Midgut Neuroendocrine Tumours Clinical Trial
— CLARINET FORTEOfficial title:
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
| Verified date | September 2022 |
| Source | Ipsen |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 99 |
| Est. completion date | October 24, 2019 |
| Est. primary completion date | October 16, 2019 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| Belgium | Cliniques Unversitaires Saint Luc | Bruxelles | |
| Belgium | Erasme Hospital | Bruxelles | |
| Belgium | Antwerp University Hospital | Edegem | |
| Belgium | UZ Leuven | Leuven | |
| Denmark | Aarhus University Hospital | Aarhus | |
| Denmark | Rigshospitalet | København | |
| France | Hôpital Beaujon | Clichy | |
| France | Hôpital Edouard Herriot | Lyon | |
| France | Institut Paoli Calmette | Marseille | |
| France | Institut Gustave Roussy | Villejuif | |
| Germany | Charité - CVK | Berlin | |
| Germany | Universitätsklinikum Erlangen | Erlangen | |
| Germany | Nationales Centrum für Tumorerkrankungen (NCT) | Heidelberg | |
| Ireland | St Vincent's University Hospital | Dublin | |
| Italy | Azienda Ospedaliera - Universitaria Careggi | Firenze | |
| Italy | Fondacione IRCCS Istituto Nazionale Dei Tumori | Milano | |
| Italy | Università degli Studi "Federico II" di Napoli | Napoli | |
| Italy | Azienda Ospedaliera sant'Andrea | Roma | |
| Italy | IRCCS Azienda Ospedaliera Universitaria | San Martino | Genova |
| Netherlands | Academic Medical Center | Amsterdam | |
| Netherlands | AVL/NKI Medisch Oncologie | Amsterdam | |
| Netherlands | Erasmus MC | Rotterdam | |
| Poland | Samodzielny Publiczny Szpital Kliniczny nr 5 | Katowice | |
| Poland | Katedra i Klinika Endokrynologii | Poznan | |
| Poland | Centrum Diagnostyczno-Lecznicze "GAMMED" | Warsaw | |
| Spain | Hospital Universitario Vall D'hebron | Barcelona | |
| Spain | Hospital Universitario 12 De Octubre | Madrid | |
| Spain | Hospital Universitario Ramón Y Cajal | Madrid | |
| Spain | Hospital Universitario Central de Asturias | Oviedo | |
| United Kingdom | Queen Elizabeth Medical Center | Birmingham | |
| United Kingdom | Royal Free Hospital | London | |
| United Kingdom | The Christie Hospital NHS Foundation Trust | Manchester |
| Lead Sponsor | Collaborator |
|---|---|
| Ipsen |
Belgium, Denmark, France, Germany, Ireland, Italy, Netherlands, Poland, Spain, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Median Progression Free Survival (PFS) | 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. | From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort | |
| Secondary | Median Time to Progression | 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. | From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort | |
| Secondary | Percentage of Subjects Alive and Progression Free | 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. | Weeks 12, 24, 36, 48, 60 (for both cohorts) and Weeks 72, 84 and 96 (for midgut NET cohort) | |
| Secondary | Overall Survival | 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. | From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort | |
| Secondary | Objective Response Rate (ORR) | 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. | Weeks 12, 24, 36, 48, 60 (for both cohorts) and Weeks 72, 84, and 96 (for midgut cohort) | |
| Secondary | Disease Control Rate (DCR) | 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. | Weeks 24 and 48 | |
| Secondary | Best Overall Response Rate | 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. | From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort | |
| Secondary | Median Duration of Stable Disease | 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. | From Day 1 up to Week 60 for the panNET cohort and Week 103 for the midgut NET cohort | |
| Secondary | Factors Associated With PFS | 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 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. |
Screening/Baseline (Day 1) | |
| Secondary | Mean Change From Baseline in Number of Stools and Flushing Episodes | 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. | Baseline (Day 1), Weeks 8,12, 48 and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET cohort) | |
| Secondary | Mean Change From Baseline in QoL Measured Using EORTC, QLQ-C30 v3.0 (Global Health Status Sub-score) | 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. |
Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) | |
| Secondary | Mean Change From Baseline in EQ-5D-5L v1.0 Questionnaire (Descriptive System) | 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. |
Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) | |
| Secondary | Mean Change From Baseline in EQ-5D-5L v1.0 Questionnaire (VAS) | 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. | Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) | |
| Secondary | Mean Change From Baseline in QoL Questionnaire Gastrointestinal Neuroendocrine Tumour 21 (QLQ-GI.NET21; 2006) | 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. | Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET (and overall) cohort) | |
| Secondary | Mean Change From Baseline in Nonspecific Tumour Biomarkers | 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. | Baseline (Day 1) and end of study (approximately 64 weeks for panNET cohort and 108 weeks for midgut NET cohort) | |
| Secondary | Mean Change From Baseline in PanNet Specific Tumour Biomarkers: Pancreatic Polypeptide, Gastrin | 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. | Baseline (Day 1) and end of study (approximately 64 weeks) | |
| Secondary | Mean Change From Baseline in PanNet Specific Tumour Biomarkers: Glucagon | 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. | Baseline (Day 1) and end of study (approximately 64 weeks) |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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