Neuroendocrine Tumors in Lung
Conditions
Brief summary
This is a Phase 3, prospective, multi-center, randomized, double-blind, study evaluating the efficacy and safety of LAN plus BSC versus placebo plus BSC for the treatment of well-differentiated, metastatic and/or unresectable, typical or atypical bronchopulmonary NETs. This study contains two phases: the Double-Blind (DB) Phase, and the Open Label (OL) Phase. The DB Phase includes: Screening, Baseline and Treatment period. The OL Phase will consist of two periods: Treatment Period and Follow-Up Period. The primary objective will be to describe the antitumour efficacy of Lanreotide Autogel/Depot 120 mg (LAN) plus Best Supportive Care (BSC) every 28 days, in terms of progression-free survival (PFS), measured by central review using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria, every 12 weeks, in subjects randomized to LAN with unresectable and/or metastatic well differentiated, typical or atypical bronchopulmonary neuroendocrine tumours. Recent updates of National Cancer Institute Cancer Network (NCCN) & European Neuroendocrine Tumor Society (ENETS) guidelines recommend SSA in first line for the treatment of locoregional unresectable or metastatic bronchopulmonary NETs as an option beyond 'observation' leading to slow and difficult recruitment in SPINET study. Consequently, it was decided to prematurely stop the recruitment in the SPINET study and to transition all subjects still treated in the double-blind phase to the open label (OL) treatment and follow-up phases following respective country approvals of Amendment #5. The new aim of this Phase 3, multicenter, prospective, randomized placebo-controlled clinical study is to describe the antitumor efficacy and safety of Lanreotide Autogel/Depot 120 mg (LAN) plus Best Supportive Care (BSC) in subjects with well-differentiated, metastatic and/or unresectable, typical or atypical, bronchopulmonary NETs.
Detailed description
As planned initially, a total of 216 eligible patients with well-differentiated typical or atypical, metastatic and/or unresectable bronchopulmonary NETs, and a positive somatostatin receptor imaging (SRI) (Octreoscan® ≥ grade 2 Krenning scale; Ga-PET scan: uptake greater than liver background), were to be randomized 2:1 to either LAN plus BSC (120mg/28 days) or placebo plus BSC following the stratification of 1) typical versus atypical and 2) prior chemotherapy versus no prior chemotherapy\*. \* cytotoxic chemotherapy or molecular targeted therapy or interferon. At the time of the premature stop of the recruitment (as per Protocol Amendment #5), 77 patients were enrolled. All patients still treated in the DB Phase were entered into the OL Phase (either for Follow up or for OL treatment periods). The transition to the OL periods was done on a country-basis and per patient, at the following planned scheduled visit (i.e. approximately 28 days from the last injection). Patients enrolled into the study not progressing at the time of study stop, and who agree to stay on LAN therapy (i.e. OL Treatment Period) receive the study active treatment until evidence of disease progression (based on local radiological assessment then confirmed centrally), development of unacceptable toxicity, or premature withdrawal for any reason or up a maximum of 18 months after the last patient randomized. After disease progression patients are followed for survival, QoL and all subsequent anticancer treatments in the OL Follow-up period up to the end of the study (i.e up to 18 months after the last patient randomized).
Interventions
DRUGBest Supportive Care
Best Supportive Care is best available therapy at the choice of the investigator
DRUGPlacebo
Saline solution 0.9% administered via deep subcutaneous injection every 28 days until disease progression.
