| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Poorly differentiated extra-pulmonary neuroendocrine carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
| Poorly differentiated (faster growing) neuroendocrine carcinoma that started in the gastrointestinal tract and has spread |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057270 |
| E.1.2 | Term | Neuroendocrine carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The trial aims to determine whether treatment with the combination of liposomal irinotecan/5-fluorouracil/folinic acid or treatment with docetaxel improves time to further progression in patients with advanced neuroendocrine carcinoma (that has originated outside the lungs) who have previously received a platinum-based first-line chemotherapy. The two treatments are not being compared against each other but are being examined to determine which treatment is suitable to take forward into a larger Phase III trial. If both treatments are deemed sufficiently efficacious, selection criteria will be applied to determine which treatment to take forward. |
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| E.2.2 | Secondary objectives of the trial |
To determine whether treatment with liposomal irinotecan/5-FU/folinic acid or docetaxel improves survival.
To determine the objective response rate of liposomal irinotecan/5-FU/folinic acid treatment and docetaxel treatment, which is the percentage of patients whose cancer shrinks or disappears after treatment.
To determine the toxicity of liposomal irinotecan/5-FU/folinic acid treatment and docetaxel treatment as per Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
To determine whether liposomal irinotecan/5-FU/folinic acid treatment and docetaxel treatment improves the quality of life of patients.
To determine whether neuron-specific enolase levels are predictive of treatment response in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma receiving second-line treatment with nal-IRI/5-fluorouracil/folinic acid or docetaxel.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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). (Carcinoma of unknown primary is allowed if lung primary has been excluded).
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 (Appendix 1).
6. Eastern Co-operative Oncology Group (ECOG) performance status ≤2 (see Appendix 2).
7. Adequate renal function with serum creatinine ≤1.5 times upper limit of normal (ULN) and creatinine clearance ≥50ml/min according to Cockroft-Gault or Wright formula (see Appendix 3).
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.
* Women of reproductive potential are defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
** Men of reproductive potential are defined as post-pubescent and not permanently sterile by vasectomy or bilateral orchidectomy.
*** Highly effective contraception is defined as one of the following: combined (oestrogen and progesterone-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; practising true abstinence (when this is in line with the preferred and usual lifestyle of the subject).
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| E.4 | Principal 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 and medicines known to inhibit or induce either CYP3A4 or CYP3A5 (see Appendix 8 of protocol for list*).
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 > CTCAE grade 2 from previous platinum-based therapy.
5. First line treatment administered within 4 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to treatment start in this study.
6. 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.
7. 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.
8. Documented brain metastases, unless adequately treated (surgery or radiotherapy only), with no evidence of progression and neurologically stable off anticonvulsants and steroids.
9. 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).
10. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion.
11. New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure**.
12. 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).
13. Known active hepatitis B virus, hepatitis C virus or HIV infection.
14. Active chronic inflammatory bowel disease.
15. Breastfeeding women.
16. 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.
17. 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.
18. Medical or psychiatric conditions that impair the ability to give informed consent.
19. Any other serious uncontrolled medical conditions (in the opinion of the treating clinician).
* For patients receiving any of these medications, use of an alternative agent is recommended.
** It is recommended that subjects should have a systolic blood pressure of either less than 150 mmHG, and/or a diastolic blood pressure of less than 100 mmHg at rest (average of 3 consecutive readings 3-5 minutes apart). Anti-hypertensive drugs may be used to achieve these values. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 6 month progression-free survival rate, defined as a binary outcome (progression-free or not) within the timeframe of treatment start date until 6 months after randomisation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Each participant will be evaluated at the point 6 months after randomisation. Final analysis will take place 6 months after the last participant is randomised. |
|
| E.5.2 | Secondary end point(s) |
• Progression-free survival is defined as the time from randomisation to progression or death from any cause. Individuals will be censored if they are lost to follow-up or are still alive and progression-free at the time of analysis.
• Overall survival is defined as the time from randomisation to death from any cause. Individuals will be censored if they are lost to follow-up or still alive at the time of the analysis.
• Objective response rate is defined using RECIST v1.1.
• Toxicity is defined as the AE and SAEs reported on the trial according to CTCAE v4.03.
• Quality of life will be assessed according to the patient reported outcome measures; EORTC QLQ-C30 and EORTC QLQ-GI.NET21.
• Concentration of neuron-specific enolase
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Participants will be followed up until 6 months after the last participant is randomised. Final analysis will take place 6 months after the last participant is randomised. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial is defined as the date of the collection of the last participant’s last data item. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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