Efficacy and Safety of Lanreotide Autogel/ Depot 120 mg vs. Placebo in Subjects With Lung Neuroendocrine Tumours

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase 3, Prospective, Randomized, Double-blind, Multi-center Study of the Efficacy and Safety of Lanreotide Autogel®/Depot 120 mg Plus BSC vs. Placebo Plus BSC for Tumour Control in Subjects With Well Differentiated, Metastatic and/or Unresectable, Typical or Atypical, Lung Neuroendocrine Tumours

Conditions
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Neuroendocrine Tumors in Lung

Intervention / Treatment
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* Drug: Lanreotide (Autogel formulation)
* Drug: Placebo
* Drug: Best Supportive Care


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lanreotide (Autogel formulation)<br>120mg every 28 days until disease progression, death, or unacceptable toxicity | Drug: Lanreotide (Autogel formulation)<br>* 120mg every 28 days until disease progression, death, or unacceptable toxicity<br>* Other names: Lanreotide Depot (US);Drug: Best Supportive Care<br>* Best Supportive Care is best available therapy at the choice of the investigator<br>* Other names: BSC;|
| Placebo Comparator: Placebo<br>120mg every 28 days until disease progression, death, or unacceptable toxicity during the double-blind phase. The patient may enter open-label phase for treatment with Lanreotide. | Drug: Placebo<br>* Saline solution 0.9% administered via deep subcutaneous injection every 28 days until disease progression.<br>Drug: Best Supportive Care<br>* Best Supportive Care is best available therapy at the choice of the investigator<br>* Other names: BSC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to a maximum of 33 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to a maximum of 15 months | 
| 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. | Up to a maximum of 15 months | 
| 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. | Up to a maximum of 15 months | 
| 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. | Up to a maximum of 15 months | 
| 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. | 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) | 
| 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). | Baseline and Week 8 in the double-blind phase; Baseline and Week 8 in the open-label treatment phase | 
| 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). | 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) | 
| 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). | 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) | 
| 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. | 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) |