A Phase 2 interventional study of Lanreotide Autogel 120 mg and Temozolomide (TMZ) in Gastroenteropancreatic Neuroendocrine Tumors, sponsored by Ipsen. Completed at 10 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-05-06.
Sponsored by Ipsen · Phase 2, Interventional, and Treatment
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).
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Exclusion Criteria:
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 · Drug: Temozolomide (TMZ)
Lanreotide Autogel 120 mg subcutaneous (s.c) - injection, every 28 days (+/-2 days).
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.
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.
Time frame: 6 months
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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline (week 1) and weeks 4, 12, 24 and 48
57 subjects entered a combination phase and received lanreotide ATG 120 mg plus temozolomide for 6 months. A 6 month maintenance phase then followed where subjects received either lanreotide ATG 120 mg or no treatment, dependent upon whether they had functioning or non-functioning NET, clinical benefit and allocation following randomisation.
| Milestone | Combination Phase | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|---|
| Started | 57 | 0 | 0 | 0 |
| Completed | 37 | 0 | 0 | 0 |
| Not completed | 20 | 0 | 0 | 0 |
| Withdrew: Adverse event | 10 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 2 | 0 | 0 | 0 |
| Withdrew: Disease progression | 6 | 0 | 0 | 0 |
| Withdrew: Did not meet inclusion criteria | 1 | 0 | 0 | 0 |
| Withdrew: Protocol violation | 1 | 0 | 0 | 0 |
| Milestone | Combination Phase | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|---|
| Started | 0 | 11 | 14 | 12 |
| Completed | 0 | 8 | 9 | 7 |
| Not completed | 0 | 3 | 5 | 5 |
| Withdrew: Disease progression | 0 | 3 | 4 | 3 |
| Withdrew: Adverse event | 0 | 0 | 1 | 2 |
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.
| percentage of subjects | Combination Phase |
|---|---|
| Disease Control Rate (DCR) After 6 Months | 73.5 (58.9 to 85.1) |
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.
| percentage of subjects | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|
| DCR After 12 Months | 54.5 (23.4 to 83.3) | 71.4 (41.9 to 91.6) | 41.7 (15.2 to 72.3) |
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.
| months | Intention-to-treat (ITT) Population |
|---|---|
| Progression-Free Survival (PFS) Within 12 Months | 11.1 (8.3 to NA) |
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).
| months | Intention-to-treat (ITT) Population |
|---|---|
| Time To Response (TtR) Within 12 Months | NA (NA to NA) |
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.
| months | Intention-to-treat (ITT) Population |
|---|---|
| Duration of Response (DoR) Within 12 Months | NA (NA to NA) |
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.
| Participants | Combination Phase |
|---|---|
| Week 12- PD | 8 |
| Week 12 - SD | 15 |
| Week 12- PR | 10 |
| Week 12 - Missing | 1 |
| Week 24 - PD | 5 |
| Week 24 - SD | 9 |
| Week 24 - PR | 7 |
| Week 24 - Missing | 0 |
| Early Withdrawal - PD | 1 |
| Early Withdrawal - SD | 2 |
| Early Withdrawal - PR | 1 |
| Early Withdrawal - Missing | 14 |
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.
| Participants | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|
| Week 24 - PD | 2 | 1 | 2 |
| Week 24 - SD | 3 | 4 | 2 |
| Week 24 - PR | 0 | 3 | 3 |
| Week 24 - Missing | 0 | 1 | 2 |
| Week 36 - PD | 1 | 1 | 3 |
| Week 36 - SD | 2 | 4 | 2 |
| Week 36 - PR | 0 | 1 | 4 |
| Week 36 - Missing | 0 | 1 | 0 |
| Week 48 - PD | 1 | 1 | 2 |
| Week 48 - SD | 0 | 2 | 3 |
| Week 48 - PR | 1 | 2 | 1 |
| Week 48 - Missing | 0 | 0 | 0 |
| Early Withdrawal - PD | 1 | 2 | 1 |
| Early Withdrawal - SD | 0 | 0 | 0 |
| Early Withdrawal - PR | 0 | 1 | 1 |
| Early Withdrawal - Missing | 2 | 0 | 0 |
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.
