Neuroendocrine Tumours
Conditions
Brief summary
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.
Interventions
DRUGLanreotide (Autogel formulation) and Temozolomide
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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: 1. for chemotherapy no more than 1 line prior to V1 2. 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 3. 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) Assessed Locally at Month 9 | Up to Month 9; for sensitivity analysis-2, up to 10.5 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) Assessed Locally and Centrally | From Day 1 up to end of study, 52 weeks | 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. |
| Median Time to Response (TTR) Assessed Locally and Centrally | From Day 1 up to end of study, 52 weeks | 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. |
| Median Duration of Response (DOR) Assessed Locally and Centrally | From Day 1 up to end of study, 52 weeks | 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. |
| Median Time to Progression (TTP) Assessed Locally and Centrally | From Day 1 up to end of study, 52 weeks | 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. |
| Best Overall Response (BOR) Assessed Locally and Centrally | From Day 1 up to end of study, 52 weeks | 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. |
| Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12 | 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. |
| DCR Assessed Locally and Centrally at Month 12 | 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. |
| DCR Assessed Centrally at Month 9 | Up to 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. |
| Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Baseline (Day 1) and Week 4, 12, 24, 36 and 52 | 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. |
| Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | Baseline and Weeks 4, 12, 24, 36 and 52 | 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. |
| Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | From Screening period (-4 weeks) up to Week 52 | 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. |
| Influence of Biomarkers Expression on Locally and Centrally Assessed ORR at Months 9 and 12 | Screening period, 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. |
| Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Screening period, 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. |
| Coefficient of Agreement Between Central and Local Assessment of Tumor Radiological Response at Month 9 | 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. |
| DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Up to Month 9 | 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. |
Countries
Italy
Participant flow
Recruitment details
This pilot study was conducted at 11 investigational sites in Italy between 06 July 2016 and 18 June 2019.
Pre-assignment details
The study consisted of a screening period (maximum 4 weeks), followed by an open label treatment period of up to a maximum of 52 weeks or until disease progression, death or unacceptable toxicity, or subject/physician decision.
Participants by arm
| Arm | Count |
|---|---|
| Lanreotide ATG Plus Temozolomide Lanreotide ATG 120 mg was administered by deep subcutaneous injection on Day 1 (baseline) and every 28 days for up to 52 weeks. Participants also received temozolomide 250 mg capsule orally once daily for 5 consecutive days every 28 days for up to 52 weeks. The dose of temozolomide could subsequently be reduced to 180 mg daily for 5 consecutive days every 28 days in case of bone marrow toxicity. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Other | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Lanreotide ATG Plus Temozolomide |
|---|---|
| Age, Continuous | 64.9 years STANDARD_DEVIATION 11.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 40 |
| other Total, other adverse events | 38 / 40 |
| serious Total, serious adverse events | 9 / 40 |
Outcome results
Primary
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.
Time frame: Up to Month 9; for sensitivity analysis-2, up to 10.5 months
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Disease Control Rate (DCR) Assessed Locally at Month 9 | DCR at Month 9 | 35.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Disease Control Rate (DCR) Assessed Locally at Month 9 | Sensitivity analysis-1 | 45.2 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Disease Control Rate (DCR) Assessed Locally at Month 9 | Sensitivity analysis-2 | 45.0 percentage of participants |
Comparison: Comparison of DCR to 30% clinically relevant threshold.p-value: 0.2968Binomial proportion test
Comparison: Comparison of DCR to 10% clinically relevant threshold.p-value: <0.0001Binomial proportion test
Comparison: Sensitivity Analyisis-1: Comparison of DCR to 30% clinically relevant threshold.p-value: 0.0534Binomial proportion test
Comparison: Sensitivity Analyisis-1: Comparison of DCR to 10% clinically relevant threshold.p-value: <0.0001Binomial proportion test
Comparison: Sensitivity Analyisis-2: Comparison of DCR to 30% clinically relevant threshold.p-value: 0.032Binomial proportion test
Comparison: Sensitivity Analyisis-2: Comparison of DCR to 10% clinically relevant threshold.p-value: <0.0001Binomial proportion test
Secondary
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.
Time frame: From Day 1 up to end of study, 52 weeks
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: CR | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: PR | 7.7 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: SD | 71.8 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: NCR/NPD | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: PD | 20.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: NE | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Local assessment: Not applicable | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: CR | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: PR | 13.2 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: SD | 65.8 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: NCR/NPD | 2.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: PD | 15.8 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: NE | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Best Overall Response (BOR) Assessed Locally and Centrally | Central assessment: Not applicable | 2.6 percentage of participants |
Secondary
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.
Time frame: Month 9
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide ATG Plus Temozolomide | Coefficient of Agreement Between Central and Local Assessment of Tumor Radiological Response at Month 9 | 0.71 kappa coefficient |
Secondary
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.
