Neoadjuvant PRRT With Y-90-DOTATOC in pNET (NeoNet)

Neoadjuvant Peptide Receptor Radionuclide Therapy (PRRT) With 90Y-DOTATOC in Pancreatic Neuroendocrine Tumours.

Neuroendocrine tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, that tend to be slow growing and are often diagnosed when metastatic. Surgery is the sole curative option, but is feasible only in a minority of patients.

Peptide Receptor Radionuclide Therapy (PRRT) has been experimented for almost 20 years and is an established effective therapeutic modality for well/moderately differentiated, inoperable or metastasized gastro-entero-pancreatic (GEP) and bronchial NETs. Clinical studies demonstrated that partial and complete objective responses can be obtained in up to 30% of patients. Side effects may involve the kidneys and the bone marrow and are usually mild. Renal protection is used to minimize the risk of a late decrease of renal function.

A new application for P-NETs is preoperative PRRT. Since surgery is the only curative option for GEPNETs, preoperative PRRT could increase the efficacy of surgery. However, this modality has not been fully explored in dedicated studies and there are just few sporadic case reports that described the preoperative use of PRRT in pancreatic NETs who could then be operated on successfully. Moreover there are few experiences demonstrating the advantage of PRRT associated to surgery in a multidisciplinary setting. In addition, the possibility of detecting the circulating NET transcripts by means of transcriptome analysis could represent an early marker of response to PRRT and improve the patient management.

Aim of this study is to evaluate the response and rate of R0 surgery in patients with unresectable or borderline resectable PNETs eligible to PRRT with 90Y-DOTATOC and correlate the response to the variation in circulating NET transcripts measured before and after the end of PRRT. It has been recently shown that a PCR-based 51 transcript signature is significantly more sensitive and efficient than single analytes (e.g. CgA) in NET diagnosis and follow up.

30 patients will be enrolled in the study; each of them will receive 1.85 GBq/cycle of 90Y-DOTATOC with a cumulative activity of 9.25-11.1 GBq in 5-6 cycles (depending on personalized dosimetry). Therapy response will be assessed by morphological (CT/MRI) and functional (PET/CT or Octreoscan) imaging after 3 and 6 months from the completion of PRRT and compared with transcript analysis.

Based on literature reports we expect a response rate of about 35% of patients.

Study Overview

• Status: Terminated
• Conditions: Pancreatic Neuroendocrine Tumor
• Intervention / Treatment: Drug: peptide receptor radionuclide therapy with Y-90-DOTATOC

Detailed Description

GEP-NETs tend to be slow growing (although aggressive forms exist) and are often diagnosed when they have already metastasized, when a radical treatment is no longer possible.

Treatment of NETs is typically multidisciplinary and should be individualized according to tumor type, burden, and symptoms. Therapeutic tools include surgery, interventional radiology and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues [Modlin 2008]. Several clinical trials have indicated that PRRT with somatostatin analogues 90Y-DOTATOC, 177Lu-DOTATATE and 177Lu-DOTATOC, is an efficient tool in the management of NETs (30% objective responses with a great survival benefit) which compares favorably to classic chemotherapy results (up to 20% responses) [Kwekkeboom 2005].

Dosimetric studies demonstrated that these radiopeptides are able to deliver high radiation doses to somatostatin receptor sst2-expressing tumors and acceptable doses to normal organs [Cremonesi 2010]. Side effects, usually mild, may involve kidneys and bone marrow. Renal protection is used to minimize the risk of a late function decrease [Bodei 2003].

Pts are selected for PRRT based on molecular imaging with 111In-pentetreotide or, more recently, a 68Ga-SSA-PET, such as 68Ga-DOTATOC/DOTATATE/DOTANOC [Virgolini 2010], which have revolutionized the NET imaging, with an overall sensitivity of >90%, and specificity ranging from 92% to 98% [Ambrosini 2012].

PRRT is an innovative therapeutic approach for inoperable or metastasized, well/moderately differentiated GEP and bronchial NETs. PRRT in P-NETs has demonstrated efficacy in terms of objective response and impact on survival parameters. Since surgery is the only curative option for patients with GEP-NETs, it is proposed that neoadjuvant treatment will improve outcome by enabling disease regression that will enable surgical resection.

Identification of disease regression as assessed by a PCR-blood based analysis of circulating neuroendocrine tumor transcripts will provide objective and quantifiable molecular genomic early information that is additive to imaging criteria of regression. This will objectively establish PRRT treatment efficacy and thereby facilitate the identification and selection of individuals that would then benefit from surgical intervention.

The two most commonly used radiopeptides, 90Y-DOTATOC and 177Lu-DOTATATE, produce overall objective response rates of 15-35%. Particularly relevant is the outcome in terms of both progression-free and overall survivals, which compare favorably with biotherapies. PRRT is generally well tolerated with mild toxicity, if the necessary precautions, such as the co-administration of nephron-protective amino acids or the adjustment of the administered activity, are taken.

