Neoplasms

All Conditions

Rare Diseases

Neuroendocrine Tumors

Carcinoid Tumor

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Gastro-enteropancreatic Neuroendocrine Tumor

Neuroepithelioma

Pharmaceutical Solutions

All Drugs and Chemicals

Antineoplastic Agents

Fluorodeoxyglucose F18

Olaparib

Somatostatin

Lutetium Lu 177 dotatate

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Lu-177-DOTATATE and escalating doses of olaparib to determine the maximum-tolerated dose (MTD)

Lu-177-DOTATATE will be given by IV every 8 (+/-2) weeks for a total of 4 administrations

Lu-177-DOTATATE

Olaparib is given as a pill taken orally and is to be taken twice a day, starting from 2 days before the first administration of Lu-177-DOTATATE until 4 weeks after the last administration

Ga68-DOTATATE PET/CT scan will be done at baseline, at week 32, then every 24 weeks in followup period.

Ga dotatate scanning

F18-FDG PET/CT scan will be done at baseline, at week 32, then every 24 weeks in followup period.

FDG-PET scanning

Concomitant administration of an IV infusion of an amino acid (AA) solution will also be done for renal protection. The AA infusion will begin at least 30-60 minutes prior to injection of Lu-177-DOTATATE and will continue during and after the Lutathera infusion until the entire prescribed amount is infused.

Amino Acid infusion

Joy Zou, R.N.

Frank I Lin, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

A neuroendocrine tumor is a rare type of tumor. It comes from body cells called neuroendocrine cells. Sometimes, these tumors develop in the gastrointestinal tract and pancreas. Researchers want to find out if a combination of drugs can shrink these tumors.

Objective:

To learn if people with certain neuroendocrine tumors can take a combination of 2 drugs, Lutathera and Olaparib, without having severe side effects, and if this treatment makes the tumors shrink.

Eligibility:

Adults 18 and older who have a neuroendocrine tumor in the pancreas or intestine that cannot be cured by surgery and has somatostatin receptors on the cells.

Design:

Participants will be screened under protocol 01-C-0129. They may have a tumor biopsy.

Eligible participants will get Lutathera through an intravenous (IV) infusion every 8 weeks for 4 cycles. One cycle is 8 weeks. Each cycle includes a follow-up visit at week 4. For the IV, a small plastic tube is put into an arm vein.

Participants will also take Olaparib by mouth twice a day for 4 weeks of each cycle. They will use a medicine diary to track the doses.

During the study, participants will have physical exams. They will have blood and urine tests. They will fill out questionnaires about their general well-being and function. Their heart function will be tested. They will have scans of their chest, abdomen, and pelvis. One type of scan will use an IV infusion of a radioactive tracer.

Participants will have a follow-up visit about 4 weeks after treatment ends. Then they will have follow-up visits every 12 weeks for 3 years. Then they will have yearly phone calls.

Background:

* Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and heterogeneous, but clinically important, group of neoplasms with unique tumor biology, natural history, and clinical management issues.
* While the treatment of localized NETs is surgical resection, a variety of therapeutic options are available for patients with advanced NETs. These include medical control of excess hormone levels and associated symptoms, cytoreductive surgery for patients with advanced disease, radioembolization, chemoembolization, systemic chemotherapy, interferon, longacting somatostatin analogs, receptor-targeted radionuclide therapy, and or liver transplantation.
* Somatostatin receptors (SSTR) have been shown to be overexpressed in a number of human tumors, including neuroblastoma, prostate cancer, pheochromocytomas, paragangliomas, and NETs, among many others.
* Lu-177-DOTATATE (Lutathera) is a SSTR-agonist agent which emits ionizing radiation that causes DNA damage to its target cells through both direct and indirect mechanisms. In addition, ionizing radiation has also been shown to induce cell death through what is known as the bystander effect, a phenomenon where cellular signaling from irradiated cells towards non-irradiated cells induces cellular damage and eventually death in nearby surrounding cells.
* Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an established safety

profile and it is under investigation in several different cancers.

- The rationale behind using combination therapies in cancer stems from the potential of synergistic mechanisms of action of the involved agents. Olaparib is a PARP-inhibitor which blocks the repair of single-stranded DNA breaks and is especially effective when combined with other agents which induces DNA damage.

