A multi-centre, randomised, parallel group, open-label, phase II, single-stage selection trial of nanoliposomal 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)

INTERVENTION: Trade Name: Liposomal irinotecan (Onivyde) Product Name: Liposomal irinotecan (Onivyde) Product Code: MM‐398 Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Irinotecan Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 5‐ Trade Name: 5‐Fluorouracil Product Name: 5‐Fluorouracil Pharmaceutical Form: Solution for injection INN or Proposed INN: 5‐Fluorouracil CAS Number: 51‐21‐8 Other descriptive name: Fluorouracil Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50‐ Trade Name: Docetaxel Product Name: Docetaxel Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Docetaxel Other descriptive name: Taxotere Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ CONDITION: Poorly differentiated extra‐pulmonary neuroendocrine carcinoma ; MedDRA version: 20.0 Level: PT Classification code 10057270 Term: Neuroendocrine carcinoma System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: ; 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; 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. PRIMARY OUTCOME: ; Secondary Objective: 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.; Main Objective: 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. 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. 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. 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/mi