Theranostics of Neuroendocrine Tumors with Somatostatin Antagonists
Researchers: Wolfgang Weber, MD, PhD; Diane Reidy-Lagunes, MD Locations: Memorial Sloan Kettering Cancer Center State: New York Year: 2013 Status: Finished
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To conduct a clinical trial for patients with carcinoid cancer for both treatment with the radionuclide, Lutetium-177 and imaging with the radionuclide, Gallium-68. This trial may provide proof of concept data to assess the potential for peptide receptor radionuclide therapy with somatostatin antagonists as a new treatment strategy for neuroendocrine tumor patients. This could pave the way for development of a new treatment and diagnostic imaging strategy for patients with neuroendocrine tumors in the US.
Peptide Receptor Radionuclide Therapy (PRRT) is a technique widely used in Europe for the management of patients with metastatic neuroendocrine tumors. There are currently clinical trials in the United States for PRRT with somatostatin agonists as described below.
PRRT delivers targeted radiation therapy by exploiting the physiology of neuroendocrine tumors. Most neuroendocrine tumors, including carcinoid, have specialized cellular receptors that bind to somatostatin, a hormone that exists naturally in the human body. Scientists have developed artificial “analogs” of somatostatin to attach to these receptors. These are called somatostatin agonists and they include agents like octreotide. Somatostatin agonists are able to target neuroendocrine tumors by binding to the somatostatin receptors present on tumor cells.
The PRRT currently in use typically combines a somatostatin agonist with a radioactive substance called a radionuclide to form highly specialized molecules calledradiopeptides. These radiopeptides can bind receptors on tumor cells where they emit radiation that can either 1) be read for diagnostic imaging or 2) kill tumor cells.
Studies have suggested that PRRT with somatostatin agonists can lead to a decrease in tumor size and alleviation of symptoms in some patients. However, not all patients respond and there can be serious side effects including kidney failure.To date, randomized prospective clinical trials, of the nature typically required by the FDA for regulatory approval have not yet been completed. However, there is currently a prospective randomized clinical trial of PRRT with somatostatin agonists in the United States enrolling patients at multiple centers.
The Memorial Sloan-Kettering Clinical Trial
To improve effectiveness while reducing side effects, Dr. Weber and his collaborators have developed a technique for “next generation” PRRT.Instead of somatostatin agonists, this next generation PRRT will employ somatostatin antagonists. Based on preclinical data, Dr. Weber believes that somatostatin receptor antagonists can be more effective and generate fewer side effects than the substances that are currently being used to treat patients.
Specifically, this trial will assess the potential viability of 68 Ga-DOTA-JR11 and 177 Lu-DOTA-JR11 as a pair of diagnostic and therapeutic radiopeptides for neuroendocrine tumor patients. Gallium 68 is a radionuclide that can be used in diagnostic PET scans. Lutetium 177 is a radionuclide often used with somatostatin analogs to form therapeutic radiopeptides. This study will assess the sensitivity of gallium 68 and the safety of lutetium 177 when combined with the somatostatin antagonist, DOTA-JR11 developed by the researchers. Eight patients with progressive, metastatic and inoperable tumors will participate in a clinical trial of peptide receptor radionuclide therapy with the somatostatin antagonist DOTA-JR11. Thanks to funding from another large Foundation these eight patients will enroll alongside an additional 12 patients for a total of 20 patients enrolled.
This trial may provide proof of concept data to assess the potential for peptide receptor radionuclide therapy with somatostatin antagonists as a new treatment for patients in the United States. Furthermore, strong data from this trial could enhance the commercial potential of these specific compounds. This could pave the way for development of a new treatment and diagnostic imaging strategy for patients with neuroendocrine tumors in the United States.
Assess biodistribution and tumor uptake of 68Ga-DOTA-JR11 and compare the sensitivity of 68Ga-DOTA-JR11 PET with conventional imaging
Determine tumor and normal organ doses after administration of 177Lu-DOTA-JR11; and
Obtain preliminary data on tumor response to 177LU-DOTA-JR11.
Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs has been developed in the 1990s, and is now frequently used in Europe for treatment of metastatic neuroendocrine tumors. However, not all patients respond well to PRRT; there are serious side effects, most notably chronic renal failure due to the renal excretion of the radiopeptides. Thus, there is a clear need to develop new ligands with higher tumor uptake and a more favorable tumor-to-kidney dose ratio.
To address this need, members of our group have developed radiolabeled somatostatin receptor type 2 antagonists. These are the first radiolabeled somatostain receptor antagonists. In this project we will study the second generation somatostatin receptor antagonists, 68Ga-DOTA-JR11 and 177Lu-DOTA-JR11, as a pair of diagnostic/therapeutic radiopharmaceuticals (theranostics) in patients with neuroendocrine tumors. Specifically, we will (i) assess biodistribution and tumor uptake of 68Ga-DOTA-JR11 and to compare the sensitivity of 68Ga-DOTA-JR11 PET with conventional staging procedures; (ii) determine tumor and normal organ doses after administration of 177Lu-DOTA-JR11; and (iii) obtain preliminary data on tumor response to 177Lu-DOTA-JR11.
We will conduct a clinical trial including 8 patients with well to moderately differentiated, progressive and inoperable midgut carcinoids. Patients will first undergo a PET/CT with 68Ga-DOTA-JR11. Patients with sufficient tumor uptake of 68Ga-DOTA-JR11 will be offered therapy with 177Lu-DOTA-JR11. Therapy will be preceded by a dosimetric study to determine the amount of radioactivity that can be safely administered.
Research Progress and Results:
This clinical trial is now open. For information about the study, including the inclusion and exclusion criteria for eligibility, click here.
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