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Gastro-enteropancreatic Neuroendocrine Tumor

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All Drugs and Chemicals

Lutetium Lu 177 dotatate

Edotreotide

Radiopharmaceuticals

on month before first cycle of 177Lu-DOTATATE, after second cycle and one year after first cycle

Simultaneous 68Ga-DOTATOC PET-MRI

Catherine ANSQUER

Louis DE MESTIER

LEBTAHI Rachida, Pr

Louis DE MESTIER, Dr

Yann TOUCHEFEU, Pr

Catherine ANSQUER, Dr

Operandi project aims to address unmet clinical needs in the current management of GEP-NETs treated with PRRT by exploring new opportunities provided by imaging-based artificial intelligence (AI) and data augmentation, simultaneous PET-MRI imaging, and novel approaches to increase patient selection and PRRT efficacy (genomic profiling, radiopotentiators, and new radionuclides). The study aim to identify predictive and early markers indicative of PRRT effectiveness based on a large prospective cohort of GEP-NET patients. This cohort will be used to uncover relevant predictive signatures within the morphological, functional, and molecular imaging data using novel imaging-based AI approaches with a new patient imaging pathway including simultaneous PET-MRI.

Considering this global objective, the objective of this clinical research protocol is to provide clinical, molecular and imaging data in a prospective standardized study, notably by performing systematic PET-MRI at baseline, at middle course of PRRT and at 1 year of the beginning of PRRT, in patients with advanced GEP-NETs treated with PRRT.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are considered rare neoplasms. Their incidence has been increasing over the last few decades, and due to generally prolonged survival of patients, the prevalence of GEP-NETs is higher than the combined prevalence of other more common gastrointestinal cancers, including oesophageal cancers, gastric adenocarcinomas, and pancreatic adenocarcinomas. Prognosis is related to several factors and especially to liver tumour involvement.

Peptide Receptor Radionuclide Therapy (PRRT) is a type of targeted radionuclide therapy that has been used in the treatment of patients with GEP-NETs for over two decades. The molecular target for PRRT in NETs is the somatostatin receptor (SSTR), mainly the subtype 2, which is highly expressed in most of these tumours. The 177lu-DOTATATE, a radiolabelled somatostatin analog, has reached a wide use due to a combination of high anti-tumour activity and a low level of toxicity. 177Lu-DOTATATE was granted marketing authorisation by the European Medicines Agency in 2017 and by the Food and Drug Administration in 2018 for the treatment of GEP-NETs. PRRT is a recent therapeutic approach in GEP-NET. Due to its high efficacy, it has become one of the most relevant therapeutic option for patients with inoperable and/or metastatic GEP-NETs. PRRT exert antitumor effects based on radio-biological (DNA damages) and immunological mechanisms.

Response evaluation - PRRT exerts antitumor effects based on radio-biological (DNA damages) and immunological mechanisms. While highly promising, patient stratification and early identification of responders are currently insufficient due to the lack of pertinent imaging biomarkers, either non-invasive or invasive. Furthermore, prior therapy-induced DNA damages may lead to tumour resistance, therefore reducing PRRT efficacy. Hence, the absence of a personalized treatment strategy is an unmet need for patients with GEP-NETs. This may result in survival disadvantage for non-responders, who could benefit otherwise from early treatment change, with expected more favourable outcomes.

Simultaneous PET-MRI: OPERANDI project proposes a completely innovative and holistic approach via PET-MRI guided therapy. Our hypothesis is that simultaneous PET-MRI imaging provides more robust non-invasive predictive biomarkers than classical approach. This requires technological development of PET-MRI, with most methodological challenges being attenuation correction, reducing the impact of organ motion due to respiration and cardiac motion, and minimizing truncation and susceptibility artefacts.

A PET/MRI scan is a two-in-one test that combines images from a positron emission tomography (PET) scan and a magnetic resonance imaging (MRI) scan. This new hybrid technology harnesses the strengths of PET and MRI to produce some of the most highly detailed images currently available. MRI scans use a strong (1.5 to 3T for clinical use) magnetic field to produce detailed morphologic images and some sequences provide functioning information (such as diffusion-weighted, dynamic contrast-enhanced, MR elastography sequence). PET scan use tracers according to the clinical indications to highlight metabolism or biological changes.

Until now, scientists could not integrate PET and MRI for simultaneous scanning because MRI's powerful magnets interfered with the imaging detectors on the PET scanner. PET and MRI scans have been conducted separately, and the separate images later merged. That merger, however, requires a complex computer process. The newly-available PET/MRI scanners can perform both types of scans at the same time to gather more information than merged PET and MRI scans. Beside the benefit of increased diagnostic and staging performance, it Improves safety from significantly reduced radiation exposure: Compared to PET/CT scans, PET/MRI exposes patients to about 50% less radiation.

