Second-line Therapy for Patients With Progressive Poorly Differentiated Extra-pulmonary Neuroendocrine Carcinoma (NET02)

A Multi-centre, Randomised, Parallel Group, Open-label, Phase II, Single-stage Selection Trial of Liposomal Irinotecan (Nal-IRI) and 5-fluorouracil (5-FU)/Folinic Acid or Docetaxel as Second-line Therapy in Patients With Progressive Poorly Differentiated Extra-pulmonary Neuroendocrine Carcinoma (NEC))

There is currently no standard treatment beyond first-line etoposide/platinum-based chemotherapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma. Therefore the treatment of patients whose disease progresses on or after this first-line treatment is an area of unmet need.

Combination regimens such as irinotecan/5-fluorouracil/folinic acid are a second-line treatment option currently used in Europe and world-wide for this subset of patients. However, there is currently no trial evidence supporting this treatment regimen in these patients.

Results of the NAPOLI-1 phase III trial of liposomal irinotecan in the treatment of patients with metastatic pancreatic adenocarcinoma after gemcitabine-based therapy reported improved survival for those patients who received a combination of liposomal irinotecan with 5-FU/folinic acid compared to those patients who received 5-FU/folinic acid alone. Liposomal irinotecan has been found to show an improved distribution into tumour tissue in comparison to irinotecan, and this may have clinical benefit in patients with extra-pulmonary neuroendocrine carcinoma.

Docetaxel is standardly used as a second-line treatment option in patients with small cell lung cancer who have progressed on primary etoposide-platinum combination therapy. Therefore this drug could also have clinical benefit in patients with extra-pulmonary neuroendocrine carcinoma as the biology of the disease is similar to small cell lung cancer.

The overall aim of the NET-02 trial is to select a treatment for continuation to a Phase III trial. The intention of the trial is to determine whether liposomal irinotecan/5-fluorouracil/folinic acid and docetaxel are sufficiently active in this population of patients. If both treatments are found to be efficacious, selection criteria will be applied to select a treatment to take forward.

102 eligible participants will be randomised to receive either liposomal irinotecan/5-fluorouracil/folinic acid given every 14 days, or docetaxel given every 21 days. Participants will be treated for a minimum of 6 months or until discontinuation of treatment as per protocol.

Study Overview

• Status: Completed
• Conditions: Oncology; Neuroendocrine Carcinoma
• Intervention / Treatment: Drug: Liposomal Irinotecan; Drug: Fluorouracil; Drug: Folinic Acid; Drug: Docetaxel

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom
    • The Beaston West of Scotland Cancer Center, NHS Greater Glasgow and Clyde
  • London, United Kingdom
    • Hammersmith Hospital, Imperial College Healthcare NHS Trust
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Sheffield, United Kingdom
    • Weston Park Hospital, Sheffield Teaching Hospitals, NHS Trust

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥18 years and life expectancy ≥3 months.
2. Diagnosed with poorly differentiated (as defined by the World Health Organisation in 2010, Ki 67 ≥20%) extra-pulmonary neuroendocrine carcinoma (NEC grade 3, confirmed by histology). (Carcinoma of unknown primary is allowed if lung primary has been excluded following review by the multi-disciplinary team).
3. Prior treatment with first-line platinum-based chemotherapy for NEC in the advanced setting and ≥28 days from Day 1 of the previous treatment cycle.
4. Documented radiological evidence of disease progression OR discontinuation of first-line platinum-based chemotherapy due to intolerance.
5. Measurable disease according to RECIST 1.1
6. Eastern Co-operative Oncology Group (ECOG) performance status ≤2
7. Adequate renal function with serum creatinine ≤1.5 times upper limit of normal (ULN) and creatinine clearance ≥50ml30ml/min according to Cockroft-Gault or Wright formula. If the calculated creatinine clearance is less than 30 ml/min, glomerular filtration rate (GFR) may be assessed using either Cr51-EDTA or 99mTc-DTPA clearance method to confirm if GFR is ≥30 ml/min).
8. Adequate haematological function: Hb ≥90g/L, WBC ≥3.0 x 109/L, ANC ≥1.5 x 109/L, platelet count ≥100 x 109/L.
9. Adequate liver function: serum total bilirubin 1.5 x ULN (biliary drainage is allowed for biliary obstruction) and ALT and/or AST 2.5 x ULN in the absence of liver metastases, or 5 x ULN in the presence of liver metastases.
10. A negative pregnancy test is required at registration in women of childbearing potential.
11. Men and women of reproductive potential must agree to use a highly effective form of contraception during the study and for 6 months following the last dose of trial treatment. In addition, male participants should use a condom during study participation and for 6 months following the last dose of trial treatment.
12. Patients must be able to provide written informed consent.
13. Patients must be able and willing to comply with the terms of the protocol.

Exclusion Criteria:

1. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients.
2. Use (including self-medication) within one week of randomisation and for the duration of the study of any of the following: St. John's wort, grapefruit, Seville oranges, medicines known to inhibit UGT1A1 (e.g. atazanavir, gemfibrozil, indinavir) and medicines known to inhibit or induce either CYP3A4 or CYP3A5
3. Previous treatment (for neuroendocrine carcinoma) with any of the components of combination chemotherapy regimens detailed in this study (nal-IRI or 5-FU or irinotecan or topoisomerase inhibitors or taxane-based therapy).
4. Incomplete recovery from previous therapy in the opinion of the investigator (surgery/adjuvant therapy/radiotherapy/chemotherapy in advanced setting), including ongoing peripheral neuropathy of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 from previous platinum-based therapy.
5. Concurrent palliative radiotherapy involving target lesions used for this study (<28 days from discontinuation of radiotherapy). Radiotherapy for non-target lesions is allowed if other target lesions are available outside the involved field.