120mg every 28 days until disease progression, death, or unacceptable toxicity
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have metastatic and/or unresectable pathologically confirmed well-differentiated, typical or atypical neuroendocrine tumor of the bronchopulmonary * Histologic evidence of Well differentiated Neuroendocrine tumors (NETs) of the bronchopulmonary (typical and atypical according to the World Health Organisation (WHO criteria), evaluated locally) * Has a mitotic index \<2 mitoses/2 mm2 for typical carcinoid (TC) and \<10 mitoses/2 mm2 and/or foci of necrosis for atypical carcinoid (AC) * At least one measurable lesion of the disease on imaging (CT or MRI; RECIST 1.1) * Positive Somatostatin receptors (SSTR) imaging
Exclusion criteria
* Poorly differentiated or high grade carcinoma, or patients with neuroendocrine tumors not of bronchopulmonary origin * Has been treated with a Somatostatin analog (SSA) at any time prior to randomization, except if that treatment was for less than 15 days (e.g. peri-operatively) of short acting SSA or one dose of long acting SSA and the treatment was received more than 6 weeks prior to randomization * Has been treated with Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization * Has been treated with more than two lines of cytotoxic chemotherapy or molecular targeted therapy or interferon for bronchopulmonary NET
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) Time in Subjects Randomised to Lanreotide in the Double-Blind Phase or Open-Label Treatment Phase, Assessed by Central Review | Up to a maximum of 33 months | PFS for subjects randomised in the lanreotide group, assessed by central review using Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST v1.1) criteria every 12 weeks, defined as the time from randomisation to disease progression or death from any causes during either the double-blind phase, or the open-label treatment phase. The distribution of PFS times were estimated using the Kaplan-Meier product limit method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median PFS Time in the Double-Blind Phase, Assessed by Local Review | Up to a maximum of 15 months | PFS was assessed by local review using RECIST v1.1 criteria every 12 weeks, defined as the time from randomisation to disease progression or death from any causes during the double-blind phase. The distribution of PFS times were estimated using the Kaplan-Meier product limit method. |
| Objective Response Rate (ORR) in the Double-Blind Phase | Up to a maximum of 15 months | ORR was assessed by central review and local review using RECIST v1.1 criteria every 12 weeks, defined as the percentage of subjects who achieved a best overall response of complete response or partial response in the double-blind phase. |
| Time to Treatment Failure (TTF) in the Double-Blind Phase | Up to a maximum of 15 months | TTF was defined as the time from randomisation to disease progression using RECIST v1.1, death, consent withdrawn, an adverse event, protocol deviations, lost to follow-up, the appearance of carcinoid syndrome or other hormone related syndrome necessitating the initiation of SSAs (rescue octreotide and/or long-acting release SSA), or initiation of anticancer treatment in the double-blind phase. The distribution of TTF times were estimated using the Kaplan-Meier product limit method. |
| Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Baseline, Weeks 8, 12, 24, and 48, and post-treatment in the double-blind phase (a maximum of 15 months); Baseline, Weeks 12, 24, and 48, and post-treatment in the the open-label treatment phase (a maximum of 33 months) | Blood samples were collected to determine plasma CgA. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). The x of upper limit of normal (ULN) was calculated as raw value/ULN. |
| Median PFS Time in the Double-Blind Phase, Assessed by Central Review | Up to a maximum of 15 months | PFS was assessed by central review using RECIST v1.1 criteria every 12 weeks, defined as the time from randomisation to disease progression or death from any causes during the double-blind phase. The distribution of PFS times were estimated using the Kaplan-Meier product limit method. |
| Mean Changes From Baseline in Quality of Life (QoL), as Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Global Health Status/QoL Score | Baseline and post-treatment in the double-blind phase (a maximum of 15 months); Baseline and post-treatment in the open-label treatment phase (a maximum of 33 months) | The EORTC QLQ-C30 (V3.0) consisted of 30 questions. The final 2 questions were related to global health status/QoL, with responses requested on a 7-point scale from 1 ('Very poor') to 7 ('Excellent'). The global health status/QoL scale ranges in score from 0 to 100. A high score for the global health status/QoL scale represents a high QoL, thus, an increase in score represents an increase in QoL. 95% Clopper-Pearson confidence intervals were estimated using the exact method for binomial distributions. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). |
| Percentage of Subjects Who Experienced QoL Deterioration | Baseline and post-treatment in the double-blind phase (a maximum of 15 months); Baseline and post-treatment in the open-label treatment phase (a maximum of 33 months) | QoL deterioration was defined by a decrease from baseline in EORTC QLQ-C30 Global Health Status/QoL Score of at least 10 points. The EORTC QLQ-C30 (V3.0) consisted of 30 questions. The final 2 questions were related to global health status/QoL, with responses requested on a 7-point scale from 1 ('Very poor') to 7 ('Excellent'). The global health status/QoL scale ranges in score from 0 to 100. A high score for the global health status/QoL scale represents a high QoL, thus, an increase in score represents an increase in QoL. 95% Clopper-Pearson confidence intervals were estimated using the exact method for binomial distributions. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). |
| Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Baseline, Weeks 8, 12, 24, and 48, and post-treatment in the double-blind phase (a maximum of 15 months); Baseline, Weeks 12, 24, and 48, and post-treatment in the the open-label treatment phase (a maximum of 33 months) | Measured in subjects with an elevated 5-HIAA at baseline (≥2 x ULN). The assessment of urinary 5-HIAA required subjects to collect their urine for the 24 hour period prior to the study visit. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). The x of ULN was calculated as raw value/ULN. |
| Percentage of Subjects With a Decrease of CgA ≥30% From Baseline at Week 8 in the Double-Blind Phase and Open-Label Treatment Phase | Baseline and Week 8 in the double-blind phase; Baseline and Week 8 in the open-label treatment phase | Measured in subjects with an elevated CgA at baseline (≥2 x ULN). Blood samples were collected to determine plasma CgA. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). |
Countries
Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 37 investigation sites in 10 countries in North America and Europe between 06 March 2017 and 28 February 2020 in adult subjects with well differentiated, metastatic and/or unresectable, typical or atypical bronchopulmonary (BP) neuroendocrine tumours (NETs) who did not require somatostatin analogue (SSA) treatment for symptom control.
Pre-assignment details
This study consisted of two phases: the double-blind phase, and the open-label phase. 77 subjects were randomised to receive study treatment until disease progression, unacceptable toxicity, withdrawal for any reason, or up to 18 months after the last subject was randomised. Subjects were randomised 2:1 to either lanreotide autogel/depot 120 milligrams (mg) plus best supportive care (BSC) every 28 days (Q4 weeks) or placebo plus BSC Q4 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Lanreotide Subjects received deep SC injections of lanreotide autogel/depot 120 mg Q4 weeks plus BSC. Following protocol amendment #5 (28 Jan 2019), all ongoing subjects in the double-blind phase, who had not yet progressed (assessed locally and confirmed centrally) were offered to enter the open-label treatment phase and receive deep SC injections of lanreotide autogel/depot 120 mg Q4 weeks plus BSC. If a subject progressed during the double-blind phase or open-label treatment phase they entered the open-label follow-up phase. The follow-up phase ended at the same time as the open-label treatment phase (18 months after the last subject randomised). | 51 |
| Placebo Subjects received deep SC injections of placebo (saline solution 0.9%) Q4 weeks plus BSC in the double-blind phase. Following protocol amendment #5 (28 Jan 2019), all ongoing subjects in the double-blind phase, who had not yet progressed (assessed locally and confirmed centrally) were offered to enter the open-label treatment phase and receive deep SC injections of lanreotide autogel/depot 120 mg Q4 weeks plus BSC. If a subject progressed during the open-label treatment phase they entered the open-label follow-up phase. The follow-up phase ended at the same time as the open-label treatment phase (18 months after the last subject randomised). | 26 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Phase | Adverse Event | 0 | 1 |
| Double-blind Phase | Disease Progression | 5 | 2 |
| Double-blind Phase | Lost to Follow-up | 1 | 0 |
| Double-blind Phase | Withdrawal by Subject | 4 | 2 |
| Open-label Follow-up Phase | Lost to Follow-up | 1 | 0 |
| Open-label Follow-up Phase | Other | 8 | 1 |
| Open-label Follow-up Phase | Study Termination by the Sponsor | 6 | 4 |
| Open-label Follow-up Phase | Withdrawal by Subject | 3 | 3 |
| Open-label Treatment Phase | Disease Progression | 1 | 2 |
| Open-label Treatment Phase | Other | 1 | 0 |
| Open-label Treatment Phase | Study Termination by the Sponsor | 18 | 9 |
| Open-label Treatment Phase | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Lanreotide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.4 years STANDARD_DEVIATION 11.94 | 65.8 years STANDARD_DEVIATION 13.89 | 66.2 years STANDARD_DEVIATION 12.54 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 42 Participants | 22 Participants | 64 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 9 Participants | 4 Participants | 13 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Missing | 12 Participants | 7 Participants | 19 Participants |
| Race/Ethnicity, Customized Race More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 35 Participants | 19 Participants | 54 Participants |
| Sex: Female, Male Female | 23 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Male | 28 Participants | 14 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 51 | 0 / 26 | 0 / 40 | 7 / 26 |
| other Total, other adverse events | 48 / 51 | 25 / 26 | 26 / 40 | 0 / 26 |
| serious Total, serious adverse events | 10 / 51 | 7 / 26 | 1 / 40 | 0 / 26 |
Outcome results
Primary
Median Progression-Free Survival (PFS) Time in Subjects Randomised to Lanreotide in the Double-Blind Phase or Open-Label Treatment Phase, Assessed by Central Review
PFS for subjects randomised in the lanreotide group, assessed by central review using Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST v1.1) criteria every 12 weeks, defined as the time from randomisation to disease progression or death from any causes during either the double-blind phase, or the open-label treatment phase. The distribution of PFS times were estimated using the Kaplan-Meier product limit method.
