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

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 (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.

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 a series of whole-body gamma scans combined with dosimetry SPECT/Computed Tomography (CT) scans and collection of blood and urine samples prior to each cycle.
• 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 8 weeks after the last study drug administration for an end of treatment (EOT) visit. After EOT, visits will continue every 12 weeks for years 1-3, or until disease progression and every 6 months for years 4-6 (or after disease progression through 6 years) for safety and efficacy assessments. Beyond 6 years (until up to 10 years), participants will be contacted annually through any NIH-approved platform to assess for overall survival and health status.

• 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 per 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 percent 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.
• Individuals of child-bearing potential (IOCBP) and individuals who can father children must agree to use an effective method of contraception (barrier, hormonal, intrauterine device [IUD], surgical sterilization, abstinence) at study entry and at least 6 months after the last dose of the study agent(s).
• Nursing participants must be willing to discontinue nursing 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 i IOCBP 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.