Objectives:

* Phase I:

  * Characterize the safety profile and tolerability of the olaparib + Lu-177-DOTATATE combination.
  * Determine the maximum tolerated dose (MTD) dose of the combination using the 3+3 dose escalation design.
* Phase II:

  * Measure the Best Overall Response Rate (BOR) by RECIST 1.1 at the MTD dose at completion of 4 cycles of treatment.

Eligibility:

* Clinical diagnosis of GEP-NET disease, histologically confirmed to be consistent with neuroendocrine tumor.
* Inoperable disease (metastatic, non-candidate for surgery with curative intent, locally advanced into vessels or other critical structures, etc.).
* Age \>=18 years.
* Must have presence of SSTR+ disease as documented by positive Ga-68-DOTATATE PET scan within 12 weeks prior to anticipated treatment.
* ECOG Performance Status \<= 1.

Design:

* Open-label, single-arm, single-center, phase I/II study evaluating the safety and efficacy of the Lu-177-DOTATATE + olaparib combination in patients with inoperable GEP-NET.
* For phase I, a standard 3+3 design will be used to determine MTD. It is estimated that approximately 15 to 24 patients will be required. Phase II will involve the use of a Simon optimal two-stage design to determine sample size and interim stopping rule.
* Assuming a combination of inevaluable patients or loss-to-follow-up of 10%, up to 24 patients will be accrued to phase I and 15 patients to phase II including the 6 phase I patients at MTD, with a total accrual ceiling of 42 patients to allow for a small number of inevaluable patients.

Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)

Phase I/II Study of Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Depending on what the speed of dose escalation and the final MTD dose, it is estimated that for 4 dose levels with up to 6 patients at each level, approximately 12 to 24 patients will be required for the phase I portion of the study. Standard 3+3 design will be used.

Proportion of patients who have a partial or complete response to therapy.

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

Preliminary information on the BOR will be presented as a percentage with 95% confidence intervals. Only evaluate patients will be included. Kaplan-Meier curves of PFS will be constructed. Median PFS will be reported with 95% confidence intervals.

National Cancer Institute (NCI)

Nervous System Diseases

Gland and Hormone Related Diseases

Adenoma

Pituitary Diseases

Prolactinoma

Pituitary Neoplasms

Neoplasms, Glandular and Epithelial

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Endocrine Gland Neoplasms

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Cardiotonic Agents

Anti-Dyskinesia Agents

Dopamine

Cabergoline

Pasireotide

Dopamine Agonists

Hormones

Hormone Antagonists

Antiparkinson Agents

Dopamine Agents

Neurotransmitter Agents

For non-cured patients with prolactinomas resistant to cabergoline, MRI will be performed immediately before and six months after the onset of pasireotide treatment. The anti-secretory effect will be evaluated by prolactin dosage every month.

For patients harboring a NFPA, treatment will be started at least 3 months after neurosurgery, when a pituitary MRI clearly shows the presence of a residual tumor without any possible misinterpretation of postsurgical changes. In this case, the drug efficacy will be evaluated clinically by visual field and by MRI six months after pasireotide treatment.

In patients with non-functioning pituitary adenoma, treatment will be started at least 3 months after neurosurgery, when a pituitary MRI clearly shows the presence of a residual tumor without any possible misinterpretation of postsurgical changes. The drug response will be evaluated clinically by visual field and by Magnetic resonance imaging (MRI) before medical treatment and after six months of cabergoline treatment at maximum dose.

The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at the dosage of 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for six months.

The patients with resistant prolactinomas will be treated with pasireotide at the dosage of 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for 6 months.

The patients with resistant prolactinomas will be treated with pasireotide at 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

cabergoline

Mônica R. Gadelha, PhD

There are no available medical treatment options for patients with non-functioning pituitary adenomas (NFPA) or with resistant prolactinomas to dopamine agonists (DA) who are not cured by surgery. The study of the receptors by quantitative messenger ribonucleic acid (mRNA) expression levels and immunohistochemistry analysis might end with a better understanding of these tumors. Besides that, it will be assessed the in vitro and in vivo responses to pasireotide (for NFPA and prolactinomas) and cabergoline (for NFPA). These responses will be compared with the receptor expressions which may be a tool as a predicting element of the response to these compounds.

