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Radiopharmaceuticals

Dose Escalation to determine MTD/MFD in 32 patients receiving up to 4 administrations of \[212Pb\]VMT-α-NET approximately 8 weeks apart.

A dosimetry sub-study utilizing \[203Pb\]VMT-α-NET has been incorporated into the study.

Patients with positive uptake on FDA approved SSTR2 PET/CT will receive a fixed dose of \[212Pb\]VMT-α-NET IV administered every 8 weeks for a maximum of four doses

[212Pb]VMT-α-NET

Patients with positive uptake on FDA approved SSTR2 PET/CT will receive a fixed dose of \[212Pb\]VMT-α-NET IV administered at the RPh2D and schedule determined in Phase I dose escalation

Markus Puhlmann, MD, MBA

Jason Starr, MD

Chih-Yi Liao, MD

Yusuf Menda, MD

Yvonne Taul

Lowell Anthony, MD, FACP

Lilja Solnes, MD

Neda Tehrani

Thorvardur R Halfdanarson, MD

John Crandall

Richard Wahl, MD

Samuel Mehr, MD

This study is Phase I/IIa First-in-Human Study of \[212Pb\]VMT-α-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

This is a prospective, multi-center open-label dose escalation, dose expansion study of \[212Pb\]VMT01 in up to 52 adult subjects with unresectable or metastatic SSTR2-expressing neuroendocrine tumors (NETs) who have not received prior peptide receptor radionuclide therapy (PRRT).

The radioactivity dose escalation period (phase I) tests up to 4 escalating radioactivity dose cohorts of up to 8 subjects (administered at approximately 8-week intervals) at the assigned cohort radioactivity dose.

Pre-specified dose adjustments and individual stopping rules for repeat treatment cycles are based on observed dose-limiting toxicities (DLTs) and adverse events (AEs).

The Maximum Tolerated Dose (MTD) will be determined based on observed DLTs within 42 days of the first treatment cycle.

The recommended expansion dose(s) will be determined following a holistic analysis of observed DLTs, AEs, estimated cumulative organ radiation exposure, and efficacy signals over the course of all treatment cycles for all dose cohorts.

If MTD can not be identified within the 4 radioactivity dose cohorts, a Maximum Feasible Dose (MFD), incorporating manufacturing and logistical considerations for \[212Pb\]VMT-α-NET production, may be determined.

Reno-protective amino acids will be co-administered in a separate IV line prior to each \[212Pb\]VMT-α-NET dose in all subjects. Escalation will be based on a modified toxicity probability interval design \[mTPI-2\] until MTD is identified or the pre-specified rules are met.

A lead-in dosimetry sub-study will be conducted during the dose escalation period in which all subjects in the first two dose cohorts will undergo dosimetric evaluation prior to receiving the therapeutic agent.

A Phase I/IIa First-in-Human Study of \[212Pb\]VMT-α-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

A Phase I/IIa First-in-Human Study of [212Pb]VMT-α-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

Any untoward medical occurrence in a clinical investigational participant administered \[212Pb\]VMT-α-NET and which does not necessarily have a causal relationship with this treatment

Determination of the overall response rate (ORR) by RECIST v1.1 in subjects with neuroendocrine tumors

Biodistribution will be calculated by utilizing SPECT/CT scans.

Perspective Therapeutics

Diseases and Abnormalities at or Before Birth

Symptoms and General Pathology

Multiple Endocrine Neoplasia

Multiple Endocrine Neoplasia Type 1

Neoplasms, Multiple Primary

Syndrome

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Radiotherapy for pancreatic NET will be delivered in an image-guided, hypofractionated scheme of 5 fractions of 8 Gy, prescribed to 95% of the planning target volume (PTV). Treatment is delivered on alternate days 2 or 3 times a week with a maximum overall treatment time of 14 days on the 1.5T MR-Linac (Elekta Unity MR-Linac).

The Gross Tumor Volume (GTV) is defines as the pNET visible on pre-treatment CT and MRI scan. No clinical target volume (CTV) is used. The PTV is made by adding a 3mm margin to the GTV.