PRRT in P-NETs has demonstrated efficacy in terms of objective response and impact on survival parameters. Response rates are >35%, higher than in small intestine tumors. In particular, in 342 patients with P-NETs, out of the whole series of 1109 patients treated with 90Y-DOTATOC, 47% objective responses were reported by Imhof in 2011. In 2013, Sansovini reported 39% partial and complete responses using 177Lu-DOTATATE at full dosage, while 60.3% partial responses were reported by Ezziddin in 2014 using the same peptide. Reported progression free survival (PFS) rates are > 30 months.

An interesting new application for P-NETs is the neoadjuvant setting, which was suggested by sporadic case reports that described the successful surgical resection in patients with initially inoperable P-NETs treated with PRRT. However, this treatment modality has not been fully explored in dedicated studies.

Moreover, there are few experiences demonstrating the advantage of PRRT associated to surgery in a multidisciplinary setting [Bertani 2014, 2016].

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20141
    • Chiara Maria Grana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients affected by unresectable or borderline resectable P-NETs and limited liver disease
• Multidisciplinary evaluation in which a global therapy approach is proposed with PRRT in a neoadjuvant setting.
• Histopathologic diagnosis of WHO G1/G2 P-NET
• Conserved hematological, liver and renal parameters: hemoglobin >/= 10 g/dL, absolute neutrophil count (ANC) >/= 1.5 x 109 /L, platelets >/= 100 x 109 /L, bilirubin </= 1.5 X UNL (upper normal limit), ALT < 2.5 X UNL (< 5 X UNL in presence of liver metastases), creatinine < 2 mg/dL.
• Age more than 18 years.
• Patients with documented disease will be admitted to therapeutic phase only if the diagnostic receptor imaging (Ga-68-peptides PET/CT or OctreoScan) demonstrate a significant uptake in the tumor (grade 2 or 3, according to a preset scoring, where grade 1= equal to normal liver, grade2 = higher than normal liver, grade 3= higher than kidneys and spleen), that may allow delivering a low absorbed dose to normal organs and a high dose to the tumor [Cremonesi 1999, Cremonesi 2010].
• Disease must be measurable by means of conventional imaging (CT or MRI)
• Before treatment clinical history data will be collected, physical examination will be performed and diagnostic and laboratory data will be examined.
• Patients must not receive other treatments (e.g. chemo- or radiotherapy) from one month before to two months after the completion of 90Y-DOTATOC cycles.
• Patients must be naive from previous radionuclide treatments with radiopeptides (e.g. 111Inpentetreotide, Lu-177-petides) or other radiopharmaceuticals (e.s. 131I-MIBG, 131I).

Exclusion Criteria:

• - Pregnancy/breastfeeding (a pregnancy test not older than 7 days is mandatory).
• Assessed bone marrow invasion > 25%.
• Other concomitant neoplasm (excluding in situ basaliomas and radically treated cervical cancers).
• ECOG score higher than 2.
• Expectancy of life shorter than 6 months.
• Patients with psycho-physical conditions that are not suitable for entering this clinical study and fulfilling its requirements.
• No multidisciplinary indication to surgery after PRRT

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Y-90-DOTATOC; Patients will receive PRRT with Y-90-DOTATOC	Drug: peptide receptor radionuclide therapy with Y-90-DOTATOC; Patients with unresectable or borderline resectable pNETs will recive PRRT with 90Y-DOTATOC; Other Names: PRRT; Y-90-DOTATOC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response evaluation	objective responses (partial and complete responses, stable disease) will be evaluated according to modified RECIST criteria (mRECIST).	3 months after end of PRRT
objective response evaluation	objective responses (partial and complete responses, stable disease) will be evaluated according to modified RECIST criteria (mRECIST).	6 months after end of PRRT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of operability	to evaluate the rate of operability 3 months after the end of PRRT.	3 months after the end of PRRT.
rate of operability	to evaluate the rate of operability 6 months after the end of PRRT.	3 months after the end of PRRT.
analysis of tumor specific circulating NET transcripts	Assess the response to PRRT by means of a neuroendocrine tumor specific PCR-blood based multianalyte molecular algorhythmic analysis of circulating NET transcripts	before PRRT, and 3 and 6 months after therapy.

Collaborators and Investigators

• Sponsor: European Institute of Oncology
• Collaborators: Agenzia Italiana del Farmaco

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2020
• Primary Completion (Actual): September 23, 2022
• Study Completion (Actual): November 11, 2024

Study Registration Dates

• First Submitted: September 23, 2022
• First Submitted That Met QC Criteria: September 30, 2022
• First Posted (Actual): October 5, 2022

Study Record Updates

• Last Update Posted (Estimated): November 20, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Neoplasms; Neuroendocrine Tumors; Adenoma, Islet Cell; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Edotreotide
• Other Study ID Numbers: IEO 906

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No