The goals of this study are: to verify whether cabergoline and pasireotide are effective in NFPA to control tumor re-growth as adjuvant therapy after neurosurgery and whether pasireotide is capable of normalizing the prolactin levels in patients with prolactinomas resistant to cabergoline; to assess the mRNA levels of dopamine receptor type 2 (DR2) and SSTR1-5 and their protein expression; to evaluate the in vitro hormonal response to cabergoline, octreotide and pasireotide; and to determine whether the mRNA DR2/SSTR1-5 and/or protein expression and/or in vitro hormonal response to cabergoline, octreotide and pasireotide correlates with the in vivo response to the former and to the last one. With this data the investigators intend to establish if the mRNA analysis and/or protein expression in NFPA and resistant prolactinomas might be predictive or foretelling factors concerning drug treatment in patients with this kind of pituitary tumors and also evaluate if there is any response in vitro or in vivo to the treatment with pasireotide in NFPA and resistant prolactinomas and with cabergoline in NFPA.

Response to Cabergoline and Pasireotide in Non-functioning Pituitary Adenomas and Resistant Prolactinomas

Somatostatin and Dopamine Receptors Expression in Non-functioning Pituitary Adenomas and Resistant Prolactinomas: Correlation With in Vitro and in Vivo Responsiveness to Somatostatin Analogs and Dopamine Agonist

Magnetic resonance imaging (MRI) of the sella and prolactin will be performed before (baseline) and after 6 months of treatment with cabergoline or pasireotide. Disease progression will be defined as tumor growth \> 25%, stable disease as changes \< 25% and significant tumor shrinkage as \> 25% in tumor volume compared to baseline MRI (baseline to six months).

Universidade Federal do Rio de Janeiro

Principal Investigator

For non-cured patients with resistant prolactinomas , MRI will be performed immediately before and six months after the onset of pasireotide . The efficacy will be evaluated by prolactin dosage every month.

For patients harboring a NFPA, treatment will be started at least 3 months after neurosurgery. In this case, the drug efficacy will be evaluated by MRI six months after pasireotide.

Pasireotide: The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at the dosage of 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for six months.

The patients with resistant prolactinomas will be treated with pasireotide at the dosage of 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

In patients with non-functioning pituitary adenoma, treatment will be started at least 3 months after neurosurgery. The drug response will be evaluated clinically by visual field and by Magnetic resonance imaging (MRI) before medical treatment and after six months of cabergoline treatment at maximum dose.

cabergoline: The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for 6 months.

The patients with resistant prolactinomas will be treated with pasireotide at 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

For non-cured patients with resistant prolactinomas , MRI will be performed before and six months after the onset of pasireotide. The efficacy will be evaluated by prolactin dosage every month.

For patients harboring a NFPA, treatment will be started at least 3 months after neurosurgery. In this case, the drug efficacy will be evaluated clinically by MRI six months after pasireotide.

Pasireotide: The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at the dosage of 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for six months.

The patients with resistant prolactinomas will be treated with pasireotide at the dosage of 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

Total

Age, Continuous

Sex: Female, Male

Brazil

Region of Enrollment

Monica Gadelha

For non-cured patients with resistant prolactinomas, MRI will be performed immediately before and six months after the onset of pasireotide. The efficacy will be evaluated by prolactin dosage every month.

For patients harboring a NFPA, treatment will be started at least 3 months after neurosurgery. In this case, the drug efficacy will be evaluated by MRI six months after pasireotide.

Pasireotide: The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at the dosage of 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for six months.

The patients with resistant prolactinomas will be treated with pasireotide at the dosage of 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

Tumor Volume Changes for NFPA and Prolactin Level Changes for Prolactinoma

Non-cured patients with resistant prolactinomas, MRI will be performed immediately before and six months after the onset of pasireotide. The efficacy will be evaluated by prolactin dosage every month.

Patients with a nonfunctioning pituitary adenoma (NFPA), treatment will be started at least 3 months after neurosurgery. The efficacy will be evaluated by MRI 6 months after pasireotide.

Pasireotide: The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at the dosage of 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for 6 months.

The patients with resistant prolactinomas will be treated with pasireotide at the dosage of 600 µg s.c. twice a day. After 4 weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for 6 months.