Time frame: Up to a maximum of 33 months
Population: The ITT population included all randomised subjects. Subjects were analysed as randomised, regardless of the treatment received. One subject randomised to lanreotide should have been censored in the PFS analysis treatment for discontinuation for toxicity or other reasons, however the baseline central radiological assessment was performed prior to the randomisation date, therefore the subject was excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study: Lanreotide | Median Progression-Free Survival (PFS) Time in Subjects Randomised to Lanreotide in the Double-Blind Phase or Open-Label Treatment Phase, Assessed by Central Review | 16.6 months |
Secondary
Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase
Blood samples were collected to determine plasma CgA. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). The x of upper limit of normal (ULN) was calculated as raw value/ULN.
Time frame: Baseline, Weeks 8, 12, 24, and 48, and post-treatment in the double-blind phase (a maximum of 15 months); Baseline, Weeks 12, 24, and 48, and post-treatment in the the open-label treatment phase (a maximum of 33 months)
Population: Double-blind phase: The ITT population included all randomised subjects with non-missing measurements. Subjects were analysed as randomised, regardless of the treatment received. Open-label phase: The open-label ITT population included all ITT subjects with non-missing measurements entering the open-label phase who received at least one injection of lanreotide autogel/depot in the open-label phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Overall Study: Lanreotide | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 24 | -3.42 x of ULN | Standard Deviation 14.122 |
| Overall Study: Lanreotide | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 8 | -213.63 x of ULN | Standard Deviation 1293.111 |
| Overall Study: Lanreotide | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 12 | -214.49 x of ULN | Standard Deviation 1344.401 |
| Overall Study: Lanreotide | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 48 | -4.07 x of ULN | Standard Deviation 8.066 |
| Overall Study: Lanreotide | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Post-treatment | 12.22 x of ULN | Standard Deviation 64.053 |
| Double-Blind Phase: Placebo | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 48 | 1.24 x of ULN | Standard Deviation 2.969 |
| Double-Blind Phase: Placebo | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Post-treatment | 160.11 x of ULN | Standard Deviation 596.759 |
| Double-Blind Phase: Placebo | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 8 | 0.09 x of ULN | Standard Deviation 2.578 |
| Double-Blind Phase: Placebo | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 24 | 60.41 x of ULN | Standard Deviation 193.327 |
| Double-Blind Phase: Placebo | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 12 | 5.73 x of ULN | Standard Deviation 15.519 |
| Open-Label Treatment Phase: All Subjects | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Post-treatment | -31.59 x of ULN | Standard Deviation 167.515 |
| Open-Label Treatment Phase: All Subjects | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 12 | -28.27 x of ULN | Standard Deviation 149.11 |
| Open-Label Treatment Phase: All Subjects | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 24 | -1.42 x of ULN | Standard Deviation 8.338 |
| Open-Label Treatment Phase: All Subjects | Mean Change From Baseline in the Biomarker Chromogranin A (CgA) in the Double-Blind Phase and Open-Label Treatment Phase | Week 48 | -1.66 x of ULN | Standard Deviation 0.925 |
Secondary
Mean Changes From Baseline in Quality of Life (QoL), as Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Global Health Status/QoL Score
The EORTC QLQ-C30 (V3.0) consisted of 30 questions. The final 2 questions were related to global health status/QoL, with responses requested on a 7-point scale from 1 ('Very poor') to 7 ('Excellent'). The global health status/QoL scale ranges in score from 0 to 100. A high score for the global health status/QoL scale represents a high QoL, thus, an increase in score represents an increase in QoL. 95% Clopper-Pearson confidence intervals were estimated using the exact method for binomial distributions. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide).
