Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy and tolerability of the combination of Lanreotide Autogel 120 mg and Temozolomide in patients with progressive gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) graded as G1 or G2 (G1/G2). All progressive tumours classified according to Response Evaluation Criteria In Solid Tumours (RECIST, 1.1).

Official Title
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Phase II, Multicentre, Open Label Study to Evaluate the Efficacy of the Combination of Lanreotide Autogel 120mg and Temozolomide in Patients With Progressive Gastro-entero-pancreatic Neuroendocrine Tumours (GEP-NET) G1/G2 - A Pilot-Study

Conditions
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Gastroenteropancreatic Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Lanreotide Autogel 120 mg
* Drug: Temozolomide (TMZ)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent prior to any study related procedures Inoperable, Gastro-Entero-Pancreatic-Neuroendocrine Tumour G1 or G2 (Proliferation Index, Ki67-Index: 0 to ≤20%) confirmed by pathological/histological assessment Progressive disease within 12 months before inclusion (RECIST 1.1: increase of >20% tumour load; by Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) Measurable disease according to RECIST 1.1. Metastatic disease confirmed by CT/MRI. Functioning or non-functioning NET (G1, G2). Positive Octreo-Scan (≥ Grade 2 Krenning scale) or positive DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-TATE (Tyr3-Thre8-Octreotide or DOTA-Tyr3-octreotate)/TOC (Tyr3-octreotide) -PET (Positron-Emission-Tomography) -CT within 12 months prior to screening Exclusion Criteria: Has the diagnosis of Insulinoma Has a diagnosis of a multiple endocrine neoplasia (MEN)

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 120mg & Temozolomide<br>Combination phase for first 6 months: Lanreotide Autogel 120 mg and Temozolomide. Followed by either 6 months Lanreotide Autogel 120 mg maintenance or 6 months of no treatment. | Drug: Lanreotide Autogel 120 mg<br>* Lanreotide Autogel 120 mg subcutaneous (s.c) - injection, every 28 days (+/-2 days).<br>Drug: Temozolomide (TMZ)<br>* Temozolomide capsule (variable dose). 150 mg/m2 per day for 5 days in the first month. 200 mg/m2 per day for 5 days in months 2, 3, 4, 5 and 6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) After 6 Months | All tumour assessments were performed using the Response Evaluation Criteria In Solid Tumours (RECIST) criteria (1.1). Computer Tomography (CT-scan) or Magnetic Resonance Imaging (MRI) could be used for as method of tumour measurement and the same method of tumour measurement was used throughout the study for each subject. CT scans/MRI were performed at screening or baseline visit then at weeks 12, 24 and at early withdrawal or at anytime during the study in the case of any clinical or biological signs of tumour progression. The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months of combination treatment and was described in the ITT population along with its 95% Confidence Interval (CI) and was compared to 45% with an exact binomial proportion test. The Last Observation Carried Forward (LOCF) method was used to replace missing assessments at the end of the combination phase. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DCR After 12 Months | All tumour assessments were performed using the RECIST criteria (1.1). CT-scan or MRI could be used for as method of tumour measurement and the same method of tumour measurement was used throughout the study for each subject. CT scans/MRI were performed at screening or baseline visit then at baseline, weeks 12, 24, 36, 48 (end of study) and at study withdrawal or at anytime during the study in the case of any clinical or biological signs of tumour progression. The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months combination treatment followed by either 6 months of lanreotide ATG 120 mg maintenance treatment or no treatment. The DCR was described in the ITT population along with its 95% CI and was compared to 45% with an exact binomial proportion test. The LOCF method was used to replace missing assessments at the end of the maintenance phase. | 12 months | 
| Progression-Free Survival (PFS) Within 12 Months | PFS was defined as the time from the date of treatment start to the date of the first documented disease progression or death due to any cause within the first 12 months of treatment. If a subject had not progressed or died after 12 months of treatment or when any further anti-neoplastic therapy was received, PFS was censored at the time of the last tumour assessment before the analysis cut-off date or the anti-neoplastic therapy date. A Kaplan-Meier estimate of the PFS was calculated to determine the number of subjects at risk. Median PFS time (50% of subjects who would not progress or die) of the ITT population is presented along with 95 % CI. | 12 months | 