The OPERANDI project aims to address unmet clinical needs in the current management of GEP-NETs treated with PRRT by exploring new opportunities provided by imaging-based artificial intelligence (AI) and data augmentation, simultaneous PET-MRI imaging, and novel approaches to increase patient selection and PRRT efficacy (genomic profiling, radiopotentiators, and new radionuclides). The study aim to identify predictive and early markers indicative of PRRT effectiveness based on a large prospective cohort of GEP-NET patients. This cohort will be used to uncover relevant predictive signatures within the morphological, functional, and molecular imaging data using novel imaging-based AI approaches with a new patient imaging pathway including simultaneous PET-MRI.

Considering this global objective, the objective of this clinical research protocol is to provide clinical, molecular and imaging data in a prospective standardized study, notably by performing systematic PET-MRI at baseline, at middle course of PRRT and at 1 year of the beginning of PRRT, in patients with advanced GEP-NETs treated with PRRT.

Multi-modal Characterisation of Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETs) Treated With Targeted Radionuclide Therapy (TRT): Prospective Interventional Multicentre National Cohort

Assistance Publique - Hôpitaux de Paris

Skin and Connective Tissue Diseases

Melanoma

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

\[131\]ICF01012 at a therapeutic dose of 800 MBq/m² , single dose at D11 (intravenous administration)

\[131\]ICF01012 at a therapeutic dose of 1600 MBq/m² , single dose at D11 (intravenous administration)

\[131\]ICF01012 at a therapeutic dose of 2700 MBq/m² , single dose at D11 (intravenous administration)

\[131\]ICF01012 at a therapeutic dose of 4000 MBq/m² , single dose at D11 (intravenous administration)

* 1 diagnostic injection (D0) at a diagnostic dose of 185 MBq. This first dose permits to pre-select patients who will received a therapeutic dose according to the dosimetry results ( binding on at least a tumoral lesion, an acceptable radiation absorbed dose to major organs)
* 1 therapeutic injection (D11) at a dose of 800 MBq/m²

[131I]ICF01012 (therapeutic dose level 1)

* 1 diagnostic injection (D0) at a diagnostic dose of 185 MBq. This first dose permits to pre-select patients who will received a therapeutic dose according to the dosimetry results ( binding on at least a tumoral lesion, an acceptable radiation absorbed dose to major organs)
* 1 therapeutic injection (D11) at a dose of 1600 MBq/m²

[131I]ICF01012 (therapeutic dose level 2)

* 1 diagnostic injection (D0) at a diagnostic dose of 185 MBq. This first dose permits to pre-select patients who will received a therapeutic dose according to the dosimetry results ( binding on at least a tumoral lesion, and an acceptable radiation absorbed dose to major organs)
* 1 therapeutic injection (D11) at a dose of 2700 MBq/m²

[131I]ICF01012 (therapeutic dose level 3)

* 1 diagnostic injection (D0) at a diagnostic dose of 185 MBq. This first dose permits to pre-select patients who will received a therapeutic dose according to the dosimetry results ( binding on at least a tumoral lesion, and an acceptable radiation absorbed dose to major organs)
* 1 therapeutic injection (D11) at a dose of 4000 MBq/m²

[131I]ICF01012 (therapeutic dose level 4)

Florent CACHIN, Pr

Florent Cachin, Pr

Sandrine Mansard, MD

This study is a phase I clinical trial aimed to determine the recommended dose of \[131I\]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma (binding \[131I\]ICF01012 ). The \[131I\]ICF01012 is a targeted radionuclide therapy with a high affinity for melanin.

This study will include a maximum of 36 patients. This study will begin with a preselection part that consists of an injection of \[131I\]ICF01012 at a diagnostic dose (185 MBq) in order to preselect patients who will receive the therapeutic dose according to the dosimetry results : binding of \[131I\]ICF01012 on at least a tumoral lesion and an acceptable radiation absorbed dose to major organs.

The second phase will consist of a therapeutic part with a single administration of \[131I\]ICF01012 at a therapeutic dose. This part is a dose escalation model (4 levels of therapeutic dose were tested)

Targeted Radionuclide Therapy for Metastatic Melanoma [131I] ICF01012

Targeted Radionuclide Therapy for Metastatic Melanoma [131I] ICF01012: Phase I Study

defined as the highest dose at which the percentage of DLT (dose limiting toxicity) is less than 33%. The DLT is defined as:

* all non hematologic toxicities NCI-CTC grade 3-4 except for alopecia, nausea, vomiting and fever that can be controlled by appropriate measures.
* hematologic toxicities as thrombopenia and anemia of grade 4, neutropenia of grade 4 for more than 5 days, thrombopenia of grade 3 with bleeding and all other hematologic toxicities of grade 3 clinically significant of more than 3 weeks

binding of \[131I\]ICF01012 compared to standard evaluation of metastatic lesion (standard imaging (CT Scan, TEP ...) or clinical evaluation)

adverse events assessed by NCI-CTC Version 4.03

radiation counting of serum, whole blood and urinary samples

Response will be categorized according to the criteria from RECIST 1.1 and PERCIST criteria: complete response, partial response, stable disease and progressive disease

assessed by whole-body planar studies and tomographic imaging with single-photon emission computed tomography (SPECT)/CT

Centre Jean Perrin

Up to 192 participants treated with \[177Lu\]Lu-FAP-2286 in tumor-specific participant groups in monotherapy and in combination with chemotherapy.