| Participants | Combination Phase - Functioning NET |
|---|---|
| Week 12 - Progression | 4 |
| Week 12 - Response | 6 |
| Week 12 - Not evaluable | 1 |
| Week 12 - Missing | 6 |
| Week 24 - Progression | 6 |
| Week 24 - Response | 3 |
| Week 24 - Not evaluable | 1 |
| Week 24 - Missing | 3 |
| Early Withdrawal - Progression | 0 |
| Early Withdrawal - Response | 1 |
| Early Withdrawal - Not Evaluable | 0 |
| Early Withdrawal - Missing | 7 |
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.
| Participants | Maintenance Phase - Functioning NET, Lanreotide |
|---|---|
| Week 24 - Progression | 6 |
| Week 24 - Response | 3 |
| Week 24 - Not evaluable | 1 |
| Week 24 - Missing | 1 |
| Week 36 - Progression | 3 |
| Week 36 - Response | 3 |
| Week 36 - Not evaluable | 0 |
| Week 36 - Missing | 3 |
| Week 48 - Progression | 4 |
| Week 48 - Response | 2 |
| Week 48 - Not evaluable | 0 |
| Week 48 - Missing | 2 |
| Early Withdrawal - Progression | 0 |
| Early Withdrawal - Response | 0 |
| Early Withdrawal - Not evaluable | 0 |
| Early Withdrawal - Missing | 3 |
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.
| Participants | Combination Phase - Functioning NET |
|---|---|
| Diarrhoea - Reduction | 4 |
| Diarrhoea - Increase | 2 |
| Diarrhoea - Stability | 5 |
| Diarrhoea - Missing | 6 |
| Flushing - Reduction | 4 |
| Flushing - Increase | 4 |
| Flushing - Stability | 3 |
| Flushing - Missing | 6 |
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.
| Participants | Maintenance Phase - Functioning NET, Lanreotide |
|---|---|
| Diarrhoea - Reduction | 4 |
| Diarrhoea - Increase | 1 |
| Diarrhoea - Stability | 3 |
| Diarrhoea - Missing | 3 |
| Flushing - Reduction | 2 |
| Flushing - Increase | 3 |
| Flushing - Stability | 3 |
| Flushing - Missing | 3 |
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.
| units on a scale | Combination Phase |
|---|---|
| Global health status | -4.9 ± 18.2 |
| Physical functioning | -9.6 ± 19.4 |
| Role functioning | -8.3 ± 27.6 |
| Emotional functioning | -4.7 ± 17.7 |
| Cognitive functioning | -5.9 ± 15.8 |
| Social functioning | -11.8 ± 23.8 |
| Fatigue | 6.9 ± 20.1 |
| Nausea and vomiting | 6.9 ± 14.9 |
| Pain | -1.0 ± 31.0 |
| Dyspnoea | 12.7 ± 30.7 |
| Insomnia | 0.0 ± 34.9 |
| Appetite loss | 2.0 ± 24.5 |
| Constipation | 6.9 ± 33.6 |
| Diarrhoea | -3.9 ± 34.6 |
| Financial difficulties | 2.9 ± 17.1 |
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.
