Efficacy and Safety of Lanreotide Autogel (ATG) in Combination With Temozolomide in Subjects With Thoracic Neuroendocrine Tumors.

Study Overview
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Brief Summary
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The purpose of the protocol is to evaluate the efficacy and safety of Lanreotide ATG 120 mg in combination with Temozolomide in subjects with unresectable advanced neuroendocrine tumours of the lung or thymus as Disease Control Rate at 9 months.

Official Title
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Efficacy and Safety of Lanreotide ATG 120 mg in Combination With Temozolomide in Subjects With Progressive Well Differentiated Thoracic Neuroendocrine Tumors. A Phase II, Multicentre, Single Arm, Open-label Trial.

Conditions
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Neuroendocrine Tumours

Intervention / Treatment
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* Drug: Lanreotide (Autogel formulation) and Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological documented unresectable advanced (locally or metastatic) well or moderately differentiated neuroendocrine tumors of the lung or thymus (typical and atypical carcinoids according to the World Health Organisation (WHO) 2004 criteria); Imaging documented progression within 12 months before screening visit (V1), according to RECIST criteria v 1.1; Measurable disease, as defined by RECIST criteria v 1.1, on a CT scan performed at screening visit (V1); Octreoscan or Ga68-DOTA-TATE/TOC/NOC-PET-TC within 12 months before screening visit (V1); Adequate liver, renal and bone marrow function. Exclusion Criteria: Poorly differentiated neuroendocrine carcinoma and mixed Neuroendocrine tumours (NET), according to WHO 2004 criteria Neuroendocrine tumours other than lung or thymus Non-neuroendocrine thymic neoplasm Received a prior therapy with Peptide Receptor Radionuclide Therapy (PRRT) within 6 months prior to screening visit (V1) Treated with systemic therapies (chemotherapy, interferon-alpha, somatostatin analogues, molecular target therapies) within 1 month prior to screening visit (V1) Treated with a number of systemic therapy lines > 3 prior to screening visit (V1), and any of the following: for chemotherapy no more than 1 line prior to V1 for somatostatin analogue no more than 1 line therapy, considered as treatment lasting more than 6 months, prior to V1 no therapy with Temozolomide (TMZ) prior to V1 Received a prior therapy with Peptide Receptor Radionuclide Therapy (PRRT) within 6 months prior to screening visit (V1) Received external palliative radiotherapy within the last 28 days prior to screening visit (V1) Received locoregional therapies (Transarterial embolization, Transcatheter arterial chemoembolization, thermo-ablation with radio-frequency) and Selective internal radiotherapy within 3 months prior to screening visit (V1) Presence of symptomatic brain metastasis Subjects with symptomatic cholelithiasis at screening visit (V1)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lanreotide (Autogel formulation) and Temozolomide<br>Lanreotide ATG 120 mg every 28 days, deep subcutaneous injection for a maximum of 48 weeks, for a total number of 12 injections. Temozolomide 250 mg hard capsules, for 5 consecutive days every 28 days, oral route, for a maximum of 48 weeks. | Drug: Lanreotide (Autogel formulation) and Temozolomide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) Assessed Locally at Month 9 | Responders were participants who showed disease control according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria v 1.1 assessed locally by the investigator. The DCR was defined as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST criteria v1.1. A sensitivity analysis-1 of local DCR was performed excluding participants withdrawn before 9 months with reason other than progressive disease (PD) or missing assessment and considering participants with PD prior or at 9 months as failures. In addition, a sensitivity analysis-2 was performed in order to consider assessments done between 7.5 and 10.5 months as 9 months assessments when 9-month assessment was missing using same methodology, i.e. considering PD prior or at 9 months and participants withdrawn with other or missing reasons as failures. | Up to Month 9; for sensitivity analysis-2, up to 10.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DCR Assessed Centrally at Month 9 | The DCR was defined as SD, PR or CR according to RECIST criteria v1.1. A second set of the original computed tomography (CT) scan images were used for a centralized RECIST v1.1 assessment by an independent radiologist. | Up to Month 9 | 
| Median Progression Free Survival (PFS) Assessed Locally and Centrally | The PFS was defined as the time from the first treatment administration to disease progression according to RECIST criteria v 1.1 or death from any cause. The PFS was assessed locally by the investigator and centrally by an independent radiologist. The distribution of PFS times was estimated using the Kaplan-Meier method. The PFS of participants who were lost to follow-up and those who had not progressed at end of study were censored at the date of the last disease assessment. | From Day 1 up to end of study, 52 weeks | 
| Median Time to Response (TTR) Assessed Locally and Centrally | The TTR was defined as the time from first treatment administration to the first objective tumor response (PR or CR according to RECIST criteria v 1.1). The TTR was assessed locally by the investigator and centrally by an independent radiologist. The distribution of TTR was estimated using the Kaplan-Meier method. The TTR of participants who were lost to follow-up or died prior to any objective tumor response were censored at the date of the last disease assessment. | From Day 1 up to end of study, 52 weeks | 
| Median Duration of Response (DOR) Assessed Locally and Centrally | The DOR was defined as the time from onset of the first objective tumor response (PR or CR) to objective tumor progression (PD) according to RECIST criteria v 1.1. The DOR was assessed locally by the investigator and centrally by an independent radiologist. | From Day 1 up to end of study, 52 weeks | 