The treatment plan is a 9-14 field intensity modulated radiotherapy (IMRT) plan with dose prescribed to 95% of the PTV. While respecting the dose constraints to adjacent tissues

MR-guided radiotherapy as described in the group information

High-dose-high precision MR-guided radiotherapy

Joanne M de Laat, Md, PhD

Gerlof D Valk, MD, PhD

Joanne M de Laat, MD, PhD

Patients with the Multiple Endocrine Neoplasia type 1 (MEN1) syndrome are genetically predisposed for developping multiple pancreatic neuro-endocrine tumours (pNET). The management of small (pNET) in both MEN1 and sporadic cases, pose a major clinical challenge. At present, pancreatic surgery is the only curative treatment but it is associated with high morbidity. To reduce the morbidity ascosiated with surgery and thereby potentially improve quality of life for MEN1 patients introduction of less invasive techniques for treatment of pNET is important. High-dose-high precision MR-guided radiotherapy (MRgRT) holds promise as a new less invasive treatment option for pNET. The aim of this study is to assess efficiacy and safety of MRgRT for treatment of pNET in MEN1 patients.

Background Patients with the Multiple Endocrine Neoplasia type 1 (MEN1) syndrome are genetically predisposed for developping multiple pancreatic neuro-endocrine tumours (pNET), with a cumulative pNET incidence of over 80% at an age of 80 years. In MEN1 patients, metastatic pNET is the primary cause of premature death.

The management of small (pNET) in both MEN1 and sporadic cases, pose a major clinical challenge. At present, pancreatic surgery is the only curative treatment. Since surgery is associated with significant short- and long-term morbidity the management of small pNET depends on carefully outweighing the risk of liver metastasis leading to premature death and the morbidity of pancreatic surgery. Guidelines advocate that for tumours smaller than 2 cm an intensive watchful waiting strategy seems to be safe. However, although most pNETs remain indolent for years, many lesions eventually progress and metastasize. To prevent the development of metastases for growing tumours or tumours above 2 cm a surgical resection is advised. Due to the high incidence of pNET in the MEN1 population many MEN1 patients receive surgery for pNET in their lifespan and cope with the morbidity of pancreatic surgery. To reduce the morbidity ascosiated with surgery and thereby potentially improve quality of life for MEN1 patients introduction of less invasive techniques for treatment of pNET is important.

High-dose-high precision MR-guided radiotherapy (MRgRT) holds promise as a new less invasive treatment option for pNET. With MRgRT accurate and precise delivery of high irradiation dose levels to the pNET is possible, while monitoring the tumor with MR imaging. The UMC Utrecht has pioneered the development of this technology, and gained experience with MRgRT treatments for patients with pancreatic adenocarcinoma and other upper abdominal malignancies.

Aim Aim of this project is to assess the safety and efficacy of high-dose-high precision MRgRT for pNET in a cohort of MEN1 patients that will require surgery in the near future.

Methods Efficacy and safety of MRgRT will be explored in a prospective cohort study of MEN1 patients with pNET, the Precision Radiotherapy using MRLInac for Pancreatic Neuroendocrine Tumours in MEN1 patients (PRIME)study. The PRIME study is a single arm interventional cohort study, recruiting 20 MEN1 patients enrolled in the Dutch MEN1 Study Groups (DMSG) longitudinal cohort. Eligible patients are patients with pNET surpassing 2.0 cm, and patients with a growing pNET measuring between 1.0- 2.0 cm. Patients who give informed consent will receive MRgRT with a minimum dose to the tumour bed of 40 Gy in 5 fractions delivered within 2 weeks. The primary outcome will be the change in maximum diameter of pNET at follow-up MRI scan at 12 months after diagnosis. Secondary outcome parameters include incidence of surgical resection following MRgRT, toxicity of radiotherapy, quality of life, endocrine and exocrine pancreatic functioning, metastases free survival, overall survival and tumour characteristics on follow-up MRI.

Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients

PRIME Study: Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients

Data will be placed in a repository and made available upon reasonable request, as stated in our data management plan.

