Pb212 VMT alpha NET in treatment and re-treatment of SSTR+ tumors

Division Of Basic Sciences - Nci

Investigators

Abstract

Background: Somatostatin receptors (SSTR), especially type 2, have been shown to be over-expressed in a number of human tumors, including GI neuroendocrine tumors (GI NET), pheochromocytoma/paragangliomas (PPGL), small cell lung cancers (SCLC), kidney cancers (KC), and some head and neck cancers. -Targeted radioligand therapy (TRT) is a class of cancer therapeutic agents formed by attaching a radioactive isotope to a ligand which 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 binding characteristics of the ligand-receptor/transporter pair. While there have been clinical successes with treating 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 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 Lu-177. TRT agents using alpha emitters are considered to be more potent than beta emitting TRTs. 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 SPECT imaging. These images can be used to assess drug product biodistribution throughout the body. We are initiating two phase I clinical trials to assess the safety and efficacy of [212]Pb-VMT-alpha-NET in SSTR tumors including GI NET, PPGL, SCLC, KC, or HN: 1. a Phase I Trial of [212Pb]VMT-alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive GI Neuroendocrine Tumors, Pheochromocytoma/Paragangliomas, Small Cell Lung, Renal Cell, and Head and Neck Cancers. The study seeks to evaluate the safety and effectiveness of [212]Pb-VMT-alpha-NET in SSTR tumors including GI NET, PPGL, SCLC, KC, or HN. -[203Pb]VMT-alpha-NET will be used in these SSTR tumors to assess biodistribution throughout the body. Objectives: -Determine the MTD of [212Pb]VMT-alpha-NET using a 3+3 dose escalation design in several different SSTR+ tumor types. Eligibility: -Age 18 years. Histopathologically confirmed GI NET, PPGL, SCLC, KC, or H&N cancers that are metastatic or inoperable. Evidence of SSTR expression on at least 50% of the radiographically identifiable (i.e. visible on an anatomic scan such as CT or MRI) tumor, as indicated by a positive (uptake qualitatively identifiable as above the local background) SSTR PET scan. ECOG Performance Status 0-1. 2. a Phase I/II Trial of [212Pb]VMT-alpha-NET in Metastatic or Inoperable GI Neuroendocrine Tumors and Pheochromocytoma/Paragangliomas Previously Treated with Systemic Radioligand Therapy. The study seeks to evaluate the safety and effectiveness of [212]Pb-VMT-alpha-NET in GI NET and PPGL patients who have been previously treated with at least 1 cycle of beta-emitting systemic radionuclide therapy. [203Pb]VMT-alpha-NET will be used to assess biodistribution throughout the body.