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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

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.

European Institute of Oncology

Director - surgeon

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
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 carcinoid