Change in maximal diameter of pNET measured at follow-up MRI

Number of patients with signs of growth or metastasis at follow-up

Number of patients that require surgical treatment following MRgRT

Toxicity of radiotherapy graded according to Common Terminology Criteria for Adverse Events v4.0 scale

fasting glucose in evaluation of endocrine and exocrine pancreatic function

blood cell count in evaluation of endocrine and exocrine pancreatic function

vitamin B12 in evaluation of endocrine and exocrine pancreatic function

folate in evaluation of endocrine and exocrine pancreatic function

faecal fat test in evaluation of endocrine and exocrine pancreatic function

faecal trypsin in evaluation of endocrine and exocrine pancreatic function

faecal elastase in evaluation of endocrine and exocrine pancreatic function

Radboud University Medical Center

Erasmus Medical Center

Maastricht University Medical Center

Leiden University Medical Center

University Medical Center Groningen

J.M. de Laat

Principal Investigator (Md, PhD)

The investigators retrospectively analyzed data for patients who underwent contrast-enhanced MDCT for the evaluation of G3 PNETs at the Second Affiliated Hospital of Zhejiang University School of Medicine (n = 12) between January 2011 and May 2019, patients with G3 PNET who underwent MDCT at the First Affiliated Hospital of Zhejiang University School of Medicine (n = 4) and the Military Medical University of Air Force (The Fourth Military Medical University) (n = 4) between January 2013 and October 2018

Patients with PDAC who underwent MDCT at the Second Affiliated Hospital of Zhejiang University School of Medicine (n = 58) from February 2014 to August 2015.

No intervention

Risheng Yu

1. Imaging findings (including CT and MRI images) of both well-differentiated G3 PNET and poorly differentiated PNET were studied;
2. The CT imaging findings of G3 stage PNET and pancreatic cancer were compared to establish a Logistic regression diagnostic model, and the survival analysis of the two was compared.
3. Cox regression was used to study the risk factors for survival prognosis of well-differentiated and poorly differentiated PNET based on CT image features

According to the latest WHO Classification of Neuroendocrine Neoplasms (NET) in 2019, pancreatic neuroendocrine neoplasms (PNET) are divided into well-differentiated and poorly differentiated PNETs.The former is divided into G1, G2, and well differentiated G3.There are few studies on the survival outcomes of these two differentiated PNET types.The G3 imaging manifestations of the two types of differentiation have not been studied yet, and G3 PNET is often clinically misdiagnosed as pancreatic cancer, so it is necessary to differentiate the imaging manifestations and survival time of the two types.

A total of 71 patients with PNET in our hospital from January 2012 to January 2019 and 58 patients with pancreatic cancer from February 2014 to August 2015 were retrospectively collected. Complete survival time data of all patients after telephone follow-up were obtained.Since G3 PNET is very rare, the investigators enrolled 9 patients with G3 PNET in the First Affiliated Hospital of Zhejiang University School of Medicine and 7 patients with G3 PNET in the Affiliated Hospital of Air Force Military Medical University from January 2013 to October 2018.

CT images of PNET and pancreatic cancer were analyzed independently by two radiologists specializing in abdominal diagnosis, in which G3 lesions were evaluated simultaneously on MRI images and the others were evaluated only on CT images.Records clinical data and imaging characteristics: gender, age, tumor markers, tumor shape, size, tumor characteristics, edge, the expansion of the shrinking, pancreas, pancreatic pancreatitis, enhancement scan, arterial phase and portal phase lesions and the ratio of pancreatic parenchyma around, liver metastasis, peripheral vascular invasion, lymph node metastasis.