Overall Study

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Hematinics

Gastrointestinal Agents

Liver Extracts

Octreotide

Lanreotide

Antineoplastic Agents, Hormonal

1. Patients with cirrhosis without HCC in all liver function classes already receiving specific therapy for cirrhosis who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study
2. Patients with cirrhosis with multifocal HCC and clinical and/or radiological signs of persistence or recurrence of HCC in presence or absence of trombosis of the portal vein, with a single nodule of \>6 cm in size or multiple nodules of \>3 cm in size who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study

Octreotide-LAR intramuscular, dose of 30 mg every 28 days to increase up to 60 mg; lanreotide autogel 120 mg deep subcutaneous every 28 days for 3 months then uptitrated according with the protocol.

Octreotide-LAR, Lanreotide Autogel

Locoregional treatments

Annamaria Colao, MD, PhD

The hepatocellular carcinoma (HCC) represents more than 5% of all human malignancies, with more than 500,000 deaths per year (1). In Campania region, mortality for HCC is 2 times higher than in the rest of Italy because of a higher locally prevalence of hepatitis-C virus infection.

Development of HCC in liver cirrhosis is associated with increased DNA synthesis and regeneration of hepatocytes (2). Hepatocyte growth factor, the transforming growth factor-α, the fibroblast growth factor are well studied (3,4) while the insulin-like growth factor system (IGF-I, IGF-II and their binding proteins) has been less investigated. IGF-I and IGF-II modulate growth, metabolism and cell differentiation and have specific receptors in the liver (5). IGF-I levels in the upper normal range have been associated with an increased risk to develop prostate cancer (6), breast cancer (7) and colon cancer (8). Some data report increased expression of IGF-II in HCC (9,10) and others suggest a role of increased IGF-I bioavailability in HCC (11). We reported increased IGF-I/IGFBP-3 ratio in patients with HCC compared with those with cirrhosis with a similar liver function, so suggesting increased IGF-I bioavailability in HCC (12).

There is no currently medical treatment for patients with advanced HCC which has a very poor prognosis (survival \<6 months). Because of limited liver function, classical chemotherapy cannot be applied (13). In patients with HCC without cirrhosis, surgery is possible only in 5% while in those with cirrhosis first-line treatment is still questioned as survival is \<50% three years after operation. Patients suitable for local resection of HCC are only those with Child-Pugh's "hyper A" liver function class, who are a minority (14-16). Percutaneous resection treatments may treat approximately 70%-90% of tumors with maximal diameters of \<3 cm (15,17-19).

Somatostatin analogues are indicated in patients with neuroendocrine tumors expressing somatostatin receptors type 2 and 5 and has excellent safety profile. In advanced HCC, some studies demonstrated beneficial effects (20,21) while some others did not (22,23).

Only a few data are available on somatostatin receptor expression in HCC (24,25). Somatostatin analogues have also a clear-cut inhibitory effect on circulating IGF-I levels with a potential additional effect in delaying HCC progression.

Study objectives

1. To evaluate relationships between GH/IGF-I and IGF-II axis and development and progression of HCC;
2. To evaluate the expression of somatostatin receptor expression in biopsies of HCC by quantitative RT-PCR and immunohistochemistry and in vivo by octreoscan;
3. To evaluate the efficacy of octreotide-LAR or lanreotide-autogel as compared to placebo on clinical symptoms, liver function, biological markers and tumor dimensions by ultrasonography in advanced HCC patients;
4. To correlate the response to somatostatin analogues to somatostatin receptor expression in vitro and in vivo and suppression of the IGF-I and -II axis.

Study design

This is a pilot, open, prospective, monocentric study addressed to:

1. patients with liver cirrhosis and multifocal HCC with or without portal vein invasion;
2. patients with liver cirrhosis and single HCC nodule of \>6 cm in size with or without portal vein invasion \[principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)\];
3. patients with liver cirrhosis and more than 3 HCC nodules of \> 3 cm in size with or without portal vein invasion \[principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)\];
4. patients with cirrhosis without HCC.

Study protocol All enrolled subjects will be subjects to a baseline evaluation and a post-treatment evaluation according with the treatment protocol (see below).

