Neoplasms

All Conditions

Rare Diseases

Carcinoma

Carcinoma, Neuroendocrine

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Somatostatin

Hormones

Hormone Antagonists

30 patients (18-80 years, males and females) affected by histologically-proven neuroendocrine neoplasms, locally advanced or metastatic, originating from pulmonary or gastro-entero-pancreatic (GEP) tract, candidate to medical therapy.

Patients affected by other non-malignant endocrine disease, e.g. benign thyroid disfunction (18-80 years, males and females)

According to current ENETS guidelines, patients will be treated by somatostatin analogs or chemotherapy, recommended respectively as first line therapy in neuroendocrine tumours or neuroendocrine neoplasms.

Somatostatin analog; chemotherapy

Andrea M Isidori, MD, PhD

Elisa M Giannetta, MD, PhD

Elisa Giannetta, MD, PhD

Antongiulio Faggiano, MD, PhD

Mary Anna Venneri, PhD

Maria Grazia Tarsitano, MD, PhD

Giulia Puliani, MD

Tiziana Feola, MD

Franz Sesti, MD

Francesca Sciarra, PhD

This is a multicentre, controlled, observational prospective study on new biomarkers, as immune profiling, angiogenetic markers and circRNA from TEPs in the diagnosis and in the evaluation of treatment response in pulmonary and gastro-entero-pancreatic NENs.

Neuroendocrine Neoplasm (NEN) are heterogeneous disease in terms of origin, localization and clinical presentation. Annual incidence of NEN is increasing in the last 30 years, even if the reasons underlying this rise have not been completely identified.

Many biomarkers have been used in the diagnosis and follow-up of patients with NEN. In non-functioning NEN general tumor markers, such as chromogranin A (CgA) and neuron specific enolase (NSE), are commonly used but their sensibility and specificity are quite low.

Recently, high-throughput tissue microarray and immunohistochemistry assessments have been performed to observe the expression pattern of new potential markers for NEN. In order to overcome limitations of tissue acquisition, the use of liquid biopsies has been advocated. It has been reported that tumor-educated platelets (TEPs) may easily enable blood-based cancer diagnostics. TEPs take up tumor-derived secreted membrane vesicles containing RNAs, of which circular RNAs (circRNAs) that can serve as a potential biomarker source for cancer diagnostics. This innovative approach in cancer detection has not yet been transferred to the NEN field.

Flow cytometric analysis furnishes important insights into the immune status by providing information about the numbers and phenotypes of the immune cells, which are known to be altered in many types of neoplasms. In NEN, leukocytes subpopulations and peripheral blood mononuclear cells (PBMCs) are not been completely investigated but immunological alterations could represent a signal of neoplastic spread.

Inflammatory and angiogenetic pathways' involvement in NEN behavior has recently received increasing attention. It is well known that NEN are known to be highly vascularized neoplasms and somatostatin analogues (SSA), used as first line drugs for most well differentiated NEN, can reduce tumour proliferation by various direct and indirect mechanism including the inhibition of angiogenesis.

Tumor angiogenesis is a complicated process consisting of several steps, the angiogenesis cascade, regulated by endogenous and exogenous factors, including the system Angiopoietin-1 (Ang-1) and -2 (Ang-2) / Tie2 and Prokineticins. These systems are involved in neoplastic angiogenesis and inflammation in various types of cancer. Despite these evidences, the role of inflammatory and angiogenic factors in NEN detection and follow-up has not been completely clarified.

The aim of the study is to evaluate immune profiling, angiogenetic markers and circularRNA sequencing in patients affected by locally advanced or metastatic pulmonary or GEP NENs and controls. Moreover, NENs patients will be evaluated also after 1 and 3 months of first line medical treatment.

Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)

Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN. REBORN Study

Modification of sTie (soluble Tie2) after treatment

Comparison of basal levels of sTie between patients and controls

Validation of the use of circular RNAs sequencing from tumor educated platelets (TEPs) in NETs diagnosis, through the comparison between patients and controls

Modification in circular RNAs sequencing from tumor educated platelets (TEPs) in patients after treatment

Comparison of basal level of other circular and cellular angiogenesis mediators between patients and controls (Angiogenic factors: ANG1, ANG2, FGF1, FGF2, NRP1, NRP2, VEGFA, VEGFB, VEGFC, HIF1A, NOS3, PROK1, PROK2; Cytokines: CCL11, CCL2, CXCL1, CXCL10, CXCL5, CXCL6, CXCL9, IL1B, IL6, TNF; Receptors and other angiogenic factors: VEGFR1, VEGFR2, TIE2, PDGFR, TGFBR, MMP14, MMP2, MMp9, TIMP1, TIMP2, TIMP3, PROKR1, PROKR2)

Modification of other circular and cellular angiogenesis mediators in patients after treatment (Angiogenic factors: ANG1, ANG2, FGF1, FGF2, NRP1, NRP2, VEGFA, VEGFB, VEGFC, HIF1A, NOS3, PROK1, PROK2; Cytokines: CCL11, CCL2, CXCL1, CXCL10, CXCL5, CXCL6, CXCL9, IL1B, IL6, TNF; Receptors and other angiogenic factors: VEGFR1, VEGFR2, TIE2, PDGFR, TGFBR, MMP14, MMP2, MMp9, TIMP1, TIMP2, TIMP3, PROKR1, PROKR2)

Quatification of peripheral blood mononuclear cells (PBMC) subpopulations in patients and controls

Modification of peripheral blood mononuclear cells (PBMC) subpopulations in patients after treatment

Comparison of basal serum level of classical neuroendocrine markers (chromogranin a and neuron specific enolase) between patients and controls

Modification of classical neuroendocrine markers (chromogranin a and neuron specific enolase) in patients after treatment

Frequencies and severity of infectious diseases will be evaluated by modified Infectious Diseases Questionnaire (GNC). This questionnaire includes questions on infectious diseases of upper and lower respiratory tract, gastrointestinal tract, skin and urogenital tract contracted during the previous 12 months. Questions investigate on the number and duration of infections, necessity of antibiotic or antifungal therapy, hospital stay and days of absence from work. Final score represents the frequency of infections. Moreover, some questions investigate possible susceptible or protective factors for infectious diseases: vaccinations, use of corticosteroids, concomitant diseases, previous appendectomy, tonsillectomy, adenoidectomy, splenectomy or thymectomy.

Quality of life will be evaluated by the Physical Component score and the Mental Component score of the self-administered questionnaire SF-36-Item Health Survey questionnaire. This questionnaire measures eight scales: physical functioning, role physical, bodily pain, general health (physical component) and vitality, social functioning, role emotional, mental health (mental component).

Interpretation of the score will be the following: at each item of the questionnaire corresponds a percentage value (from 0% to 100%). The average of the single items constitutes the scale total percentage (from 0% to 100%); missing data are not considered during calculation. High score defines a more favorable health state.

University of Roma La Sapienza

Full Professor

Lutetium Lu 177 dotatate

Radiopharmaceuticals

Intravenous administration of lutetium Lu 177 dotatate once every 8 weeks for up to 4 total cycles.

Intended administered radioactivity:

Cycle 1: 200 millicuries (mCi) Cycles 2, 3, and 4: based upon dosimetry for radiation exposure to bone marrow (no more than 1 Gy per administration) and kidneys (maximum dose 28 Gy total). Not to exceed 400 millicuries (mCi) per cycle (1400 mCi maximum for all cycles).

Intravenous administration of lutetium Lu 177 dotatate once every 8 weeks for up to 4 total cycles. Each cycle is intended to receive 200 millicuries of radioactivity for a total treatment of 800 millicuries.

LUTATHERA is an FDA approved radiopharmaceutical therapy for gastroenteropancreatic neuroendocrine tumor (GEP-NET). This radiopharmaceutical binds to somatostatin receptors, which are overexpressed on GEP-NET cells, and subsequently delivers beta particle radiation to the tumor cells.

Lutetium Lu 177 dotatate therapy

Stephen A Graves, Ph.D., DABR

Yusuf Menda, MD

Kristin Gaimari-Varner, RN, BSN

Kellie Bodeker, Ph.D.