Time frame: Baseline and post-treatment in the double-blind phase (a maximum of 15 months); Baseline and post-treatment in the open-label treatment phase (a maximum of 33 months)
Population: Double-blind phase: The ITT population included all randomised subjects with non-missing measurements. Subjects were analysed as randomised, regardless of the treatment received. Open-label phase: The open-label ITT population included all ITT subjects with non-missing measurements entering the open-label phase who received at least one injection of lanreotide autogel/depot in the open-label phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Study: Lanreotide | Mean Changes From Baseline in Quality of Life (QoL), as Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Global Health Status/QoL Score | -2.7 score on a scale | Standard Deviation 18.27 |
| Double-Blind Phase: Placebo | Mean Changes From Baseline in Quality of Life (QoL), as Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Global Health Status/QoL Score | -19.4 score on a scale | Standard Deviation 17.33 |
| Open-Label Treatment Phase: All Subjects | Mean Changes From Baseline in Quality of Life (QoL), as Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Global Health Status/QoL Score | 0.0 score on a scale | Standard Deviation 19.67 |
Secondary
Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase
Measured in subjects with an elevated 5-HIAA at baseline (≥2 x ULN). The assessment of urinary 5-HIAA required subjects to collect their urine for the 24 hour period prior to the study visit. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide). The x of ULN was calculated as raw value/ULN.
Time frame: Baseline, Weeks 8, 12, 24, and 48, and post-treatment in the double-blind phase (a maximum of 15 months); Baseline, Weeks 12, 24, and 48, and post-treatment in the the open-label treatment phase (a maximum of 33 months)
Population: Double-blind phase: The ITT population included all randomised subjects with non-missing measurements and elevated 5-HIAA at baseline. Subjects were analysed as randomised, regardless of the treatment received. Open-label phase: The open-label ITT population included all ITT subjects with non-missing measurements and elevated 5-HIAA at baseline entering the open-label phase who received at least one injection of lanreotide autogel/depot in the open-label phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Overall Study: Lanreotide | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 8 | -2.90 x of ULN | Standard Deviation 5.368 |
| Overall Study: Lanreotide | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 12 | 0.21 x of ULN | Standard Deviation 1.904 |
| Overall Study: Lanreotide | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 24 | 0.15 x of ULN | Standard Deviation 3.041 |
| Overall Study: Lanreotide | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 48 | -3.00 x of ULN | Standard Deviation 8.9 |
| Overall Study: Lanreotide | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Post-treatment | -1.27 x of ULN | Standard Deviation 7.007 |
| Double-Blind Phase: Placebo | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 24 | -1.40 x of ULN | Standard Deviation 2.734 |
| Double-Blind Phase: Placebo | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 48 | 1.13 x of ULN | — |
| Double-Blind Phase: Placebo | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 8 | 2.78 x of ULN | Standard Deviation 4.215 |
| Double-Blind Phase: Placebo | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 12 | 5.38 x of ULN | Standard Deviation 4.342 |
| Double-Blind Phase: Placebo | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Post-treatment | -5.13 x of ULN | Standard Deviation 11.597 |
| Open-Label Treatment Phase: All Subjects | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 24 | -4.84 x of ULN | Standard Deviation 10.019 |
| Open-Label Treatment Phase: All Subjects | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Post-treatment | 0.60 x of ULN | Standard Deviation 3.583 |
| Open-Label Treatment Phase: All Subjects | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 12 | -0.47 x of ULN | Standard Deviation 1.886 |
| Open-Label Treatment Phase: All Subjects | Mean Changes From Baseline in Urinary 5-hydroxyindoleacetic Acid (5-HIAA) Levels in the Double-Blind Phase and Open-Label Treatment Phase | Week 48 | -2.47 x of ULN | — |
Secondary
Median PFS Time in the Double-Blind Phase, Assessed by Central Review
PFS was assessed by central review using RECIST v1.1 criteria every 12 weeks, defined as the time from randomisation to disease progression or death from any causes during the double-blind phase. The distribution of PFS times were estimated using the Kaplan-Meier product limit method.