A) Clinical study in vivo diagnostic routine analysis (clinical evaluation, ECG, chest X-ray, blood chemistry, analysis of liver function, α-FP assay, CEA, liver ultrasonography and angio-ultrasonography, abdominal CT scan or MRI); blood sampling for GH, IGF-I, IGF-II, IGFBP-3, ALS, insulin, IGFBP-1 and IGFBP-2; whole body scintigraphy with radiolabeled octreotide (octreoscan) liver biopsy in patients in good clinical condition according with good clinical practice procedures. Biopsy will be performed under ultrasonography guidance with a 19G or 21G needle after local subcutaneous anesthesia (lidocaine 2%). Abdominal ultrasonography will followed biopsy to exclude hemorrage. The tissue sample will be stores at -80° until analysis.

B) Morphological in vitro study the expression of somatostatin receptors will be performed by immunohistochemistry in sequential sections as well as by RT-PCR using specific primers for all receptors; the study includes an analysis of classical histology and immunohistochemical markers. The study includes positive and negative controls for an appropriate analysis of the results.

Study duration

The first study is a pilot study which expected number of patients fulfilling the inclusion criteria is 15 to address the issue of liver cirrhosis with HCC. The enrollment period will be of 12 months or shorter if the 15 patients are enrolled in a shorter time. The observational period is expected to be 3-12 months, according with previous studies. Treatment will be continued in all survivors even if the study will end after 12 months, according with previous studies. Subsequently, the study will proceed with a placebo-controlled randomized study according with the results obtained in the pilot study and will enroll 30-60 in case of patients with HCC without cirrhosis and 20-40 for patients with liver cirrhosis and HCC. All patients will be registered in dedicated CRF and data will be collected by investigators not involved in data analysis.

Withdrawal from the study

The causes of early study withdrawal will be recorded according with:

1. adverse events;
2. no treatment response or patients' clinical condition deterioration according with the investigator judgment;
3. major protocol violation;
4. patient's withdrawal of the consent.

Concomitant therapies All patients will continue all treatments as per investigator judgment. In case some therapy will be withdrawn this will be recorded in the CRF and analyzed as a potential beneficial effect of somatostatin analogues therapy.

Main outcome measures A) Efficacy parameters

For cirrhosis:

Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

For HCC:

Prolongation of the survival curve (\>6 months) Stabilization or reduction of tumor size Reduction or disappearance of portal vein thrombosis Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

Expected results

The expected results are:

1. Both cirrhotic and normal liver express somatostatin receptors. The different receptor pattern can suggest a role of this receptor subtype in HCC development. The correlation study can also give insight into any role of somatostatin receptors in differentiation, staging and prognosis of HCC.
2. Treatment with somatostatin analogues will prolong survival in advanced HCC patients. This should occur according with liver function before starting the treatment. We expect that patients having tumors with high expression of SS-2 receptors on their HCC will have the longest survival.

GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma

Treatment of Advanced Hepatocellular Carcinoma With Depot Somatostatin Analogues: a Pilot Prospective Study Based on Somatostatin Receptors Tumors Expression

Ospedali dei Colli

Federico II University

Annamaria Colao

The injection volume will be up to 5 mL over 20 seconds with an activity of 10 MBq/kg body weight (range between min. 500 and max. 800 MBq). To ensure application of the complete activity additionally 10 mL of 0.9% saline will be infused via the same system.

only one arm - the administration of \[99mTC\]-Tc-TECANT1 in all patients included

[99mTc]Tc-TECANT1

Alicja Hubalewska-Dydejczyk, Prof.

The main goal of the study is to expand cancer preclinical research results on the usefulness of SSTR2-Antagonist \[99mTc\]Tc-TECANT1 in clinical practice. Detection of NEN and monitoring of response to therapy is still challenging due to their cellular heterogeneity. Initial preclinical studies suggest that NEN imaging with the use of SSTR2-Antagonist may be advantageous in comparison to the widely used SSTR2-Agonists.

Recently, novel radiopharmaceuticals, based on SSTR2-Antagonists, were shown to provide superior SSTR2 visualisation than currently used agonists. The need for molecular imaging of NEN is expected to grow significantly in the near future due to their increasing incidence and prevalence. Although a persistent trend to shift the molecular imaging of NEN from conventional SPECT/CT gamma cameras to PET/CT has been observed in the last decade, labelling the compound with Tc-99m offers significant advantages by its extremely wide availability, low cost and low radiation exposure to patients. Effective and accessible molecular imaging methods as an integral part of personalised patient management are needed to optimise selection and follow-up of available therapeutic modalities. The Tc-99m-labeled SSTR2-Antagonist \[99mTc\]Tc-TECANT1 is expected to be an effective, widely available compound for quantitative assessment of SSTR2 NEN status, allowing a personalised therapeutic approach.