David Bushnell, MD

Janet Pollard, MD

Parren McNeely, MD

Michael Graham, MD, PhD

Kristin Plichta, MD, PhD

Stephen Graves, PhD

Stephen Graves, Ph.D., DABR

The goal of this study is to learn if individualized dosimetry-based prescribing of Lutetium-177 DOTATATE (Lutathera, Novartis Pharmaceuticals) improves treatment outcomes for adults with unresectable neuroendocrine tumors. To investigate this, study participants will:

* Undergo Somatostatin Receptor (SSTR) positron emission tomography (PET) imaging, such as a DOTATOC PET/CT scan
* Be randomized to receive standard treatment (as per FDA guidelines) or investigational treatment (customized dosing of Lutathera based upon dosimetry)
* Undergo blood tests for 4 to 8 weeks after each Lutathera treatment
* Complete patient reported outcome questionnaires
* Visit the clinic for follow-up about every 8 weeks.

This is a randomized controlled clinical trial evaluating the impact of forward planning dosimetry for Lutetium-177 DOTATATE (Lutathera, Novartis Pharmaceuticals), a radiopharmaceutical approved to treat neuroendocrine tumors by the U.S. FDA.

If a patient consents to participate, and is deemed eligible to move forward, there is a 2 out of 3 chance to receive the investigational treatment (the Lutathera treatment customized to tumor uptake and kidney uptake). The standard treatment is 200 millicuries (mCi) of Lutathera per cycle, with potential adjustments for safety per the FDA-approved package insert.

Regardless of the assigned group (investigational treatment or standard treatment), the first treatment is 200 mCi. This is given with amino acids, which is required for this treatment.

Participants in the standard treatment continue to receive 200 mCi per treatment, with or without adjustment based on package insert instructions, for up to 4 treatments total.

Participants in the investigational treatment will receive a customized dose of Lutathera, up to 400 mCi per treatment for treatments 2 - 4, in the hopes that escalation will be safe and effective in many patients based on individualized dosimetry.

Participants randomized to the investigational treatment will receive specialized imaging (SPECT/CT) following administration of Lutathera. This will identify where the Lutathera went and how long it remains there (in the tumors, kidneys, or bone marrow). After the first dose of Lutathera, this imaging is done on the first day of treatment and then once a day for the next 3 to 4 days. Each scan lasts about an hour. Following treatments 2 and 3, this imaging is only done on the first day and then once at about 3 to 4 days after the treatment. There are also blood samples collected to measure the radioactivity in the blood.

All participants must be actively followed to assess for side effects of therapy as well as treatment outcomes. This means participants must return to the treatment site at 2, 3, 6, and 12 months after the last cycle of therapy. All participants must have a CT scan completed at 6 months after treatment as well.

Radiation side effects can take years to develop. For this reason, it is very important that participants remain in touch with the study investigator and team. Participants have life-long follow-up for this study.

177Lu-DOTATATE Modified Delivery Based on Individualized Dosimetry

Data will only be shared if the trial participant has consented to sharing.

Trial data to share:

imaging (CT, PET, MRI), dosimetry plans, participant demographics (race, ethnicity, age at consent), disease stage, organ contours for dosimetry, lutathera prescription, treatment history, concomitant medications, and dose modification and holds.

Protocol, blank case report forms, and statistical analysis plan will be retained and shared.

Imaging data are shared DICOM format. Adverse events will be categorized utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Determine objective response rate in patients with grade 1 or 2 gastroenteropancreatic neuroendocrine tumors (GEP-NET) treated with dosimetrically-determined LUTATHERA administration compared to active control.

Determine treatment-emergent toxicity, as graded by the NCI's Common Terminology Criteria for Adverse Events (CTCAE) version 5 in patients with grade 1 or 2 gastroenteropancreatic neuroendocrine tumor (GEPNET) treated with dosimetrically derived Lutathera compared to standard treatment. Endpoints are Incidence and severity of toxicities

Determine time to progression in patients with grade 1 or 2 gastroenteropancreatic neuroendocrine tumor (GEPNET) treated with dosimetrically derived Lutathera compared to standard treatment

Assess correlation between hematologic toxicity and bone marrow dose in patients with grade 1 or 2 gastroenteropancreatic neuroendocrine tumor (GEPNET) treated with dosimetrically derived LUTATHERA compared to active control

Novartis

University of Iowa

Assistant Professor

Symptoms and General Pathology

Neoplasm Metastasis

Antineoplastic Agents

Hematinics

Capecitabine

Temozolomide

Liver Extracts

Antimetabolites

Antineoplastic Agents, Alkylating

Alkylating Agents

Capecitabine 750 mg/m2 twice daily orally for 14 days and temozolomide 200 mg/m2 orally on Days 10-14, with 14 days between cycles, to be continued until 1) disease progression or 2) intolerable toxicities.