6. Patients must not have a history of other malignant diseases (within the previous 3 years, and there must be no evidence of recurrence), other than:

   • Extra-pulmonary neuroendocrine carcinoma.
   • Non-melanoma skin cancer where treatment consisted of resection only or radiotherapy.
   • Ductal carcinoma in situ (DCIS) where treatment consisted of resection only.
   • Cervical carcinoma in situ where treatment consisted of resection only.
   • Superficial bladder carcinoma where treatment consisted of resection only.
7. Documented brain metastases, unless adequately treated (surgery or radiotherapy only), with no evidence of progression and neurologically stable off anticonvulsants and steroids.
8. Clinically significant gastrointestinal disorder (in the opinion of the treating clinician) including hepatic disorders, bleeding, inflammation, obstruction, or diarrhoea ≥CTCAE grade 1 (at time of study entry).
9. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion.
10. New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure .
11. Severe bone marrow failure or bone marrow depression after radiotherapy or treatment with other antineoplastic agents (defined as haematological values of haemoglobin or white blood cells or neutrophils or platelets not meeting inclusion criteria).
12. Known active hepatitis B virus, hepatitis C virus or HIV infection.
13. Active chronic inflammatory bowel disease.
14. Breastfeeding women.
15. Evidence of severe or uncontrolled systemic diseases which, in the view of the treating clinician, makes it undesirable for the patient to participate in the trial.
16. Evidence of significant clinical disorder or laboratory finding which, in the opinion of the treating clinician, makes it undesirable for the patient to participate in the trial.
17. Medical or psychiatric conditions that impair the ability to give informed consent.
18. Any other serious uncontrolled medical conditions (in the opinion of the treating clinician).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: nal-IRI, 5-FU and racemic folinic acid; liposomal Irinotecan (naI-IRI) (80mg/m*2 intravenously over 90 minutes (± 10 minutes) prior to Fluorouracil (5-FU) 5-FU 2400 mg /m*2 BSA infusor over 46 hours racemic folinic acid (as per local standard practice) every 14 days	Drug: Liposomal Irinotecan; Arm I; Other Names: Onivyde; Drug: Fluorouracil; Arm I; Drug: Folinic Acid; Arm I
Active Comparator: docetaxel; 75mg/m*2 intravenously over 60 minutes) every 21 days]	Drug: Docetaxel; Arm II

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival defined as a binary outcome (progression-free or not)	treatment start date until 6 months, assessed at 8 weekly intervals by CT scan

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival defined as time from randomisation to progression or death from any cause.	Individuals will be censored if they are lost to follow-up or still alive and progression-free at the time of analysis.	randomisation until 6 months after the last participant is randomised (end of trial), assessed at 8 weekly intervals by CT scan and death is continuously assessed
Overall survival defined as time from randomisation to death from any cause.	Individuals will be censored if they are lost to follow-up or still alive and progression-free at the time of analysis.	randomisation until 6 months after the last participant is randomised (end of trial), death is continuously assessed
Objective response rate defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.		start of treatment until 6 months after the last participant is randomised (end of trial)
Toxicity defined as the number of participants with treatment-related adverse events as assessed by common terminology criteria for adverse events (CTCAE) v5.0.		treatment start date until 6 months after the last participant is randomised (end of trial), assessed at 2 (nal-IRI/5-FU/folinic acid) or 3 (docetaxel) weekly intervals
Quality of life assessed according to the patient reported outcome measures; European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30		randomisation until 6 months after the last participant is randomised (end of trial), assessed at 6 weekly intervals
Neuron-specific enolase (NSE) measurements.		baseline until 6 months after the last participant is randomised (end of trial), assessed at 6 weekly intervals
Quality of life assessed according to the patient reported outcome measures; European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) GINET21.		randomisation until 6 months after the last participant is randomised (end of trial), assessed at 6 weekly intervals

Collaborators and Investigators

• Sponsor: The Christie NHS Foundation Trust
• Collaborators: University of Leeds; National Institute for Health Research, United Kingdom; Servier
• Investigators: Principal Investigator: Mairead McNamara, The Christie NHS Foundation Trust, The University of Manchester

Publications and helpful links

General Publications

• Craig Z, Swain J, Batman E, Wadsley J, Reed N, Faluyi O, Cave J, Sharma R, Chau I, Wall L, Lamarca A, Hubner R, Mansoor W, Sarker D, Meyer T, Cairns DA, Howard H, Valle JW, McNamara MG. NET-02 trial protocol: a multicentre, randomised, parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma (NEC). BMJ Open. 2020 Feb 5;10(2):e034527. doi: 10.1136/bmjopen-2019-034527.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2018
• Primary Completion (Actual): November 26, 2024
• Study Completion (Actual): November 26, 2024

Study Registration Dates

• First Submitted: September 27, 2018
• First Submitted That Met QC Criteria: February 11, 2019
• First Posted (Actual): February 12, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 27, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Carcinoma; Carcinoma, Neuroendocrine; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Micronutrients; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Protective Agents; Antidotes; Vitamin B Complex; Vitamins; Hematinics; Docetaxel; Irinotecan; Fluorouracil; Leucovorin; Levoleucovorin; Folic Acid
• Other Study ID Numbers: CFTSp116

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance).

No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project.

The CTRU encourages a collaborative approach to data sharing, and believe it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets.

• IPD Sharing Time Frame: Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data.
• IPD Sharing Access Criteria: CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree suitable requirements for release.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No