Related Studies of Imaging Features and Prognosis Between Pancreatic Neuroendocrine Tumors and Pancreatic Cancer

Grade 3 Pancreatic Neuroendocrine Tumors on MDCT: Establishing a Diagnostic Model and Comparing Survival Against Pancreatic Ductal Adenocarcinoma

Locations of the pancreas: head, neck, body and tail

solid；solid and cystic；complex cystic

Zhejiang University

The First Affiliated Hospital of the Fourth Military Medical University

Second Affiliated Hospital, School of Medicine, Zhejiang University

Gastro-enteropancreatic Neuroendocrine Tumor

Edotreotide

Emilio Bertani

In gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), radical surgery provides good long-term outcome and low recurrence rates. In GEP-NETs the actual surgical planning is established on the ground of preoperative morphology images (CT scan), and functional imaging using CT/PET with 68Ga-DOTA-TOC, since the high expression of somatostatin receptors (SSR) of these tumors. RGS in GEP-NETs, mainly with gamma-probes, has been not widely accepted since the low rates of sensitivity and, in particular, specificity, in discriminating tumoral/ non tumoral tissue and background ratio. This is a relevant issue in particular in detecting metastatic lymph-nodes both for small-intestine neuroendocrine tumors (SI-NETs) and pancreatic neuroendocrine tumors (Pan-NETs), where the presence of lymph-node metastases has been associated with worse long-term outcome. At present, it is not possible to distinguish whether a small lymph-node is site of metastases or not without performing frozen sections. In a previous study ex-vivo from European Institute of Oncology SI-NET presented a high uptake of a beta-emitting radiotracer, 90Y-DOTA-TOC. Five SI-NET showing SSR positivity at PET with 68Ga DOTA-TOC received 5 mCi of 90Y-DOTA-TOC the day before surgery. All the tumor samples showed high counts of radioactivity with a sensitivity of 96% and a specificity of 100%. These results allowed the investigators to develop a probe, which is now approved for in-vivo employment within the operating theatre. The objective of the present study is to verify in-vivo within the abdominal cavity the capability of the probe to detect 68-Ga activity within tumoral tissue thus favouring radical surgery and avoiding unnecessary demolition, in the near future. However, in the present protocol the entity of surgery will not be modified by intraoperative findings of the probe. It is reasonable to assume that results from 68Ga-DOTA-TOC might be comparable to 90Y-DOTA-TOC as radiotracer, and the detection efficacy of the probe for 68Ga could be not inferior compared to the isotope 90Y. However, while 90Y-DOTA-TOC is used as investigational drug for therapy purposes only within clinical research protocol, 68Ga-DOTA-TOC is a diagnostic radiotracer broadly used in day-to-day clinical practice since many years. Furthermore, the administration of 68Ga-DOTA-TOC can be directly injected in surgery room and thus does not require patients' admission the day before surgery.

Radical surgery is one of the most important way of treatment for solid tumors. In gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), it provides good long-term outcome and low recurrence rates. For breast cancer radio-guided surgery (RGS), using gamma radiations, is a well standardised methods because it aids to remove non-palpable lesions. In GEP-NETs the actual surgical planning is established on the ground of preoperative morphology images (CT scan), and functional imaging using CT/PET with 68Ga-DOTA-TOC, since the high expression of somatostatin receptors (SSR) of these tumors. RGS in GEP-NETs, mainly with gamma-probes, has been not widely accepted since the low rates of sensitivity and, in particular, specificity, in discriminating tumoral/ non tumoral tissue and background ratio. This is a relevant issue in particular in detecting metastatic lymph-nodes both for small-intestine neuroendocrine tumors (SI-NETs) and pancreatic neuroendocrine tumors (Pan-NETs), where the presence of lymph-node metastases has been associated with worse long-term outcome. At present, it is not possible to distinguish whether a small lymph-node is site of metastases or not without performing frozen sections. In a previous study ex-vivo from our Institute SI-NET presented a high uptake of a beta-emitting radiotracer, 90Y-DOTA-TOC. Five SI-NET showing SSR positivity at PET with 68Ga DOTA-TOC received 5 mCi of 90Y-DOTA-TOC the day before surgery. All the tumor samples showed high counts of radioactivity with a sensitivity of 96% and a specificity of 100%. These results allowed us to develop a probe, which is now approved for in-vivo employment within the operating theatre. The objective of this study is to verify in-vivo within the abdominal cavity the capability of the probe to detect 68-Ga activity within tumoral tissue thus favouring radical surgery and avoiding unnecessary demolition, in the near future. However, in the present protocol the entity of surgery will not be modified by intraoperative findings of the probe. It is reasonable to assume that results from 68Ga-DOTA-TOC might be comparable to 90Y-DOTA-TOC as radiotracer, and the detection efficacy of the probe for 68Ga could be not inferior compared to the isotope 90Y. However, while 90Y-DOTA-TOC is used as investigational drug for therapy purposes only within clinical research protocol, 68Ga-DOTA-TOC is a diagnostic radiotracer broadly used in day-to-day clinical practice since many years. Furthermore, the administration of 68Ga-DOTA-TOC can be directly injected in surgery room and thus does not require patients' admission the day before surgery.