68Ga-FAP-2286 IV administered as imaging agent for PET scan.

68Ga-FAP-2286

Phase 1:

Patients with positive uptake of 68Ga-FAP- 2286 will receive a fixed dose of 177Lu-FAP-2286 IV administered every 6 weeks for a maximum of 6 doses. Doses range between 3.7 and 9.25 GBq (100-250 mCi).

Phase 2:

Monotherapy: Patients with positive uptake of 68Ga FAP 2286 will receive a fixed dose of 177Lu FAP 2286 IV administered at the RP2D determined in Phase 1 dose escalation in every 4 weeks.

Combination therapy: Patients with positive uptake of 68Ga FAP 2286 will receive 177Lu-FAP-2286 based on dose escalation (starting with dose level 1) followed by dose expansion at selected dose.

177Lu-FAP-2286

Novartis Pharmaceuticals

Fibroblast activation protein (FAP) is a cell surface protein that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers, whereas limited expression of FAP is observed in normal tissues. In some cancers of mesenchymal origin, notably sarcoma and mesothelioma, FAP expression has also been observed on the tumor cells themselves. Given the restricted expression profile, FAP is a promising target for peptide-targeted radionuclide imaging and therapeutic agents.

Phase 1 of this study is designed to evaluate the safety and establish the recommended intravenous (IV) Phase 2 dose (RP2D) for \[177Lu\]Lu FAP 2286 monotherapy in participants with FAP expressing solid tumors.

Phase 2 is designed to evaluate the safety and efficacy of \[177Lu\]Lu FAP 2286 as monotherapy in participants with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and breast cancer (BC) and in combination with chemotherapy in participants with untreated PDAC or relapsed NSCLC.

Participants in both Phase 1 and 2 will be selected for treatment with \[177Lu\]Lu FAP 2286 based on \[68Ga\]Ga FAP 2286 imaging for determining tumor FAP expression.

Screening Period:

All participants will undergo screening assessments including disease assessments per CT or MRI per RECIST v1.1 criteria prior to administration of \[68Ga\]Ga FAP 2286. Each participant must provide informed consent and agree to provide an archival tumor tissue sample, if available, and blood samples for biomarker assessment. Participants must meet all entry criteria as specified in the protocol.

In Phase 1 only, participants will also undergo FDG-PET imaging. In the Phase 2 part, \[177Lu\]Lu FAP 2286 will be investigated in monotherapy and in combination with chemotherapy. All participants in the combination group may begin chemotherapy prior to \[177Lu\]Lu FAP 2286.

Participants meeting entry criteria will be enrolled and participants who have not had prior PET/CT imaging with \[68Ga\]Ga FAP 2286 in the previous 3 months (applicable only to Phase 1) will undergo PET imaging with \[68Ga\]Ga FAP prior to initiating treatment with \[177Lu\]Lu FAP 2286. Participants must have a positive \[68Ga\]Ga FAP PET/CT scan, as described in the criteria for continuation to \[177Lu\]Lu FAP 2286 therapy, in order to be treated with \[177Lu\]Lu FAP 2286.

Treatment Period:

A single IV dose of \[177Lu\]Lu FAP 2286 will be initially administered every 6 weeks (window of - 1 to + 7 days) up to a maximum of 6 doses in Phase 1. In Phase 2, \[177Lu\]Lu FAP 2286 will be administered every 4 weeks (28 days ± 3 days).

All participants will be monitored for safety throughout the Treatment Period. All participants will be assessed for disease status per RECIST v1.1 every 6 weeks (42 days). Participants will receive \[177Lu\]Lu FAP 2286 until the maximum doses allowed are administered, confirmed radiographic disease progression assessed by investigator based on RECIST v1.1 criteria, unequivocal clinical disease progression, unacceptable toxicity or inability to tolerate further treatment, loss to follow-up, or withdrawal of consent.

Safety data will be periodically reviewed by the DCRC during dose escalation and by a Data Monitoring Committee (DMC) during dose expansion.