| Time To Response (TtR) Within 12 Months | TtR was defined as the time from the date of treatment start to the date of the first documented objective response (CR or PR) within the first 12 months of treatment (combination and maintenance phases). A Kaplan Meier estimate of the TtR survival function was constructed. The Kaplan-Meier method was used to estimate the median TtR and its 95% CI for subjects in the ITT population (50% of subjects were expected to have a CR or PR at this time). | 12 months | 
| Duration of Response (DoR) Within 12 Months | The DoR is an estimation of the time from first documented objective response (CR or PR) to the first date of progressive disease (PD) or death due to disease progression for subjects who experienced an objective response within the first 12 months of treatment (combination and maintenance phases). The Kaplan-Meier method was used to estimate the median DoR and its 95% CI for subjects in the ITT population who had an objective response. | 12 months | 
| The Number of Subjects With a Biochemical Response Using Chromogranin-A (CgA) Levels After 6 Months | Blood samples for CgA blood tumour marker analysis were taken at baseline, weeks 12, 24 and at early withdrawal. The biochemical response after 6 months combination treatment was estimated for subjects with abnormal CgA levels at baseline. Abnormal CgA levels were defined as above the upper limit of normal range (≥100 micrograms/litre [mcg/L]). Biochemical response based on CgA levels was categorised as: PR (decrease of CgA ≥ 50%, compared to the baseline CgA), SD (decrease < 50 % or an increase ≤25%, compared to the baseline CgA) or PD (defined as an increase ≥25 %, compared to the baseline CgA). The number of subjects in each response category at each time point in the combination phase is presented. Analysis was only carried out on subjects in the ITT population who had abnormal CgA at baseline. | 6 months | 
| The Number of Subjects With a Biochemical Response Using CgA Levels After 12 Months | Blood samples for CgA blood tumour marker analysis were taken at baseline, weeks 12, 24, 36, 48 (end of study) and at early withdrawal. The biochemical response after 12 months combination and maintenance treatment was estimated for subjects with abnormal CgA levels at baseline. Abnormal CgA levels were defined as above the upper limit of normal range (≥100 mcg/L). Biochemical response based on CgA levels was categorised as: PR (decrease of CgA ≥50 % compared to the baseline CgA), SD (decrease < 50% or an increase ≤ 25% compared to the baseline CgA) or PD (defined as an increase ≥ 25%, compared to the baseline CgA). The number of subjects in each response category at each time point in the maintenance phase is presented. Analysis was only carried out on subjects in the ITT population who had abnormal CgA at baseline. | 12 months | 
| The Number of Subjects With a Biochemical Response Using 5-Hydroxy-Indol-Amino-Acid (HIAA) Levels After 6 Months | Urine samples for 5-HIAA urinary tumour marker analysis were taken at at baseline, weeks 12, 24and early withdrawal. Biochemical response based on 5-HIAA levels was categorised as: Response (5-HIAA reduction compared to baseline) or Progression (5-HIAA increase compared to baseline). The number of subjects in each response category at each time point in the combination phase is presented. Analysis was only carried out on subjects in the ITT population with functioning NET. | 6 months | 
| The Number of Subjects With a Biochemical Response Using 5-HIAA Levels After 12 Months | Urine samples for 5-HIAA urinary tumour marker analysis were taken at baseline, weeks 12, 24, 36, 48 (end of study) and early withdrawal. Biochemical response based on 5-HIAA levels was categorised as: Response (5-HIAA reduction compared to baseline) or Progression (5-HIAA increase compared to baseline). The number of subjects in each response category at each time point in the maintenance phase is presented. Analysis was only carried out on subjects in the ITT population with functioning NET. | 12 months | 
| The Number of Subjects With a Symptomatic Response After 6 Months | Symptomatic response was evaluated as absolute change from baseline in the number of episodes of the lead symptoms (i.e. diarrhoea and flushing) using the mean of the last 3 days before the visit, at each visit, as compared to baseline. Symptomatic responses were categorised as: Reduction, Increase or Stability of occurrences of diarrhoea / Reduction, Increase or Stability of occurrences of flushing. The number of subjects in each response category at week 24 (end of the combination phase) is presented. Analysis was only carried out on subjects in the ITT population with functioning NET. | 6 months | 
