Patients with metastatic neuroendocrine carcinomas of extrapulmonary origin will be eligible
Conditions
Interventions
Trade Name: cisplatine
Product Name: cisplatine
Pharmaceutical Form: Concentrate and solvent for concentrate for solution for infusion
Trade Name: Afin
Sponsors
NKI-AVL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Pathologically confirmed unresectable locally advanced NEC where no curative (chemoradiation) treatment options are available, and/or metastatic NECs of extrapulmonary origin as first line therapy NEC of extrapulmonary origin (WHO 2010 classification; Ki67 >20 %) including merkel cell carcinoma. 2. Measurable disease according to RECIST 1.1, on CT-scan or MRI 3. ECOG Performance status 0-2 (see Appendix 2) 4. Adequate bone marrow function as shown by: ANC=1.5 x 109/L, Platelets =100 x 109/L, Hb >6 mmol/L 5. Adequate liver function as shown by: Total serum bilirubin =1.5 ULN ALT and AST =2.5x ULN (=5x ULN in patients with liver metastases) 6. Adequate renal function: calculated creatinin clearance > 60ml/min. (Cockcroft-Gault formula) 7. Life expectancy of at least 3 months. 8. Male or female age = 18 years. 9. Signed informed consent. 10. Able to swallow and retain oral medication. 11. Locally advanced or Metastatic lesion(s) of which a histological biopsy can safely be obtained: a. Patients with safely accessible locally advanced or metastatic lesion(s) including bone lesions. b. Patients not known with bleeding disorders (such as hemophilia) or bleeding complications from biopsies, dental procedures or surgeries. c. Patients not using any anti-coagulant medication at the time of biopsy: all aspirin derivatives, NSAID’s, coumarines, platelet function inhibitors, heparins (including LMWHs) and oral factor Xa inhibitors are not allowed, unless medication can either be safely stopped or counteracted. d. Adequate coagulation status as measured by: i. PT =65 years) yes F.1.3.1 Number of subjects for this age range 9
Exclusion criteria
Exclusion criteria: 1. Previous chemotherapy for metastatic or unresectable NEC of extrapulmonary origin. (prior peri-operative chemotherapy or chemoradiation for curative intention is allowed if at least 6 months have elapsed between completion of this therapy and enrolment into the study). 2. Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus ) 3. Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma. 4. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) or cisplatin 5. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus 6. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary 7. Patients who have any severe and/or uncontrolled medical conditions such as: a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =6 months prior to randomization, serious uncontrolled cardiac arrhythmia. b. active or uncontrolled severe infection, c. liver disease such as cirrhosis, decompensated liver disease, and known history chronic hepatitis d. known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air), e. active, bleeding diathesis; 8. Chronic treatment with corticosteroids or other immunosuppressive agents 9. Known history of HIV seropositivity 10. Pregnant or nursing (lactating) women 11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 8 weeks after stopping study treatment. 12. Sexually active males, unless they use a condom during intercourse while taking study medication and for 8 weeks after stopping study medication. 13. History of documented congestive heart failure; angina pectoris requiring medication; evidence of transmural myocardial infarction on ECG; poorly controlled hypertension (systolic BP >180 mmHg or diastolic BP >100 mmHg); clinically significant valvular heart disease; or high risk uncontrollable arrhythmias. 14. Patients with dyspnoea at rest due to complications of advanced malignancy or other disease, or who require supportive oxygen therapy. 15. History or clinical evidence of brain metastases. 16. Any investigational drug treatment within 4 weeks of start of study treatment. 17. Radiotherapy within 4 weeks of start of study treatment (2 week interval allowed if palliative radiotherapy given to bone metastastic site peripherally and patient recovered from any acute toxicity).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary endpoint of this study will be Disease Control Rate (DCR), defined as the sum of Overall Response Rate (ORR) consisting of Complete (CR), Partial Response Rate (PR) and stable disease (SD), all according to RECIST 1.1; Secondary Objective: Secondary endpoints will be Time to relapse; Progression-free survival (PFS); Disease-free survival (DFS); Overall survival (OS); Effect on the markers chromogranin A (CgA) and neuron-specific enolase (NSE); Safety of everolimus in combination with cisplatin. Exploratory objectives will be the discovery of biomarkers for treatment response; identification of resistance mechanisms; elucidation of driver events in NEC pathogenesis; identification of potential new targets for treatment. ;Primary end point(s): Primary endpoint of this study will be Disease Control Rate (DCR), defined as the sum of Overall Response Rate (ORR) consisting of Complete (CR), Partial Response Rate (PR) and stable disease (SD), all according to RECIST 1.1;Timepoint(s) of evaluation of this end point: 28 patients need to be enrolled in the 1st stage. Of those 28 patients, at least 8 responses are needed in order to proceed to the 2nd stage of the trial (with less than 8 responses, the trial will be closed). If stage 2 is implemented, an additional 11 patients need to be recruited (total of 39 patients) | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 28 patients need to be enrolled in the 1st stage. Of those 28 patients, at least 8 responses are needed in order to proceed to the 2nd stage of the trial (with less than 8 responses, the trial will be closed). If stage 2 is implemented, an additional 11 patients need to be recruited (total of 39 patients) ;Secondary end point(s): Secondary endpoints will be Time to relapse; Progression-free survival (PFS); Disease-free survival (DFS); Overall survival (OS); Effect on the markers chromogranin A (CgA) and neuron-specific enolase (NSE); Safety of everolimus in combination with cisplatin. | — |
Countries
Netherlands
Contacts
Public Contactprincipal investigator
NKI-AVL
Outcome results
None listed