** NCT06427798

**Brief Title:** 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

**Official Title:** 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

#### Organization Study ID Info
**ID:** 10001711
#### Organization
**Class:** NIH
**Full Name:** National Institutes of Health Clinical Center (CC)
#### Secondary ID Infos
**ID:** 001711-C
### Status Module
#### Completion Date
**Date:** 2039-07-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-31

**Type:** ESTIMATED

**Last Update Submit Date:** 2024-05-30

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2029-07-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-05

**Type:** ESTIMATED

**Status Verified Date:** 2024-05-22

#### Study First Post Date
**Date:** 2024-05-24
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-23
**Study First Submit QC Date:** 2024-05-23
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** NIH

**Name:** National Cancer Institute (NCI)

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

### Description Module

**Brief Summary:** 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....

**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) 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

### Conditions Module

**Conditions:**

- Somatostatin Receptor Positive

- Gastrointestinal Neuroendocrine Tumors

- Pheochromocytoma

- Paragangliomas

**Keywords:**

- 212Pb

- Targeted Therapy

- Image-Guided Dosimetry

- VMT- -NET

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** SEQUENTIAL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 53

**Type:** ESTIMATED

**Phases:**

- PHASE1

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

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

**Intervention Names:**

- Drug: 68Ga-DOTATATE

- Drug: [203Pb]VMT-alpha-NET

- Drug: [212Pb]VMT-alpha-NET

**Label:** 1/Dosimetry Arm 1

**Type:** EXPERIMENTAL

#### Arm Group 2

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

**Intervention Names:**

- Drug: 68Ga-DOTATATE

- Drug: [212Pb]VMT-alpha-NET

**Label:** 2/Arm 2

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** \[212Pb\]VMT-alpha-NET at MTD.

**Intervention Names:**

- Drug: 68Ga-DOTATATE

- Drug: [212Pb]VMT-alpha-NET

**Label:** 3/Arm 3

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- 1/Dosimetry Arm 1

- 2/Arm 2

- 3/Arm 3

**Description:** 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.

**Name:** 68Ga-DOTATATE

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- 1/Dosimetry Arm 1

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

**Name:** [203Pb]VMT-alpha-NET

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- 1/Dosimetry Arm 1

- 2/Arm 2

- 3/Arm 3

**Description:** \[212Pb\]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.

**Name:** [212Pb]VMT-alpha-NET

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** 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).

**Measure:** Phase I: MTD of [212Pb]VMT-alpha-NET using a 3+3 dose escalation design in GI NET and PPGL in a re-treatment setting

**Time Frame:** DLT period (through 12 weeks after initial 212Pb]VMT-alpha-NET administration).

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

**Measure:** Phase II: ORR by 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

**Time Frame:** Baseline until progression or 6 years after receiving the first infusion of study drug.

#### Secondary Outcomes

**Description:** 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.

**Measure:** Progression Free Survival

**Time Frame:** Baseline until progression or 10 years after receiving the first infusion of study drug

**Description:** 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.

**Measure:** Safety of [203Pb]VMT-alpha-NET and [212Pb]VMT-alpha-NET

**Time Frame:** Study duration

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

**Measure:** Overall Survival

**Time Frame:** Baseline until progression or 10 years after receiving the first infusion of study drug

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

**Measure:** PK properties of [212Pb]VMT-alpha-NET via blood and urine sampling

**Time Frame:** After every infusion of [212Pb]VMT-alpha-NET

**Description:** 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.

**Measure:** 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)

**Time Frame:** In Dosimetry Arm 1 after every [203Pb]VMT-alpha-NET infusion

### Eligibility Module

**Eligibility Criteria:** * INCLUSION CRITERIA:
* Participants must have histopathologically confirmed gastrointestinal neuroendocrine tumors (GI NET) or pheochromocytoma/paraganglioma (PPGL) cancers that are metastatic or inoperable per Standard of Care.
* Have received at least 1 prior systemic radioligand therapy for definitive therapeutic purposes. Note: Participants with prior external beam radiation treatment (EBRT) will also be eligible as long as they have had at least 1 prior administration of a systemic radioligand therapy.
* Must have at least 1 measurable lesion by RECIST 1.1 (phase II only).
* History of progression by imaging (e.g., RECIST 1.1) or clinically (defined as increase in severity or frequency of symptoms related to disease) within the past 36 months prior to the first dose of \[203Pb\]VMT-alpha-NET.
* Evidence of somatostatin receptors (SSTR) expression on at least 50% of the radiographically identifiable (i.e., visible on an anatomic scan such as CT or magnetic resonance imaging \[MRI\]) tumor, as indicated by a positive (uptake qualitatively identifiable as above the local background) on SSTR PET scan.
* Age \>= 18 years.
* ECOG performance status \<= 1.
* Participants must have adequate organ and marrow function as defined below:

  * Leukocytes: 3,000/microliter
  * Absolute Neutrophil Count: 1,500/microliter
  * Platelets: 100,000/miroliter
  * Hemoglobin: \>= 9.0 g/dL
  * Total bilirubin: within normal institutional limits. Note: \<= 5 X institutional upper limit of normal (ULN) if bilirubin elevation is due to a benign process such as Gilbert syndrome
  * AST: \<= 2.5 X institutional ULN
  * ALT: \<= 2.5 X institutional ULN
  * Creatinine: within normal institutional limits

OR

* Calculated creatinine clearance (glomerular filtration rate (eGFR): \>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal

  * Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression at screening.
  * Participants with new or progressive brain metastases or leptomeningeal disease are eligible as long as the participant is asymptomatic and not requiring medication for symptom control from the brain lesions at screening.
  * Participants seropositive for human immunodeficiency virus (HIV) must:
* be on effective anti-retroviral therapy; and
* have an undetectable viral load at screening.
* Participants seropositive for hepatitis B virus (HBV), must have HBV viral load undetectable at screening.