Neuroendocrine neoplasms (NEN) are a heterogeneous group of malignancies that arise from various endocrine glands, endocrine cells within non-endocrine tissue and diffuse endocrine cells of the gastrointestinal, respiratory and genitourinary tract. Detection of NEN and monitoring of their response to therapy is challenging due to their varied location (often-unknown primary focus) and cellular heterogeneity. NEN exhibit a wide range of histological appearances and biological behaviors, and may all potentially behave in an aggressive manner, irrespective of the initial diagnosis. Consequently, the prediction of clinical outcomes in an individual patient is often difficult and inaccurate. According to some national registries, the incidence of NEN increased more than 6-fold and the prevalence more than 8-fold between 1973 and 2012, making NEN the second most prevalent diagnosis in gastrointestinal malignancies, thus representing a growing challenge. The rise in the incidence can be partly attributed to increased awareness of the disease and better detection methods. Diagnostic imaging is an integral part of the management of patients with NEN by localising the primary or recurrence site, determining the extent of the disease and evaluating response to therapy. Nuclear medicine with single-photon emission tomography (SPECT) and positron emission tomography (PET) is a branch of molecular imaging: in contrast to anatomical imaging, it depicts functional changes and biological characteristics of target tissues, providing a unique insight into the biology of malignant disease, and has established itself as an excellent tool in personalized medicine. The characteristic feature of NEN is an overexpression of somatostatin receptors (SSTR) on cell membranes. Molecular imaging techniques utilise the ability of SST analogues labelled with radioactive (single-photon or positron emitting) nuclides to bind to the SSTR. A combination of molecular and anatomical imaging (hybrid imaging, SPECT/CT and PET/CT) is currently the most sensitive approach to visualisation of SSTR-positive tumours. In NEN patients the prognosis depends on the grade and stage of the tumour. However, SSTR expression determines not only efficacy of staging using molecular imaging methods, but also efficacy of antiproliferative therapy with SST analogues both not radiolabelled ("cold") and labelled with a therapeutic radionuclide thus enabling Peptide Receptor Radionuclide Therapy (PRRT) as the main approach to personalised NEN patients' management. Traditionally, radiolabelled SST analogues were constructed aiming at their agonistic behaviour, based on their internalisation after SSTR activation and consequent retention within the tumour cells, believed to be crucial for efficient molecular imaging and therapy. Recently, it has been shown that novel molecular probes, SSTR antagonists, recognise more binding sites and hence improve diagnostic efficacy, especially when the density of SSTR is low. Accumulating preclinical and clinical data using both SPECT and PET tracers shows that high-affinity SSTR antagonists can provide better SSTR visualisation than agonists. Preclinical data and subsequent clinical evaluation demonstrated higher tumour uptake of an In-111-labelled antagonist \[111In\]In-DOTA-sst2-ANT (\[111In\]In-DOTA-BASS) compared to the agonist \[111In\]In-DTPA0-octreotide or \[111In\]In -DTPA0-octreotate, as well as superior tumour-to-background ratios. One of the first reports describing the SSTR2 antagonist LM3 indicates the high potential of gallium-68 (Ga-68) and copper-64 (Cu-64) radiolabelled LM3 in PET/CT. The authors demonstrated strong dependence of the affinity and pharmacokinetics of the SST-based radiolabelled antagonists on the chelator and radiometal, also confirmed using another SSTR antagonist, namely JR11. The Superiority of the SSTR antagonist was demonstrated in the Phase I/II clinical study using a positron emitter, \[68Ga\]Ga-NODAGA-JR11 and in a pilot study conducted with beta-emitting, therapeutic radionuclide (lutetium-177, Lu-177) labelled SSTR antagonist \[177Lu\]Lu-DOTA-JR11. As a result, research in the field is currently strongly focused on SSTR antagonists. Ga-68-labelled SST analogues have already established PET as a unique tool for personalising treatment of NEN. Nevertheless, single-photon emitting radiopharmaceuticals still represent the cornerstone of molecular imaging, particularly those based on Technetium-99m (Tc-99m). Its physical properties (half-life of 6 hours, optimal energy of 140 keV for imaging and lowest radiation exposure), widest on-site availability and cost-effectiveness are of major importance for routine clinical applications. Medical diagnostic imaging techniques using Tc-99m account for approximately 80% of all nuclear medicine procedures, representing 30-40 million examinations worldwide every year; even in developed countries, the number of gamma cameras in use exceeds by far the number of PET systems. Considering the above-mentioned characteristics Tc-99m is perfect for research with new radiotracers and is still recognised as the workhorse of diagnostic nuclear medicine. Quantifiable uptake of the radiopharmaceutical in target tissue using standardised methods and metrics such as standardised uptake value (SUV) is currently a unique feature of PET allowing highly personalized approaches to patient management and is part of clinical routine. It was shown also in NEN that the quantitative approach is able to adequately predict and evaluate the response to various treatments available, including "cold" and radiolabelled somatostatin analogues (PRRT). However, single-photon quantitative imaging has developed significantly and is also entering clinical routine. Identical quantitative metrics are becoming available with the use of SPECT/CT systems (SPECT SUV) with comparable accuracy and clinical applicability. The development of a quantitative SPECT imaging approach in NEN, in combination with improved, widely available radiopharmaceuticals, would therefore represent a highly significant improvement in management, tailored to the needs of each individual patient.