| units on a scale | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|
| Global health status | -11.7 ± 40.7 | -3.1 ± 10.9 | -7.1 ± 15.5 |
| Physical functioning | 8.0 ± 22.8 | -12.5 ± 17.6 | -11.4 ± 13.7 |
| Role functioning | 3.3 ± 29.8 | -2.1 ± 20.8 | -7.1 ± 13.1 |
| Emotional functioning | 15.0 ± 19.0 | -6.2 ± 20.3 | -6.0 ± 12.5 |
| Cognitive functioning | 3.3 ± 24.7 | -2.1 ± 20.8 | 2.4 ± 6.3 |
| Social functioning | 13.3 ± 34.2 | -22.9 ± 34.4 | -4.8 ± 15.9 |
| Fatigue | -22.2 ± 30.4 | -9.7 ± 24.1 | 4.8 ± 16.8 |
| Nausea and vomiting | -10.0 ± 14.9 | 4.2 ± 23.1 | 2.4 ± 6.3 |
| Pain | -13.3 ± 32.1 | 4.2 ± 24.8 | 9.5 ± 23.3 |
| Dyspnoea | -8.3 ± 41.9 | 4.2 ± 33.0 | 9.5 ± 16.3 |
| Insomnia | -13.3 ± 50.6 | -8.3 ± 34.5 | 16.7 ± 27.9 |
| Appetite loss | 0.0 ± 23.6 | 0.0 ± 39.8 | 14.3 ± 17.8 |
| Constipation | 20.0 ± 38.0 | -4.2 ± 11.8 | -4.8 ± 35.6 |
| Diarrhoea | -40.0 ± 36.5 | 8.3 ± 15.4 | 0.0 ± 27.2 |
| Financial difficulties | 6.7 ± 14.9 | 4.2 ± 27.8 | 9.5 ± 25.2 |
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.
| Units on a scale | Combination Phase |
|---|---|
| Endocrine symptoms | -1.0 ± 13.5 |
| Gastrointestinal (G.I.) symptoms | 5.7 ± 14.0 |
| Treatment related symptoms | 3.6 ± 30.1 |
| Social function | 2.3 ± 25.3 |
| Disease related worries | 1.6 ± 27.1 |
| Muscle/bone pain symptoms | 1.0 ± 37.1 |
| Body image | 0.0 ± 23.2 |
| Weight gain | -11.8 ± 30.5 |
| Information/communication function | -9.4 ± 22.8 |
| Sexual function | -4.8 ± 17.8 |
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.
| units on a scale | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|
| Endocrine symptoms | -13.3 ± 21.4 | -5.6 ± 19.7 | 1.6 ± 4.2 |
| G.I. symptoms | -4.0 ± 21.9 | 0.0 ± 19.2 | 6.7 ± 7.7 |
| Treatment related symptoms | 0.0 ± 0.0 | -11.1 ± 34.7 | — |
| Social function | -6.7 ± 23.0 | 9.7 ± 20.9 | -6.3 ± 16.8 |
| Disease related worries | -6.7 ± 36.5 | 1.4 ± 15.1 | -3.2 ± 30.6 |
| Muscle/bone pain symptoms | -6.7 ± 14.9 | 4.2 ± 33.0 | 4.8 ± 30.0 |
| Body image | 0.0 ± 23.6 | 4.2 ± 27.8 | 4.8 ± 12.6 |
| Weight gain | -20.0 ± 29.8 | 9.5 ± 25.2 | -9.5 ± 56.8 |
| Information/communication function | 0.0 ± 70.7 | 0.0 ± 17.8 | -4.8 ± 12.6 |
| Sexual function | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.0 ± 0.0 |
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.
| percentage of subjects | Combination Phase |
|---|---|
| MGMT Methylation | 100.0 (66.4 to 100.0) |
| MGMT No methylation | 84.6 (54.6 to 98.1) |
| MGMT Expression | 90.9 (58.7 to 99.8) |
| MGMT No expression | 70.0 (45.7 to 88.1) |
| SSTR 2a FE | 86.7 (59.5 to 98.3) |
| SSTR 2a CCME | 72.7 (49.8 to 89.3) |
| SSTR 5 - No Receptors | 75.0 (53.3 to 90.2) |
| SSTR 5 CE | 100.0 (15.8 to 100.0) |
| SSTR 5 FE | 81.8 (48.2 to 97.7) |
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.