Time frame: Up to Month 9
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide ATG Plus Temozolomide | DCR Assessed Centrally at Month 9 | 28.2 percentage of participants |
Secondary
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.
Time frame: Month 12
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 12 | Local assessment | 17.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 12 | Central assessment | 15.4 percentage of participants |
Secondary
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.
Time frame: Up to Month 9
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Local assessment: Typical carcinoid | 12.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Local assessment: Atypical carcinoid | 47.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Local assessment: Carcinoid NET | 27.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Central assessment: Typical carcinoid | 0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Central assessment: Atypical carcinoid | 35.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type | Central assessment: Carcinoid NET | 36.4 percentage of participants |
Secondary
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.
Time frame: Screening period, Months 9 and 12
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: SSTR2: HER-2 score; +ve (2+, 3+) | 0.90 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: SSTR2: H-score; +ve (>= 50) | 0.78 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: SSTR2: IRS score; 2-3 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: SSTR2: IRS score; 4-8 | 0.67 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: SSTR2: IRS score; 9-12 | 12.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: Ki67: <4 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: Ki67: >=25 | 1.67 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9:Local: MGMT: +ve nuclei stained; +ve(>=5%) | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: MGMT: Methylated sites; +ve (>10%) | 3.25 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: MGMT: H-score | 0.99 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: Carcinoid type: Typical | 0.16 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Local: Carcinoid type: Carcinoid NET | 0.41 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: SSTR2: HER-2 score; +ve (2+, 3+) | 1.40 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: SSTR2: H-score; +ve (>= 50) | 2.25 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: SSTR2: IRS score; 2-3 | 3.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: SSTR2: IRS score; 4-8 | 0.67 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: SSTR2: IRS score; 9-12 | 12.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: Ki67: <4 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: Ki67: >=25 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9:Central:MGMT:+ve nuclei stained; +ve(>=5%) | 0.50 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9:Central: MGMT: Methylated sites; +ve(>10%) | 5.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: MGMT: H-score | 1.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: Carcinoid type: Typical | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 9: Central: Carcinoid type: Carcinoid NET | 1.06 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: SSTR2: HER-2 score; +ve (2+, 3+) | 3.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: SSTR2: H-score; +ve (>= 50) | 4.40 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: SSTR2: IRS score; 2-3 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: SSTR2: IRS score; 4-8 | 0.70 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: SSTR2: IRS score; 9-12 | 10.50 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: Ki67: <4 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: Ki67: >=25 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12:Local:MGMT: +ve nuclei stained; +ve(>=5%) | 0.20 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: MGMT: Methylated sites; +ve(>10%) | 2.13 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: MGMT: H-score | 0.99 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: Carcinoid type: Typical | 0.46 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Local: Carcinoid type: Carcinoid NET | 0.32 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: SSTR2: HER-2 score; +ve(2+, 3+) | 2.08 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: SSTR2: H-score; +ve (>= 50) | 3.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: SSTR2: IRS score; 2-3 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: SSTR2: IRS score; 4-8 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: SSTR2: IRS score; 9-12 | 10.50 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: Ki67: <4 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: Ki67: >=25 | NA odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12:Central:MGMT:+ve nuclei stained;+ve(>=5%) | 0.14 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12:Central: MGMT: Methylated sites;+ve(>10%) | 3.00 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: MGMT: H-score | 0.99 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: Carcinoid type: Typical | 0.57 odds ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12 | Month 12: Central: Carcinoid type: Carcinoid NET | 0.40 odds ratio |
Secondary
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.
Time frame: Screening period, Months 9 and 12
Population: No analysis on ORR at 9 and 12 months was performed due to insufficient number of participants with OR events.
Secondary
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.
Time frame: From Screening period (-4 weeks) up to Week 52
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: SSTR2: HER-2 score; +ve (2+, 3+) | 0.71 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: SSTR2: H-score; +ve (>= 50) | 0.66 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: SSTR2: IRS score; 2-3 | 0.31 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: SSTR2: IRS score; 4-8 | 0.90 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: SSTR2: IRS score; 9-12 | 0.12 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: Ki67: <4 | 1.08 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: Ki67: >=25 | 1.68 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: MGMT: +ve nuclei stained; +ve (>=5%) | 2.06 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: MGMT: Methylated sites; +ve (>10%) | 0.41 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: MGMT: H-score | 1.00 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: Carcinoid type: Typical | 1.05 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Local: Carcinoid type: Carcinoid NET | 1.59 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: SSTR2: HER-2 score; +ve (2+, 3+) | 0.50 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: SSTR2: H-score; +ve (>= 50) | 0.36 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: SSTR2: IRS score; 2-3 | 0.78 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: SSTR2: IRS score; 4-8 | 0.88 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: SSTR2: IRS score; 9-12 | 0.10 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: Ki67: <4 | 0.00 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: Ki67: >=25 | 2.75 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: MGMT: +ve nuclei stained; +ve (>=5%) | 2.11 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: MGMT: Methylated sites; +ve (>10%) | 0.73 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: MGMT: H-score | 1.00 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: Carcinoid type: Typical | 0.99 hazard ratio |
| Lanreotide ATG Plus Temozolomide | Influence of Biomarkers Expression on Locally and Centrally Assessed PFS | Central: Carcinoid type: Carcinoid NET | 0.61 hazard ratio |
Secondary
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.
