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Efficacy and Safety Study in Pancreatic or Midgut Neuroendocrine Tumours Having Progressed Radiologically While Previously Treated With Lanreotide Autogel® 120 mg (CLARINET FORTE)

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ClinicalTrials.gov Identifier: NCT02651987
Recruitment Status : Completed
First Posted : January 11, 2016
Results First Posted : December 30, 2020
Last Update Posted : December 30, 2020
Sponsor:
Information provided by (Responsible Party):
Ipsen

Tracking Information
First Submitted Date  ICMJE December 11, 2015
First Posted Date  ICMJE January 11, 2016
Results First Submitted Date  ICMJE October 16, 2020
Results First Posted Date  ICMJE December 30, 2020
Last Update Posted Date December 30, 2020
Actual Study Start Date  ICMJE November 19, 2015
Actual Primary Completion Date October 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 4, 2020)
Median Progression Free Survival (PFS) [ Time Frame: From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort ]
PFS was defined as the time from first injection of lanreotide Autogel® 120 mg every 14 days to progression or death. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured by independent central review using the same imaging technique (computed tomography [CT] scan or magnetic resonance imaging [MRI]) for each subject throughout the study. The median PFS time was estimated using the Kaplan Meier method for each cohort.
Original Primary Outcome Measures  ICMJE
 (submitted: January 7, 2016)
Median Progression Free Survival (PFS) Time [ Time Frame: Every 14 days up to approximately 102 weeks ]
PFS is defined as time from first injection of lanreotide Autogel® 120 mg every 14 days to progression or death based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.0
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2020)
  • Median Time to Progression [ Time Frame: From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort ]
    Time to Progression was defined as time from first injection of lanreotide Autogel® 120 mg every 14 days to progression. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured by independent central review using the same imaging technique (CT scan or MRI) for each subject throughout the study. Median time to progression was estimated using the Kaplan Meier method for each cohort.
  • Percentage of Subjects Alive and Progression Free [ Time Frame: Weeks 12, 24, 36, 48, 60 (for both cohorts) and Weeks 72, 84 and 96 (for midgut NET cohort) ]
    The percentage of subjects alive and progression-free was assessed throughout the study up to Week 60 for the panNET cohort and Week 96 for the midgut cohort. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks measured by independent central review using the same imaging technique (CT scan or MRI) for each subject throughout the study. The percentage of subjects alive and progression free was estimated using the Kaplan Meier method for each cohort.
  • Overall Survival [ Time Frame: From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort ]
    Overall survival was defined as the time in months from the first injection of lanreotide Autogel® 120 mg every 14 days to death due to any cause. Median overall survival was estimated using the Kaplan Meier method for each cohort.
  • Objective Response Rate (ORR) [ Time Frame: Weeks 12, 24, 36, 48, 60 (for both cohorts) and Weeks 72, 84, and 96 (for midgut cohort) ]
    The ORR was defined as the percentage of subjects who achieve either complete response (CR) or partial response (PR) according to RECIST v1.0 criteria. ORR was evaluated every 12 weeks and results are presented for each cohort.
  • Disease Control Rate (DCR) [ Time Frame: Weeks 24 and 48 ]
    The DCR was defined as the percentage of subjects who achieved CR plus PR plus Stable Disease (SD), evaluated according to RECIST v1.0 criteria. The DCR at Weeks 24 and 48 is presented for each cohort.
  • Best Overall Response Rate [ Time Frame: From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort ]
    Best overall response was defined as the best response recorded from the initiation of treatment until disease progression, according to RECIST v1.0 evaluation. The percentage of subjects in each response category and those who were non-evaluable (i.e. with no tumour assessment after the start of study treatment) throughout the study are presented for each cohort.
  • Median Duration of Stable Disease [ Time Frame: From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort ]
    Median duration of SD was the time from first injection of lanreotide Autogel® 120 mg every 14 days until the first occurrence of PD by central assessment. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured using the same imaging technique (CT scan or MRI) for each subject throughout the study. Median duration of stable disease was estimated using the Kaplan Meier method for each cohort.
  • Factors Associated With PFS [ Time Frame: Screening/Baseline (Day 1) ]
    A univariate cox proportional hazards model was used to assess whether the following factors were associated with PFS:
    • Hepatic tumour load: >25% versus reference ≤25%
    • Tumour Grade: Grade 2 versus reference Grade 1,
    • Previous surgery of the primary tumour: No versus reference Yes,
    • Proliferation index Ki67: ≥10% versus reference <10%
    • Duration of treatment with lanreotide Autogel® 120 mg every 28 days by category: ≥median value versus reference <median value,
    • Age by category: ≥65 years versus reference <65 years,
    • Time from diagnosis to study entry by category: ≥3 years versus reference <3 years,
