Advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin. MedDRA version: 19.1 Level: LLT Classification code 10062476 Term: Neuroendocrine tumor System Organ Class: 100000004864
Conditions
Sponsors
GETNE (Grupo Español de Tumores Neuroendocrinos)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent obtained prior to any protocol-related procedures. 2.Age >18 years at time of study entry. 3.Subjects must have histologically confirmed diagnosis of one of the following advanced/metastatic neuroendocrine tumor types: a)Cohort 1: Well-moderately differentiated neuroendocrine tumors of the lung (mitotic count =10 mitoses/10HPF), also known as typical and atypical lung carcinoids, that have progressed to prior somatostatin analog therapy and/or one prior targeted therapy or chemotherapy (only one prior systemic therapy, with the exception of patients that have been treated with somatostatin analogues and other systemic treatment, when two prior treatments are allowed). b)Cohort 2: Well-moderately differentiated G1/G2 (WHO grade 1 and 2)Gastrointestinal neuroendocrine tumors after progression to somatostatin analogs and one targeted therapy (prior targeted therapy could be everolimus or a multikinase inhibitor). Prior therapies with interferon alpha-2b or radionucleotide therapy are allowed. c)Cohort 3: Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1 and 2) from pancreatic origin after progression to standard therapies (chemotherapy, somatostatin analogs and target therapy); patients must be treated with at least two prior systemic treatment lines and a maximum of four previous treatment lines. d)Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin of unknown primary site (excluding lung primary tumors) after progression to first-line chemotherapy with a platinum based regimen. 4.For patients included in cohorts 1, 2 and 3: WHO Classification G1/G2 (mitotic count =10 mitoses x 10 HPF) lung typical and atypical carcinoids for cohort 1, G1/G2 (Ki67=20% and mitotic count =20 mitoses/10 HPF) gastrointestinal for cohort 2 (including stomach, small intestine and colorectal origins), G1/G2 (Ki67=20% and mitotic count =20 mitoses/10 HPF) pancreatic for cohort 3. 5.For patients included in cohort 4: WHO classification G3 (Ki67>20% or mitotic count >20 mitoses/10 HPF) gastroenteropancreatic neuroendocrine carcinomas (NEC) or liver metastases of G3 NEC of unknown primary site. 6.Subjects must have evidence of measurable disease meeting the following criteria: a)In case of more than one target lesion, it should be identified at least 1 lesion of =1.0 cm in the longest diameter for a non lymph node, or =1.5 cm in the short-axis diameter for a lymph node, which is serially measurable according to RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI). If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of =1.5 cm. b)Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation or liver embolization must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion. c)Subjects must show evidence of disease progression by radiologic image techniques within 12 months (an additional month will be allowed to accommodate actual dates of performance of scans, i.e., within = 13 months) prior to signing informed consent, according to RECIST 1.1 . 7.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8.Life expectancy of at least 12 weeks. 9.Adequate normal organ and marrow function as defined below: Haemoglobin =9.0 g/dL; Absolute neutrophil count (ANC) =1.5 x 109/L (>1500/mm3); Platelet count =100 x
Exclusion criteria
Exclusion criteria: 1.Involvement in the planning and/or conduct of the study. 2.Participation in another clinical study with an investigational product within 4 weeks (w). 3.WHO Classification G3 neuroendocrine neoplasms of lung origin (oat cell/large cell lung cancer). 4.Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL-4 therapy. 5.Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, known/evidence of acute or chronic hepatitis B, hepatitis C, known history of Human Immunodeficiency Virus, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the giving of written informed consent. 6.Known/previous diagnosis of tuberculosis. 7.Current/previous immunosuppressive medication within 28 days (d) before first dose of durvalumab or tremelimumab, except for intranasal/inhaled corticosteroids or systemic corticosteroids at physiological doses(Grade 1. 17.Any anti-cancer treatment within 21d or any investigational agent within 30d prior to the first dose of the IMP, and should have recovered from any toxicity related to previous anti-cancer treatment. This does not apply to the use of somatostatin analogues for symptomatic therapy. 18.Major surgery within 3w prior to the first dose of the IMP. 19.Subjects having >1+ proteinuria (if urine dipstick testing, 24h urine collection for quantitative assessment of proteinuria will be mandatory). 20.Significant cardiovascular impairment: Congestive heart failure >NYHA Class II, unstable angina; myocardial infarction or stroke within 6m of the first dose of study drug, or cardiac arrhythmia requiring medical treatment. 21.Mean QT interval corrected for heart rate =470 ms calculated from 3 el
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Cohorts 1 to 3: Clinical benefit rate by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, which is defined as the percentage of patients achieving complete response, partial response, or stable disease at month 9 after durvalumab plus tremelimumab was started. Cohort 4: Overall survival rate, which is defined as the percentage of patients alive at month 9 after durvalumab plus tremelimumab was started.;Secondary Objective: - Overall response rate (ORR) by irRECIST. - To assess the duration of response according to irRECIST. - To assess the median progression-free survival time (PFS) according to irRECIST. - To assess the safety profile of Durvalumab and Tremelimumab in subjects with advanced neuroendocrine neoplasms. - To assess the median overall survival (OS) time. - To assess response status according to irRECIST at 6, 9 and 12 months after start of study treatment. - To evaluate biochemical response (changes in CgA and NSE levels) and its association with response rate and progression-free survival. - To assess whether baseline tumor and blood biomarkers may be predictive of response to durvalumab and tremelimumab therapy. - To explore additional hypotheses related to biomarkers and relationship to durvalumab and tremelimumab efficacy and/or toxicity and neuroendocrine tumors evolution that may arise from internal or external research activities.;Primary end point(s): - Clinical Benefit Rate according RECIST criteria. - Overall survival rate;Timepoint(s) of evaluation of this end point: 9 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Up to 12 months after the start of treatment;Secondary end point(s): - Overall response rate (ORR) by irRECIST. - Duration of response according to irRECIST. - Median progression-free survival time (PFS) according to irRECIST. - Safety profile of Durvalumab and Tremelimumab in subjects with advanced neuroendocrine neoplasms. - Median overall survival (OS) time. - Response status according to irRECIST at 6 and 12 months after start of study treatment. - Changes in CgA and NSE levels and its association with response rate and PFS. - Possible association of baseline tumor and blood biomarkers and rsponse to treatment. - Other additional relations on biomarkers, treatment efficacy, treatment toxicity and/or evolution of neuroendocrine tumours. | — |
Countries
Spain
Contacts
Public ContactFederico Nepote
MFAR Clinical Research
Outcome results
None listed