End of Treatment (EOT) Visit:

In Phase 1, participants will have an EOT Visit 6 to 8 weeks after the last dose of \[177Lu\]Lu FAP 2286 except in cases of participant death, loss to follow up, or withdrawal of consent for further follow up. Participants in Phase 2 will have an EOT visit within 28 days from the last dose of study treatment except in case of participant death, loss to follow-up, or withdrawal of consent for further follow-up.

Post treatment safety follow-up:

In Phase 2, after discontinuation of study treatment for any reason, all participants will have safety follow-up for 6 weeks (+/- 1 week) after their last study treatment administration, except in case of death, loss to follow-up or withdrawal of consent as per the schedule of assessments.

Long-term Follow-up (LFTU) Period:

Upon completion of the EOT Visit, participants will enter the LTFU Period. The LTFU Period will include safety, disease, and survival assessments, as applicable.

* Safety assessments will be performed every 12 weeks (+/- 1 week) for 2 years, then every 6 months until 5 years.
* Disease assessments will be performed for all participants who complete the EOT for a reason other than radiographic disease progression. Participants should continue to have tumor scans performed until radiographic disease progression, death, loss to follow-up, withdrawal from study, study closure or initiation of subsequent anticancer treatment.
* Survival assessments will be performed for all participants.

A Study of 177Lu-FAP-2286 in Advanced Solid Tumors (LuMIERE)

LuMIERE: A Phase 1/2, Multicenter, Open-label, Non-randomized Study to Investigate Safety and Tolerability, Pharmacokinetics, Dosimetry, and Preliminary Activity of 177Lu-FAP-2286 in Patients With an Advanced Solid Tumor

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

To evaluate the safety and tolerability of \[177Lu\]Lu FAP 2286 and determine the RP2D

Objective response is defined as a best confirmed response of CR or PR by RECIST v1.1 as assessed by the investigator. A confirmed CR or PR is a response that is maintained and documented on a subsequent tumor assessment no less than 28 days after the initial response. For Phase 2, ORR defined as the frequency and percentage of participants with a best confirmed response of CR or PR will be analyzed.

To evaluate the safety and tolerability of \[177Lu\]Lu FAP 2286 and determine the RP2D in combination with mFOLFIRNOX in PDAC and the RP2D in combination with nab-paclitaxel in NSCLC (Phase 2 dose escalation for combination therapy)

To measure the radiation dosimetry of \[177Lu\]Lu FAP 2286

To determine tumor uptake using \[68Ga\]Ga FAP 2286

To evaluate tumor uptake of \[68Ga\]Ga FAP 2286 as compared to FDG

To evaluate the PK of \[177Lu\]Lu FAP 2286

Objective response is defined as a best confirmed response of CR or PR by RECIST v1.1 as assessed by the investigator. A confirmed CR or PR is a response that is maintained and documented on a subsequent tumor assessment no less than 28 days after the initial response.

To evaluate the safety and tolerability of \[68Ga\]Ga FAP 2286.

Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented radiographic progression or death due to any cause as assessed by investigator according to RECIST v1.1.

Disease Control Rate (DCR) is defined as the frequency and percentage of participants with stable disease (SD) of at least 12 weeks (2 consecutive scans with Best Overall Response (BOR) of SD) or a best confirmed response of CR or PR.

Progression-free survival (PFS) is defined as the time from the date of randomization to the date of first evidence of radiographic progression or death due to any cause, whichever occurred first.

The distribution of adverse events of \[177Lu\]Lu FAP 2286 at the RP2D for monotherapy, the RP2D in combination with mFOLFIRNOX in PDAC and the RP2D in combination with nab-paclitaxel in NSCLC will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

The distribution of adverse events for \[68Ga\]Ga FAP 2286 will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Multi-modal Characterisation of Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETs) Treated With Targeted Radionuclide Therapy (TRT): Prospective Interventional Multicentre National Cohort	NCT06256705	Gastroenteropan... Radiotherapy	Simultaneous 68...	18 Years -	Assistance Publique - Hôpitaux de Paris
Targeted Radionuclide Therapy for Metastatic Melanoma [131I] ICF01012	NCT03784625	Melanoma	[131I]ICF01012 ... [131I]ICF01012 ... [131I]ICF01012 ... [131I]ICF01012 ...	18 Years -	Centre Jean Perrin
Targeted Radionuclide Therapy for Metastatic Melanoma [131I] ICF01012	NCT03784625	Melanoma	[131I]ICF01012 ... [131I]ICF01012 ... [131I]ICF01012 ... [131I]ICF01012 ...	18 Years -	Centre Jean Perrin
A Study of 177Lu-FAP-2286 in Advanced Solid Tumors (LuMIERE)	NCT04939610	Solid Tumor	68Ga-FAP-2286 177Lu-FAP-2286	18 Years -	Novartis

Spots Global Cancer Trial Database for targeted radionuclide therapy