    • Time interval between the two CT scans (pre-screening/screening): ≥12 months versus reference <12 months and
    • Symptoms (diarrhoea or flushing at baseline): No versus reference Yes.
    Each factor was assessed for its importance in the Cox model for PFS in a univariate fashion.
  • Mean Change From Baseline in Number of Stools and Flushing Episodes [ Time Frame: Baseline (Day 1), Weeks 8,12, 48 and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET cohort) ]
    Symptom control was measured by the total number of stools (diarrhoea) and flushing episodes during the 7 days prior to the visit, reported orally by the subject to the investigator. The mean change from baseline in number of stools and flushing episodes reported at each visit is presented for each cohort.
  • Mean Change From Baseline in QoL Measured Using EORTC, QLQ-C30 v3.0 (Global Health Status Sub-score) [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) ]
    Subjects were instructed to complete the 30 questions in the EORTC-QLQ-C30 v3.0 questionnaire at baseline and every 12 weeks throughout the study. The global health status sub-score was assessed using the last 2 questions which represented subject's assessment of overall health & QoL. Each question was coded on a 7-point scale (1=very poor to 7=excellent). The sub-score was transformed to range from 0-100, with a high score for global health status representing a high QoL. The mean change from baseline in the transformed global health status are presented for the end of study/early withdrawal visit, with a positive change indicating an improvement in QoL.
  • Mean Change From Baseline in EQ-5D-5L v1.0 Questionnaire (Descriptive System) [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) ]
    Subjects were instructed to complete the EQ-5D-5L descriptive system at baseline and every 12 weeks throughout the study. The EQ-5D-5L descriptive system comprised the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, was converted into a single index value with scores ranging from 0 (no problems) to 1 (extreme problems). The mean change from baseline at the end of study/early withdrawal visit is presented with a positive change from baseline in the index values indicating a worsening of symptoms.
  • Mean Change From Baseline in EQ-5D-5L v1.0 Questionnaire (VAS) [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) ]
    Subjects were instructed to complete the EQ-5D-5L VAS at baseline and every 12 weeks throughout the study. The EQ-5D-5L VAS recorded the subject's self-rated health on a vertical VAS which is numbered from 0 (worst health state) to 100 (best health state). The mean change from baseline at the end of study/early withdrawal visit is presented with a positive change in the VAS indicating an improvement in symptoms.
  • Mean Change From Baseline in QoL Questionnaire Gastrointestinal Neuroendocrine Tumour 21 (QLQ-GI.NET21; 2006) [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) ]
    Subjects were asked to complete the EORTC QLQ-GI.NET21 module which comprised 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Answers were converted into grading scale, with values between 0 and 100. Each individual sub-score was transformed to range from 0 to 100. The mean change from baseline at the end of study/early withdrawal visit is presented with a higher score representing more or worse problems.
  • Mean Change From Baseline in Nonspecific Tumour Biomarkers [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET cohort) ]
    Nonspecific tumour peptide biomarkers (chromogranin A [CgA], neuron specific enolase [NSE] and plasma/urinary 5-hydroxyindoleacetic acid [5-HIAA]) were evaluated in both pancreas and midgut subjects at baseline and Week 12 and every 12 weeks thereafter. At all scheduled visits, except baseline, plasma/urinary 5-HIAA was only performed in subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above upper limit of normal [ULN]) at baseline. Mean change from baseline values were normalised by the ULN (xULN) and are presented for each cohort.
  • Mean Change From Baseline in PanNet Specific Tumour Biomarkers: Pancreatic Polypeptide, Gastrin [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks) ]
    PanNET specific tumour peptide biomarkers were evaluated in pancreas subjects at baseline. Only the tumour biomarkers that were above normal range at baseline were evaluated every 12 weeks thereafter and at the end of study visit. The mean change from baseline values in picomole/liter (pmol/L) are presented for the end of study visit.
  • Mean Change From Baseline in PanNet Specific Tumour Biomarkers: Glucagon [ Time Frame: Baseline (Day 1) and end of study (approximately 64 weeks) ]
    PanNET specific tumour peptide biomarkers were evaluated in pancreas subjects at baseline. Only the tumour biomarkers that were above normal range at baseline were evaluated every 12 weeks thereafter and at the end of study visit. The mean change from baseline values in nanograms (ng)/L are presented for the end of study visit.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2016)
  • Median Time to Progression [ Time Frame: Every 14 days up to approximately 102 weeks ]
    Time to Progression is defined as time from first injection of lanreotide Autogel® 120 mg every 14 days to progression
  • Proportion of subjects alive and without progression [ Time Frame: Every 12 weeks up to approximately 102 weeks ]
    Proportion of subjects alive and without progression every 12 weeks
  • Overall Survival [ Time Frame: Week 48 and at end of the study (up to approximately 102 weeks) ]
    Overall survival defined as the time from first study treatment to death due to any cause