| ng/mL | PK Subset |
|---|---|
| Baseline | 0.44 ± 1.22 |
| Week 4 | 2.45 ± 1.16 |
| Week 12 | 5.06 ± 3.01 |
| Week 24 | 5.83 ± 1.93 |
| Week 48 | 3.68 ± 3.36 |
Collected over 13 months (12 month study treatment plus 28 days). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Combination Phase | 1/57 (1.8%) | 17/57 (29.8%) | 52/57 (91.2%) |
| Maintenance Phase - Functioning NET, Lanreotide | 1/11 (9.1%) | 3/11 (27.3%) | 9/11 (81.8%) |
| Maintenance Phase - Non-functioning NET, Lanreotide | 1/14 (7.1%) | 4/14 (28.6%) | 13/14 (92.9%) |
| Maintenance Phase - Non-functioning NET, No Treatment | 1/12 (8.3%) | 4/12 (33.3%) | 11/12 (91.7%) |
| Event | Combination Phase | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|---|
| Ocular vascular disorderEye disorders | 0/57 | 1/11 | 0/14 | 0/12 |
| PneumoniaInfections and infestations | 0/57 | 1/11 | 0/14 | 0/12 |
| Back painMusculoskeletal and connective tissue disorders | 0/57 | 1/11 | 0/14 | 0/12 |
| Abdominal painGastrointestinal disorders | 0/57 | 0/11 | 1/14 | 1/12 |
| AscitesGastrointestinal disorders | 0/57 | 0/11 | 0/14 | 1/12 |
| CholangitisHepatobiliary disorders | 2/57 | 0/11 | 1/14 | 1/12 |
| JaundiceHepatobiliary disorders | 1/57 | 0/11 | 0/14 | 1/12 |
| Multi-organ failureGeneral disorders | 0/57 | 0/11 | 0/14 | 1/12 |
| PyrexiaGeneral disorders | 0/57 | 0/11 | 0/14 | 1/12 |
| HyperglycaemiaMetabolism and nutrition disorders | 0/57 | 0/11 | 0/14 | 1/12 |
| Event | Combination Phase | Maintenance Phase - Functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, Lanreotide | Maintenance Phase - Non-functioning NET, No Treatment |
|---|---|---|---|---|
| NauseaGastrointestinal disorders | 24/57 | 1/11 | 4/14 | 1/12 |
| FatigueGeneral disorders | 19/57 | 2/11 | 4/14 | 5/12 |
| DiarrhoeaGastrointestinal disorders | 21/57 | 0/11 | 3/14 | 2/12 |
| LymphopeniaBlood and lymphatic system disorders | 8/57 | 0/11 | 2/14 | 4/12 |
| VomitingGastrointestinal disorders | 19/57 | 1/11 | 2/14 | 1/12 |
| Abdominal painGastrointestinal disorders | 12/57 | 2/11 | 4/14 | 2/12 |
| ThrombocytopeniaBlood and lymphatic system disorders | 16/57 | 1/11 | 3/14 | 0/12 |
| NasopharyngitisInfections and infestations | 7/57 | 3/11 | 2/14 | 3/12 |
| AnaemiaBlood and lymphatic system disorders | 7/57 | 0/11 | 0/14 | 3/12 |
| LeukopeniaBlood and lymphatic system disorders | 6/57 | 0/11 | 0/14 | 3/12 |
| Age, Continuous(years) | Combination Phase |
|---|---|
| Mean | 63.1 ± 11.0 |
| Sex: Female, Male(Participants) | Combination Phase |
|---|---|
| Female | 24 |
| Male | 33 |
| Race (NIH/OMB)(Participants) | Combination Phase |
|---|---|
| American Indian or Alaska Native. | 0 |
| Asian. | 0 |
| Black or African American | 0 |
| Hispanic or Latino | 0 |
| Native Hawaiian or Other Pacific Islander. | 0 |
| White | 57 |
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