Multi-center, Phase 0/I study, prospective single-arm, open-label study

Novel 99mTc-labeled Somatostatin Antaginosts in the Diagnostic Algotithm of Neuroendocrine Neoplasms

Novel 99mTc-labeled Somatostatin Antaginosts in the Diagnostic Algotithm of Neuroendocrine Neoplasms - a Feasibility Study

The number of patients with treatment-related adverse events as assessed by CTCAE v.5.0 (time frame: 2 weeks after administration)CTCAE v.5.0 (time frame: 2 weeks after administration)

Effective dose counted based on absorbed dose (energy deposited per unit mass) adjusted for radiation type and relative organ sensitivity measured in sievert (Sv)

Assessment of effective absorbed dose per injected activity \[mSv/MBq\] for critical organs (bone marrow, kidneys, bladder wall) and neoplastic lesions

1. Calculation of biological half-life of Tc-99m -SSTR2-Antagonist \[99mTc\]Tc-TECANT1 in blood (min) (based on time-activity curves)
2. Assessment of the biological half-life of Tc-99m-SSTR2-Antagonist \[99mTc\]Tc-TECANT1 (min) in normal organs, tumour lesions (based on time-activity curves)

Diagnostic accuracy assessed as the number of neoplastic lesions detected with \[99mTc\]Tc-TECANT1 in comparison to the number of lesions detected with (\[68Ga\]Ga-DOTA-TATE PET/CT)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)	NCT04086485	Gastroenteropan... Neuroendocrine ... Neuroendocrine ...	Lu-177-DOTATATE Olaparib Ga dotatate sca... FDG-PET scannin... Amino Acid infu...	18 Years -	National Institutes of Health Clinical Center (CC)
Response to Cabergoline and Pasireotide in Non-functioning Pituitary Adenomas and Resistant Prolactinomas	NCT01620138	Non-functioning... Prolactinomas	Pasireotide cabergoline	18 Years -	Universidade Federal do Rio de Janeiro
Response to Cabergoline and Pasireotide in Non-functioning Pituitary Adenomas and Resistant Prolactinomas	NCT01620138	Non-functioning... Prolactinomas	Pasireotide cabergoline	18 Years -	Universidade Federal do Rio de Janeiro
GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma	NCT00495846	Advanced Hepato...	Octreotide-LAR,... Locoregional tr...	18 Years - 75 Years	Federico II University
Novel 99mTc-labeled Somatostatin Antaginosts in the Diagnostic Algotithm of Neuroendocrine Neoplasms	NCT05871320	Neuroendocrine ...	[99mTc]Tc-TECAN...	21 Years -	Jagiellonian University
Response to Cabergoline and Pasireotide in Non-functioning Pituitary Adenomas and Resistant Prolactinomas	NCT01620138	Non-functioning... Prolactinomas	Pasireotide cabergoline	18 Years -	Universidade Federal do Rio de Janeiro

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