The Primary objectives are to evaluate the diagnostic accuracy of the combined approach with β-probe and 68Ga-68 DOTA-TOC PET/CT in the correct identification of primary tumor and lymph-node metastases, patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) undergoing surgery. The histopathological analysis of the surgical specimens will be considered the standard of reference and diagnostic accuracy will be evaluated in terms of sensitivity and specificity.

The secondary objectives are:

* the identification of the most appropriate tumor-to-background ratio (TBR) able to correctly locate the signal emitted by DOTA-TOC-positive tumors or lymph nodes compared with the signal derived by the background rumor.
* safety and toxicity analysis regarding the intraoperative application of the β-probe.
* the comparison between the signal detected by the β-probe and 68Ga-DOTA-TOC PET/CT images.
* the correlation of the signal detected by the β-probe with the DOTA-TOC expression (DOTA-TOC staining) in tumors AND lymph node metastases assessed by immuno-histochemical analysis on the surgical specimens

The pathology assessment will be assessed with Immune-histo-chemical (IHC) analysis performed on surgical specimens obtained during surgery to assess the presence of neuroendocrine tumor localizations

68Ga-DOTATOC Radio-Guided Surgery With β-Probe in GEP-NET

The histopathological analysis of the surgical specimens will be considered the standard of reference and diagnostic efficacy will be evaluated in terms of sensitivity, specificity and positive predictive value (PPV). The radiation protection considerations are related to administering 68Ga-DOTA-TOC-PET/CT to enable radio-guided surgery. The day of surgery, the patients enrolled will receive 1.1 MBq/Kg, 60-90 minutes prior to surgery. The activity has been calculated considering preliminary in humans' data recently published by Collamati at al. Moreover, on the basis of the results of the first patients, the activity to be administered could be further reduced, considering that the beta probe detection will be performed approximately 1 hour after administration and not after 3 hours as reported in the reference. In any case, for radiation protection purposes only, it will be assumed that all 12 patients will be given an activity of 1.1 MBq/Kg.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors	NCT05636618	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Carcinoid Tumor... Carcinoid Tumor Paraganglioma Pheochromocytom...	[212Pb]VMT-α-NE... [212Pb]VMT-α-NE...	18 Years - 90 Years	Perspective Therapeutics
Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients	NCT05037461	Neuroendocrine ... Multiple Endocr...	High-dose-high ...	18 Years -	UMC Utrecht
Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients	NCT05037461	Neuroendocrine ... Multiple Endocr...	High-dose-high ...	18 Years -	UMC Utrecht
Related Studies of Imaging Features and Prognosis Between Pancreatic Neuroendocrine Tumors and Pancreatic Cancer	NCT04977596	Neuroendocrine ... Carcinoma, Panc... CT	No intervention	-	Second Affiliated Hospital, School of Medicine, Zhejiang University
Related Studies of Imaging Features and Prognosis Between Pancreatic Neuroendocrine Tumors and Pancreatic Cancer	NCT04977596	Neuroendocrine ... Carcinoma, Panc... CT	No intervention	-	Second Affiliated Hospital, School of Medicine, Zhejiang University
68Ga-DOTATOC Radio-Guided Surgery With β-Probe in GEP-NET	NCT05448157	Neuroendocrine ... Neuroendocrine ... Gep Net		18 Years -	European Institute of Oncology
68Ga-DOTATOC Radio-Guided Surgery With β-Probe in GEP-NET	NCT05448157	Neuroendocrine ... Neuroendocrine ... Gep Net		18 Years -	European Institute of Oncology

Spots Global Cancer Trial Database for neuroendocrine tumor of pancreas