| Median Time to Progression (TTP) Assessed Locally and Centrally | The TTP was defined as the time from first treatment administration to the first objective tumor progression (PD) according to RECIST criteria v 1.1. The TTP was assessed locally by the investigator and centrally by an independent radiologist. The distribution of TTP times was estimated using the Kaplan-Meier method. The TTP of participants who were lost to follow-up, and those who had not progressed at end of study were censored at the date of the last disease assessment. | From Day 1 up to end of study, 52 weeks | 
| Best Overall Response (BOR) Assessed Locally and Centrally | The BOR was defined as the highest OR achieved by the participant from the time of first treatment until disease progression/recurrence or the end of study according to RECIST criteria v1.1 and was classified as: CR > PR > Non-CR/Non-progressive disease (NCR/NPD) > SD > PD > ND > not evaluable (NE). The BOR was assessed locally by the investigator and centrally by an independent radiologist. Percentages are based on the number of participants in the ITT/Safety population with non-missing observations. | From Day 1 up to end of study, 52 weeks | 
| Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12 | The ORR was defined as the percentage of participants with CR or PR according to RECIST criteria v1.1. The ORR was assessed locally by the investigator and centrally by an independent radiologist. The ORR was based on the participants with PD prior to 9 and 12 months with respectively PD at 9 and 12 months, and participants withdrawn before the assessment for reason other than PD or missing as failures. | Months 9 and 12 | 
| DCR Assessed Locally and Centrally at Month 12 | The DCR was defined as SD, PR or CR according to RECIST criteria v1.1. The DCR was assessed locally by the investigator and centrally by an independent radiologist. | Month 12 | 
| DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | The influence of type of carcinoid [typical, atypical and undetermined carcinoid neuroendocrine tumors (NET)] on the local and central DCR at 9 months was analysed. Typical carcinoids were defined with absent foci of necrosis and mitotic count < 2 mitoses/2 millimeters^2 (mm^2); atypical carcinoids were defined with presence of foci of necrosis and/or 2 mitoses/2 mm^2 <= mitotic count <= 10 mitoses/2 mm^2; and carcinoid NET were defined as confirmed carcinoid without foci of necrosis and/or mitotic count reported. The DCR was assessed locally by the investigator and centrally by an independent radiologist. | Up to Month 9 | 
| Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Participants with baseline CgA plasma levels greater than the upper limit of normal (ULN) were assessed for a biochemical response. A biochemical responder was defined as a participant who had a decrease of CgA >= 50% compared to baseline, while biochemical SD was defined as a decrease < 50% or an increase <= 25% compared to baseline. Biochemical non-responders had an increase >25% compared to baseline. Baseline was defined as value at Day 1. | Baseline (Day 1) and Week 4, 12, 24, 36 and 52 | 
| Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | The NSE and CgA levels were classified according to ULN as follows: < 1 ULN, 1-2 ULN and > 2 ULN. Baseline was defined as value at Day 1. Percentages are based on the number of participants in the ITT/Safety population who attended the visit with non-missing observations. | Baseline and Weeks 4, 12, 24, 36 and 52 | 
| Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | The following biomarkers were investigated: Immunohistochemistry assay human somatostatin receptors 2 (SSTR2) including human epidermal growth factor receptor 2 (HER-2) score [0, 1+, 2+, 3+ and positive (+ve) versus negative (-ve)]; hormone receptor score (H-score) (from 0 to 300 as quantitative variable and +ve versus -ve); immunoreactive score (IRS) score (from 0 to 12 and reference for hazard ratio was 0-1). Ki67 index (from 0% to 100% and reference for hazard ratio was 4%-25%). O^6-methylguanine-DNA methyltransferase (MGMT) expression including percentage of +ve nuclei stained and methylated sites and H-score (from 0 to 300 as quantitative variable). For all these categories, higher score indicates a higher expression of biomarkers. Carcinoid type (typical or NET) was also investigated. Prognostic value of biomarkers expression at screening on PFS were assessed locally and centrally using univariate cox proportional hazard models. | From Screening period (-4 weeks) up to Week 52 | 
| Influence of Biomarkers Expression on Locally and Centrally Assessed ORR at Months 9 and 12 | The following biomarkers were investigated: Immunohistochemistry assay SSTR2 including HER-2 score (0, 1+, 2+, 3+); H-score (from 0 to 300 as quantitative variable); IRS score (from 0 to 12). Ki67 index (from 0% to 100%). MGMT expression including percentage of +ve nuclei stained and methylated sites and H-score (from 0 to 300 as quantitative variable). For all these categories, higher score indicates a higher expression of biomarkers. Less than 5 OR (CR or PR) events were reported, therefore this analysis was not performed. | Screening period, Months 9 and 12 | 
| Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | The following biomarkers were investigated: Immunohistochemistry assay SSTR2 including HER-2 score (0, 1+, 2+, 3+ and +ve versus -ve); H-score (from 0 to 300 as quantitative variable and +ve versus -ve); IRS score (from 0 to 12 and reference for odds ratio was 0-1). Ki67 index (from 0% to 100% and reference for odds ratio was 4%-25%). MGMT expression including percentage of +ve nuclei stained and methylated sites and H-score (from 0 to 300 as quantitative variable). For all these categories, higher score indicates a higher expression of biomarkers. Carcinoid type (typical or NET) was also investigated. Prognostic value of biomarkers expression at screening on DCR were assessed locally and centrally using univariate logistic regression models. | Screening period, Months 9 and 12 | 
| Coefficient of Agreement Between Central and Local Assessment of Tumor Radiological Response at Month 9 | Differences between central radiology review and local investigator review were assessed according to the DCR status and the number of agreements and disagreements between the evaluators (central versus local) along with the p-values from the kappa test. A kappa statistic was used to evaluate the concordance between the central and the local review. | Month 9 |