Time frame: Up to a maximum of 15 months
Population: The ITT population included all randomised subjects. Subjects were analysed as randomised, regardless of the treatment received. One subject in the double-blind phase: lanreotide arm should have been censored in the PFS analysis for treatment discontinuation for toxicity or other reasons, however the baseline central radiological assessment was performed prior to the randomisation date, therefore the subject was excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study: Lanreotide | Median PFS Time in the Double-Blind Phase, Assessed by Central Review | 16.6 months |
| Double-Blind Phase: Placebo | Median PFS Time in the Double-Blind Phase, Assessed by Central Review | 13.6 months |
Comparison: The hazard ratio and the 95% confidence interval (CI) were estimated using a Cox proportional hazards model, stratified for interactive web response system (IWRS) tumour subtype (typical versus \[vs\] atypical) using the exact method for ties. P-value of stratified log rank test comparing lanreotide to placebo with strata based on the IWRS tumour subtype (typical vs atypical) stratification factor.p-value: 0.86695% CI: [0.48, 1.95]Log Rank
Secondary
Median PFS Time in the Double-Blind Phase, Assessed by Local Review
PFS was assessed by local review using RECIST v1.1 criteria every 12 weeks, defined as the time from randomisation to disease progression or death from any causes during the double-blind phase. The distribution of PFS times were estimated using the Kaplan-Meier product limit method.
Time frame: Up to a maximum of 15 months
Population: The ITT population included all randomised subjects. Subjects were analysed as randomised, regardless of the treatment received. Two subjects should have been censored in the PFS analysis, however the baseline central radiological assessment was performed prior to the randomisation date, therefore the subjects were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study: Lanreotide | Median PFS Time in the Double-Blind Phase, Assessed by Local Review | 14.1 months |
| Double-Blind Phase: Placebo | Median PFS Time in the Double-Blind Phase, Assessed by Local Review | 13.6 months |
Comparison: The hazard ratio and the 95% CI were estimated using a Cox proportional hazards model, stratified for IWRS tumour subtype (typical vs atypical) using the exact method for ties. P-value of stratified log rank test comparing lanreotide to placebo with strata based on the IWRS tumour subtype (typical vs atypical) stratification factor.p-value: 0.83795% CI: [0.48, 1.88]Log Rank
Secondary
Objective Response Rate (ORR) in the Double-Blind Phase
ORR was assessed by central review and local review using RECIST v1.1 criteria every 12 weeks, defined as the percentage of subjects who achieved a best overall response of complete response or partial response in the double-blind phase.
Time frame: Up to a maximum of 15 months
Population: The ITT population included all randomised subjects. Subjects were analysed as randomised, regardless of the treatment received. Two subjects were excluded from the analysis as they had no best response recorded in the raw data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Overall Study: Lanreotide | Objective Response Rate (ORR) in the Double-Blind Phase | Central review | 14.00 Percentage of subjects |
| Overall Study: Lanreotide | Objective Response Rate (ORR) in the Double-Blind Phase | Local review | 6.00 Percentage of subjects |
| Double-Blind Phase: Placebo | Objective Response Rate (ORR) in the Double-Blind Phase | Central review | 0.00 Percentage of subjects |
| Double-Blind Phase: Placebo | Objective Response Rate (ORR) in the Double-Blind Phase | Local review | 4.00 Percentage of subjects |
Comparison: The treatment difference compares lanreotide to placebo (central review). The 95% exact unconditional CI was used for ORR difference.95% CI: [-10.97, 37.86]
Comparison: The treatment difference compares lanreotide to placebo (local review). The 95% exact unconditional CI was used for ORR difference.95% CI: [-22.69, 26.53]
Secondary
Percentage of Subjects Who Experienced QoL Deterioration
QoL deterioration was defined by a decrease from baseline in EORTC QLQ-C30 Global Health Status/QoL Score of at least 10 points. The EORTC QLQ-C30 (V3.0) consisted of 30 questions. The final 2 questions were related to global health status/QoL, with responses requested on a 7-point scale from 1 ('Very poor') to 7 ('Excellent'). The global health status/QoL scale ranges in score from 0 to 100. A high score for the global health status/QoL scale represents a high QoL, thus, an increase in score represents an increase in QoL. 95% Clopper-Pearson confidence intervals were estimated using the exact method for binomial distributions. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide).