Trans-arterial radioembolization (TARE) on Day 7 of cycle 2 and, if needed for the other lobe, Day 7 of either cycle 3 or 4.

Capecitabine 750 mg/m2 twice daily orally for 14 days

Capecitabine Oral Product

temozolomide 200 mg/m2 orally on Days 10-14, with 14 days between cycles

Temozolomide Oral Product

Trans-arterial radioembolization (TARE) on Day 7 of cycle 2 and, if needed for the other lobe, Day 7 of either cycle 3 or 4.

transarterial radioembolization

Michael Soulen, MD

Kathleen Thomas

Deepon Paul Singh

Renuka Iyer, MD

Abashai Woodard

Michael Soulen

This is a Phase 2 evaluation of hepatic-progression free survival among patients with Grade 2 liver-dominant NET metastases undergoing combination therapy with CapTem and Y90 radioembolization.The hypothesis is to confirm safety and to assess if disease control is improved relative to expectation from either therapy alone.

Patients with liver-dominant Grade 2 NET metastases from any primary will start CapTem and undergo simulation angiography for radioembolization planning during the first cycle. If they tolerate CapTem and are not excluded from radioembolization, then TARE will be performed on Day 7 of Cycle 2, with additional TARE of Day 7 of cycle 3 or 4 as needed to treat the entire tumor burden. Patients will remain on CapTem until progression or intolerance.

Primary outcome measure is hepatic progression-free survival.

CapTemY90 for Grade 2 NET Liver Metastases

UPCC 04219 Phase 2 Study of Capecitabine-Temozolomide(CapTem) With Yttrium-90 Radioembolization in the Treatment of Patients With Unresectable Metastatic Grade 2 Neuroendocrine Tumors

Intra-hepatic progression-free survival by RECIST 1.0 is defined as the time from initiation of study therapy until first documented intra-hepatic disease progression, death due to any cause or last scan date that documented intra-hepatic progression-free status.

Overall progression-free survival is defined as the time from initiation of study therapy until first documented intra- or extra-hepatic disease progression, death due to any cause or last scan date that documented progression-free status

Intra-hepatic tumor responses will be evaluated by RECIST.

Intra-hepatic tumor responses will be evaluated by EASL criteria.

extra-hepatic tumor responses will be evaluated by RECIST.

Systemic toxicities will be individually assessed by NCI CTCAE Version 4.

Hepatic toxicities will be individually assessed by NCI CTCAE Version 4.

The primary marker is CgA. Additional cancer site-specific (i.e., gastrinoma) markers may also be assayed.

Quality of Life will be measure by a validated NET-specific instrument, EORTC. Scale is 0-100, higher scores indicate worse symptoms/functioning

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)	NCT04464122	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Somatostatin an...	18 Years - 80 Years	University of Roma La Sapienza
177Lu-DOTATATE Modified Delivery Based on Individualized Dosimetry	NCT06395402	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Lutetium Lu 177...	18 Years -	University of Iowa
Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)	NCT04464122	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Somatostatin an...	18 Years - 80 Years	University of Roma La Sapienza
CapTemY90 for Grade 2 NET Liver Metastases	NCT04339036	Neuroendocrine ... Neuroendocrine ...	Capecitabine Or... Temozolomide Or... transarterial r...	18 Years -	Abramson Cancer Center at Penn Medicine
CapTemY90 for Grade 2 NET Liver Metastases	NCT04339036	Neuroendocrine ... Neuroendocrine ...	Capecitabine Or... Temozolomide Or... transarterial r...	18 Years -	Abramson Cancer Center at Penn Medicine

Spots Global Cancer Trial Database for neuroendocrine tumor grade 2