  -Participants seropositive for hepatitis C virus (HCV) must:
* received curative treatment; and
* have an undetectable HCV viral load at screening.

  * Participants may enroll in this study while on another therapeutic trial in order to start the screening process. However, all other investigational agents should be stopped at least 28 days prior to receiving \[203Pb\]VMT-alpha-NET.
  * Women of child-bearing potential (WOCBP) and men must agree to use an effective method of contraception (barrier, hormonal, intrauterine device \[IUD\], surgical sterilization, abstinence) at study entry and up to 6 months after the last dose of the study agent(s).
  * Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 6 months after the last dose of the study agents.
  * The ability of the participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* 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.

**Maximum Age:** 120 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** zoujh@mail.nih.gov

**Name:** Joy Zou, R.N.

**Phone:** (240) 760-6153

**Role:** CONTACT

**Contact 2:**

**Email:** frank.lin2@nih.gov

**Name:** Frank I Lin, M.D.

**Phone:** (240) 760-6166

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Bethesda

**Contacts:**

***Contact 1:***

- **Email:** ncimo_referrals@mail.nih.gov

- **Name:** National Cancer Institute Referral Office

- **Phone:** 888-624-1937

- **Role:** CONTACT

**Country:** United States

**Facility:** National Institutes of Health Clinical Center

**State:** Maryland

**Zip:** 20892

#### Overall Officials

**Official 1:**

**Affiliation:** National Cancer Institute (NCI)

**Name:** Frank I Lin, M.D.

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Access Criteria:** Data from this study may be requested by contacting the PI.

**Description:** .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.

**Info Types:**

- STUDY_PROTOCOL

- SAP

- ICF

**IPD Sharing:** YES

**Time Frame:** Data from this study may be requested by other researchers after the completion of the primary endpoint.

### References Module

#### See Also Links

**Label:** NIH Clinical Center Detailed Web Page

**URL:** https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_001711-C.html

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000017599

- Term: Neuroectodermal Tumors

- ID: D000009373

- Term: Neoplasms, Germ Cell and Embryonal

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000009380

- Term: Neoplasms, Nerve Tissue

- ID: D000005770

- Term: Gastrointestinal Neoplasms

- ID: D000004067

- Term: Digestive System Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000005767

- Term: Gastrointestinal Diseases

- ID: D000007410

- Term: Intestinal Diseases

- ID: D000004701

- Term: Endocrine Gland Neoplasms

- ID: D000010182

- Term: Pancreatic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000013272

- Term: Stomach Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M20495

- Name: Neuroendocrine Tumors

- Relevance: HIGH

- As Found: Neuroendocrine Tumors

- ID: M13578

- Name: Pheochromocytoma

- Relevance: HIGH

- As Found: Pheochromocytoma

- ID: M13149

- Name: Paraganglioma

- Relevance: HIGH

- As Found: Paraganglioma

- ID: M10448

- Name: Intestinal Neoplasms

- Relevance: HIGH

- As Found: Gastrointestinal Neuroendocrine Tumor

- ID: M13110

- Name: Pancreatic Neoplasms

- Relevance: HIGH

- As Found: Gastrointestinal Neuroendocrine Tumor

- ID: M16064

- Name: Stomach Neoplasms

- Relevance: HIGH

- As Found: Gastrointestinal Neuroendocrine Tumor

- ID: M19845

- Name: Neuroectodermal Tumors

- Relevance: LOW

- As Found: Unknown

- ID: M20388

- Name: Neuroectodermal Tumors, Primitive

- Relevance: LOW

- As Found: Unknown

- ID: M12318

- Name: Neoplasms, Germ Cell and Embryonal

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M12325

- Name: Neoplasms, Nerve Tissue

- Relevance: LOW

- As Found: Unknown

- ID: M8886

- Name: Gastrointestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7256

- Name: Digestive System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10444

- Name: Intestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7863

- Name: Endocrine Gland Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M13102

- Name: Pancreatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M16062

- Name: Stomach Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4091

- Name: Neuroendocrine Tumor

- Relevance: HIGH

- As Found: Neuroendocrine Tumors

- ID: T4530

- Name: Pheochromocytoma

- Relevance: HIGH

- As Found: Pheochromocytoma

- ID: T4409

- Name: Paragangliomas 1

- Relevance: HIGH

- As Found: Paraganglioma

- ID: T2442

- Name: Gastro-enteropancreatic Neuroendocrine Tumor

- Relevance: HIGH

- As Found: Gastrointestinal Neuroendocrine Tumor

- ID: T4387

- Name: Pancreatic Cancer

- Relevance: LOW

- As Found: Unknown

- ID: T5486

- Name: Stomach Cancer

- Relevance: LOW

- As Found: Unknown

- ID: T4092

- Name: Neuroepithelioma

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000018358

- Term: Neuroendocrine Tumors

- ID: D000010673

- Term: Pheochromocytoma

- ID: D000010235

- Term: Paraganglioma

- ID: D000007414

- Term: Intestinal Neoplasms

- ID: D000010190

- Term: Pancreatic Neoplasms

- ID: D000013274

- Term: Stomach Neoplasms

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M15806

- Name: Somatostatin

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
