Second-line therapy for patients with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma
- Conditions
- euroendocrine carcinomaCancer
- Registration Number
- ISRCTN10996604
- Lead Sponsor
- The Christie NHS Foundation Trust
- Brief Summary
2020 Protocol article in https://www.ncbi.nlm.nih.gov/pubmed/32029495 protocol (added 10/02/2020)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 58
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).
Current participant exclusion criteria as of 25/11/2021:
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. 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:
6.1. Extra-pulmonary neuroendocrine carcinoma
6.2. Non-melanoma skin cancer where treatment consisted of resection only or radiotherapy
6.3. Ductal carcinoma in situ (DCIS) where treatment consisted of resection only
6.4. Cervical carcinoma in situ where treatment consisted of resection only
6.5. 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. Infection status should be confirmed in cases of clinical suspicion.
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)
19. Use of warfarin or warfarin-type anti-coagulation therapies within one week of randomisation and
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Progression-free survival rate, defined as the time from randomisation to progression or death from any cause; Timepoint(s): 6 months
- Secondary Outcome Measures
Name Time Method 1. Overall survival (OS), defined as the time from randomisation to death from any cause<br>2. Objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.11 Assessed by CT or MRI scan at baseline and then at 8-weekly intervals<br>3. Toxicity defined as the AE and SAEs reported on the trial according to CTCAE v5.0<br>4. Quality of life (QoL) using European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QLQ) validated questionnaires C30 and NET21 assessed according to the patient reported outcome measures; EORTC QLQC30 and EORTC QLQ-GI.NET21. Assessed at the point of randomisation, at 6-weekly intervals and at disease progression<br>5. Serum concentration of neuron-specific enolase (NSE) assessed at the point of randomisation, at 6-weekly intervals and at disease progression