Time frame: From Day 1 up to end of study, 52 weeks
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Median Duration of Response (DOR) Assessed Locally and Centrally | Local assessment | NA weeks |
| Lanreotide ATG Plus Temozolomide | Median Duration of Response (DOR) Assessed Locally and Centrally | Central assessment | NA weeks |
Secondary
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.
Time frame: From Day 1 up to end of study, 52 weeks
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Median Progression Free Survival (PFS) Assessed Locally and Centrally | Local assessment | 37.1 weeks |
| Lanreotide ATG Plus Temozolomide | Median Progression Free Survival (PFS) Assessed Locally and Centrally | Central assessment | 37.1 weeks |
Secondary
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.
Time frame: From Day 1 up to end of study, 52 weeks
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Median Time to Progression (TTP) Assessed Locally and Centrally | Local assessment | 37.1 weeks |
| Lanreotide ATG Plus Temozolomide | Median Time to Progression (TTP) Assessed Locally and Centrally | Central assessment | 37.1 weeks |
Secondary
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.
Time frame: From Day 1 up to end of study, 52 weeks
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Median Time to Response (TTR) Assessed Locally and Centrally | Local assessment | NA weeks |
| Lanreotide ATG Plus Temozolomide | Median Time to Response (TTR) Assessed Locally and Centrally | Central assessment | NA weeks |
Secondary
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.
Time frame: Baseline and Weeks 4, 12, 24, 36 and 52
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Baseline: <1 ULN | 40.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Baseline: 1-2 ULN | 15.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Baseline: >2 ULN | 45.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 4: <1 ULN | 34.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 4: 1-2 ULN | 22.9 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 4: >2 ULN | 42.9 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 12: <1 ULN | 46.4 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 12: 1-2 ULN | 17.9 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 12: >2 ULN | 35.7 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 24: <1 ULN | 30.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 24: 1-2 ULN | 25.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 24: >2 ULN | 45.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 36: <1 ULN | 31.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 36: 1-2 ULN | 12.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 36: >2 ULN | 56.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 52: <1 ULN | 27.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 52: 1-2 ULN | 9.1 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | CgA: Week 52: >2 ULN | 63.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Baseline: <1 ULN | 65.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Baseline: 1-2 ULN | 25.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Baseline: >2 ULN | 10.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 4: <1 ULN | 62.9 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 4: 1-2 ULN | 25.7 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 4: >2 ULN | 11.4 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 12: <1 ULN | 78.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 12: 1-2 ULN | 17.9 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 12: >2 ULN | 3.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 24: <1 ULN | 80.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 24: 1-2 ULN | 10.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 24: >2 ULN | 10.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 36: <1 ULN | 87.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 36: 1-2 ULN | 6.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 36: >2 ULN | 6.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 52: <1 ULN | 63.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 52: 1-2 ULN | 18.2 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Neuron-Specific Enolase (NSE) and CgA Biomarker Levels | NSE: Week 52: >2 ULN | 18.2 percentage of participants |
Secondary
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.
Time frame: Months 9 and 12
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12 | Local assessment: Month 9 | 2.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12 | Local assessment: Month 12 | 2.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12 | Central assessment: Month 9 | 5.1 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12 | Central assessment: Month 12 | 2.6 percentage of participants |
Secondary
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.
Time frame: Baseline (Day 1) and Week 4, 12, 24, 36 and 52
Population: The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Only participants with baseline CgA levels greater than ULN were analysed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 4: Responders | 27.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 4: SD | 59.1 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 4: Non-responders | 13.6 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 12: Responders | 37.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 12: SD | 37.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 12: Non-responders | 25.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 24: Responders | 23.1 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 24: SD | 30.8 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 24: Non-responders | 46.2 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 36: Responders | 36.4 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 36: SD | 27.3 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 36: Non-responders | 36.4 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 52: Responders | 12.5 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 52: SD | 50.0 percentage of participants |
| Lanreotide ATG Plus Temozolomide | Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels | Week 52: Non-responders | 37.5 percentage of participants |