| The Number of Subjects With a Symptomatic Response After 12 Months - Maintenance Phase | Symptomatic response was evaluated as absolute change from baseline in the number of episodes of the lead symptoms (i.e. diarrhoea and flushing) using the mean of the last 3 days before the visit, at each visit, as compared to baseline. Symptomatic responses were categorised as: Reduction, Increase or Stability of occurrences of diarrhoea / Reduction, Increase or Stability of occurrences of flushing. The number of subjects in each response category at week 48 (end of study) is presented. Analysis was only carried out on subjects in the ITT population with functioning NET. | 12 months | 
| European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Core 30 Questionnaire (QLQ-C30): Mean Change From Baseline at 6 Months | Subjects were instructed to complete the QLQ-C30 questionnaire at baseline, weeks 12, 24 or at early withdrawal. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) & 6 other single items. The last 2 questions represented subject's assessment of overall health & quality of life, coded on a 7-point scale (1=very poor to 7=excellent). The mean change from baseline at week 24 (end of the combination phase) is presented for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Each individual subscore was transformed to range from 0 to 100. A higher score represents a higher level response. Thus, a better QoL/a better level of functioning/a worse level of symptoms. | 6 months | 
| EORTC QoL Questionnaire QLQ-C30: Mean Change From Baseline at 12 Months | Subjects were instructed to complete QLQ-C30 questionnaire at baseline, weeks 12, 24, 36, 48 (end of study) or at early withdrawal. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) & 6 other single items. The last 2 questions represented subject's assessment of overall health & quality of life, coded on a 7-point scale (1=very poor to 7=excellent). The mean change from baseline at week 48 (end of study) is presented for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Each individual subscore was transformed to range from 0 to 100. A higher score represents a higher level response. Thus, a better QoL/a better level of functioning/a worse level of symptoms. | 12 months | 
| Quality of Life Gastrointestinal Neuroendocrine Tumour 21 Questionnaire (QLQ-GI.NET21): Mean Change From Baseline at 6 Months | Subjects were instructed to complete the QLQ-GI.NET21 questionnaire at baseline, weeks 12, 24 or at early withdrawal. It contained 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Each individual subscore was transformed to range from 0 to 100. The mean change from baseline at week 24 (end of combination phase) is presented with a higher score representing a higher level response. Thus, a better level of functioning/a worse level of symptoms. | 6 months | 
| QoL Questionnaire QLQ-GI.NET21: Mean Change From Baseline at 12 Months | Subjects were instructed to complete the QLQ-GI.NET21 questionnaire at baseline, weeks 12, 24, 36, 48 (end of study) or at early withdrawal. It contained 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Answers were converted into grading scale, with values between 0 and 100. Each individual subscore was transformed to range from 0 to 100. The mean change from baseline at week 48 (end of study) is presented with a higher score representing a higher level response. Thus, a better level of functioning/a worse level of symptoms. | 12 months | 
| DCR by O6-methylguanine-DNA Methyl-transferase (MGMT) Expression and Methylation and Somatostatin Receptor (SSTR) Expression After 6 Months | In all subjects whose tumour tissue was available, MGMT expression/methylation and SSTR expression was analysed. After 6 months, the DCR (SD+PR+CR) by MGMT methylation and expression and by SSTR 2a and SSTR 5 expression was evaluated. DCR in response to MGMT methylation and expression results are presented. SSTR 2a and SSTR 5 expression is categorised as: No Receptors, Cytoplasmatic Expression (CE), Focal Expression (FE), Complete Circumferent Membrane Expression (CCME). The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months of combination treatment within each methylation/expression category. The DCR was described in the ITT population along with its 95% CI and was compared to 45% with an exact binomial proportion test. | 6 months | 
| Pharmacokinetic (PK) Results: Lanreotide ATG 120 mg Serum Concentrations Within 12 Months | Lanreotide ATG levels were measured in a subset of subjects to evaluate if temozolomide co-treatment had an impact on lanreotide serum concentration over a 12 month period. Blood samples were collected for the determination of lanreotide ATG in serum at baseline, weeks 4, 12, 24 and 48 (end of study). The concentrations of lanreotide ATG in serum were determined by a validated radioimmunoassay analysis method with a lower limit of quantitation of 0.08 nanograms [ng]/mL). Serum concentrations of lanreotide ATG at each of the time points in the combination and maintenance phase are presented. Only subjects with data available for analysis are presented. | Baseline (week 1) and weeks 4, 12, 24 and 48 |