Time frame: Baseline and post-treatment in the double-blind phase (a maximum of 15 months); Baseline and post-treatment in the open-label treatment phase (a maximum of 33 months)
Population: Double-blind phase: The ITT population included all randomised subjects with non-missing measurements. Subjects were analysed as randomised, regardless of the treatment received. Open-label phase: The open-label ITT population included all ITT subjects with non-missing measurements entering the open-label phase who received at least one injection of lanreotide autogel/depot in the open-label phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Study: Lanreotide | Percentage of Subjects Who Experienced QoL Deterioration | 32.0 percentage of subjects |
| Double-Blind Phase: Placebo | Percentage of Subjects Who Experienced QoL Deterioration | 66.7 percentage of subjects |
| Open-Label Treatment Phase: All Subjects | Percentage of Subjects Who Experienced QoL Deterioration | 23.5 percentage of subjects |
Secondary
Percentage of Subjects With a Decrease of CgA ≥30% From Baseline at Week 8 in the Double-Blind Phase and Open-Label Treatment Phase
Measured in subjects with an elevated CgA at baseline (≥2 x ULN). Blood samples were collected to determine plasma CgA. Baseline was defined as the last non-missing measurement collected prior to the first dose of study treatment (lanreotide).
Time frame: Baseline and Week 8 in the double-blind phase; Baseline and Week 8 in the open-label treatment phase
Population: Double-blind phase: The ITT population included all randomised subjects with non-missing measurements and elevated CgA at Baseline. Subjects were analysed as randomised, regardless of the treatment received. Open-label phase: The open-label ITT population included all ITT subjects with non-missing measurements and elevated CgA at Baseline entering the open-label phase who received at least one injection of lanreotide autogel/depot in the open-label phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Study: Lanreotide | Percentage of Subjects With a Decrease of CgA ≥30% From Baseline at Week 8 in the Double-Blind Phase and Open-Label Treatment Phase | 63.3 percentage of subjects |
| Double-Blind Phase: Placebo | Percentage of Subjects With a Decrease of CgA ≥30% From Baseline at Week 8 in the Double-Blind Phase and Open-Label Treatment Phase | 7.7 percentage of subjects |
| Open-Label Treatment Phase: All Subjects | Percentage of Subjects With a Decrease of CgA ≥30% From Baseline at Week 8 in the Double-Blind Phase and Open-Label Treatment Phase | 73.7 percentage of subjects |
Secondary
Time to Treatment Failure (TTF) in the Double-Blind Phase
TTF was defined as the time from randomisation to disease progression using RECIST v1.1, death, consent withdrawn, an adverse event, protocol deviations, lost to follow-up, the appearance of carcinoid syndrome or other hormone related syndrome necessitating the initiation of SSAs (rescue octreotide and/or long-acting release SSA), or initiation of anticancer treatment in the double-blind phase. The distribution of TTF times were estimated using the Kaplan-Meier product limit method.
Time frame: Up to a maximum of 15 months
Population: The ITT population included all randomised subjects. Subjects were analysed as randomised, regardless of the treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study: Lanreotide | Time to Treatment Failure (TTF) in the Double-Blind Phase | 13.3 months |
| Double-Blind Phase: Placebo | Time to Treatment Failure (TTF) in the Double-Blind Phase | 9.8 months |
Comparison: The hazard ratio and the 95% CI were estimated using a Cox proportional hazards model, stratified for IWRS tumour subtype (typical vs atypical) using the exact method for ties. P-value of stratified log rank test comparing lanreotide to placebo with strata based on the IWRS tumour subtype (typical vs atypical) stratification factor.p-value: 0.58295% CI: [0.5, 1.5]Log Rank