  • Overall Response Rate (ORR) [ Time Frame: Every 12 weeks up to approximately 102 weeks ]
    ORR every 12 weeks as per RECIST v1.0. is defined as the proportion of subjects who achieve either Complete response (CR) or Partial response (PR).
  • Disease Control Rate (DCR) [ Time Frame: Weeks 24, 48 and at end of the study (up to approximately 102 weeks) ]
    The DCR is defined as the rate of CR plus PR plus Stable Disease (SD). DCR evaluated according to RECIST v1.0
  • Best overall response [ Time Frame: At end of the study (up to approximately 102 weeks) ]
    Best overall response according to RECIST v1.0 defined as the best response recorded from the initiation of treatment until disease progression
  • Median duration of Stable Disease (SD) [ Time Frame: Every 14 days up to approximately 102 weeks ]
    Median duration of SD according to RECIST v1.0 defined as the time from first injection of lanreotide Autogel® 120 mg every 14 days until the first occurrence of progressive disease by central assessment
  • Total number of stools and flushing episodes [ Time Frame: During 1 week prior to visit until end of the study (up to approximately 102 weeks) ]
    Symptom control (diarrhoea, flushing) as measured by the total number of stools and flushing episodes during the 7 days prior to the visit reported orally by the subject to the investigator.
  • Change in Quality of life (QLQ-C30) from baseline [ Time Frame: Every 12 weeks up to approximately 102 weeks ]
    Change in Quality of life from baseline every 12 weeks measured using European Organisation into the Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire Core 30 (QLQ-C30) v3.0.
  • Change in Quality of life (QLQ-GI.NET21) from baseline [ Time Frame: Every 12 weeks up to approximately 102 weeks ]
    Change in Quality of life from baseline every 12 weeks measured using Quality of Life Questionnaire Gastrointestinal Neuroendocrine Tumour 21 (QLQ-GI.NET21; 2006)
  • Change in Quality of life (EQ-5D-5L) from baseline [ Time Frame: Every 12 weeks up to approximately 102 weeks ]
    Change in Quality of life from baseline every 12 weeks measured using EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) v1.0 questionnaire.
  • Change in tumour biomarker concentrations from baseline [ Time Frame: Baseline, Weeks 2 and 12 and every 12 weeks thereafter, up to approximately 102 weeks ]
    Concentrations of non-specific (Chromogranin A, neuron specific enolase and 5-hydroxyindoleacetic acid) and specific tumour peptide biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, and somatostatin)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Study in Pancreatic or Midgut Neuroendocrine Tumours Having Progressed Radiologically While Previously Treated With Lanreotide Autogel® 120 mg
Official Title  ICMJE Efficacy and Safety of Lanreotide Autogel® 120 mg Administered Every 14 Days in Well Differentiated, Metastatic or Locally Advanced, Unresectable Pancreatic or Midgut Neuroendocrine Tumours Having Progressed Radiologically While Previously Treated With Lanreotide Autogel® 120 mg Administered Every 28 Days
Brief Summary This study aims to explore the efficacy and safety of lanreotide Autogel® 120 mg administered every 14 days in subjects with grade 1 or 2, metastatic or locally advanced, unresectable pancreatic or intestinal neuroendocrine tumours (NETs) once they have progressed on the standard dose of lanreotide Autogel® 120 mg every 28 days.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pancreatic Tumours
  • Midgut Neuroendocrine Tumours
Intervention  ICMJE Drug: Lanreotide autogel 120 mg
Study Arms  ICMJE Experimental: Lanreotide Autogel®
One subcutaneous (SC) injection of lanreotide Autogel® 120mg every 14 days until disease progression or death or unacceptable toxicity or tolerability.
Intervention: Drug: Lanreotide autogel 120 mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 29, 2019)
99
Original Estimated Enrollment  ICMJE
 (submitted: January 7, 2016)
100
Actual Study Completion Date  ICMJE October 24, 2019
Actual Primary Completion Date October 16, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histopathologically confirmed, grade 1 or 2, metastatic or locally advanced, unresectable pNET (pNET cohort) or midgut NET (midgut cohort) with or without hormone related syndromes, with a proliferation index (Ki67) ≤20%.
  • Positive somatostatin receptors type 2
  • Progression as assessed by an independent central reviewer according to RECIST v1.0 while receiving first line treatment with lanreotide Autogel® at a standard dose of 120 mg every 28 days for at least 24 weeks

Exclusion Criteria:

  • Grade 3 or rapidly progressive (within 12 weeks) NET
  • Any NET other than pancreatic and midgut
  • Previous treatment with any antitumour agent for NET other than lanreotide Autogel® 120 mg every 28 days. Exception made of prior treatment with Octreotide at standard dose stopped for other reason than disease progression.
  • Symptomatic gallbladder lithiasis at screening echography or history of cholelithiasis with no cholecystectomy since then.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Denmark,   France,   Germany,   Ireland,   Italy,   Netherlands,   Poland,   Spain,   United Kingdom
Removed Location Countries United States
 
Administrative Information
NCT Number  ICMJE NCT02651987
Other Study ID Numbers  ICMJE 8-79-52030-326
2014-005607-24 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ipsen
Study Sponsor  ICMJE Ipsen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Ipsen Medical Director Ipsen
PRS Account Ipsen
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP