A-97-52030-270

Ipsen Ltd

190 Bath Road, Slough, United Kingdom, SL1 3XE

Medical Director, Ipsen, clinical.trials@ipsen.com

Medical Director, Ipsen, clinical.trials@ipsen.com

No

No

No

Final

22 Jun 2017

Yes

22 Jun 2017

Yes

22 Jun 2017

No

The objective of the study is to assess the clinical value of enumeration of CTCs to predict the clinical symptomatic response in subjects receiving deep subcutaneous injections of lanreotide Autogel to treat the symptoms of functioning midgut NET over a period of one year.

The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Council for Harmonisation Consolidated Guideline on Good Clinical Practice and in compliance with Independent Ethics Committees and informed consent regulations.

16 May 2014

No

No

United Kingdom: 50

50

50

0

0

0

0

0

0

29

21

0

Overall Study (overall period)

Not applicable

Lanreotide Autogel

Somatuline®

Solution for injection in pre-filled syringe

Subcutaneous use

Lanreotide Autogel was injected by a healthcare professional via the deep subcutaneous route into the superior external quadrant of the buttock. All subjects received 120 mg lanreotide Autogel every 28 days for 3 months, after which doses of 60, 90 or 120 mg lanreotide Autogel were administered every 28 days according to symptomatic response.

Lanreotide Autogel

Lanreotide Autogel

CTC Presence at Baseline

Subjects with a baseline presence of CTCs, determined by either or both baseline CTC blood samples having a CTC enumeration >0. Baseline is defined as the 7 days preceding the first study treatment injection, or for subjects who required a washout period, these 7 days were during the washout period.

No CTC Presence at Baseline

Subjects with no baseline presence of CTCs, determined by both baseline CTC blood samples having a CTC enumeration = 0. Baseline is defined as the 7 days preceding the first study treatment injection, or for subjects who required a washout period, these 7 days were during the washout period.

Missing CTC Status at Baseline

Subjects whose CTC status at baseline could not be evaluated as both CTC blood samples were missing. Baseline is defined as the 7 days preceding the first study treatment injection, or for subjects who required a washout period, these 7 days were during the washout period.

This endpoint was assessed using 2 efficacy variables: • CTCs, enumerated at baseline and Weeks 5, 17, 25, 53 • Clinical symptomatic response, assessed by the use of symptom reporting Subjects recorded 24-hour symptom frequency and severity for 7 days prior to first treatment (baseline), throughout the study, and up to 28 days following final drug administration. Symptoms were recorded by answering predetermined questions on the interactive voice response system (IVRS). Subjects were considered to have a clinical symptomatic response between baseline and last study visit if any 1 of the following criteria were fulfilled: the average number of episodes of diarrhoea decreased by at least 50%, the average number of episodes of flushing decreased by at least 50%, the mode severity of flushing decreased by at least 1 level. Clinical symptomatic response was assessed as a qualitative variable (Yes/No) and reported according to CTC presence at baseline and overall.

Primary

From baseline up to Week 53.

Clinical symptomatic response as dependent variable and CTC presence at baseline as explanatory variable was used to perform the logistic regression analysis.

CTC Presence at Baseline v No CTC Presence at Baseline

40

Pre-specified

0.17

2-sided

Subjects underwent Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans at baseline, Week 25 and Week 53. Progression was assessed by investigators using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. The best overall response to study treatment is the highest time point response achieved by the subject and was assessed as a complete response, partial response, stable disease, progressive disease or non evaluable. For analysis of PFS, event dates were assigned to the first time that progressive disease was noted or the date of death. In case of progressive disease followed by death, the first event was considered in the analysis. Censoring dates were defined in subjects with no progressive disease or death before end of study. Median, minimum and maximum PFS time was analysed by CTC presence at baseline and overall and estimated using the Kaplan-Meier method. Subjects in the ITT population with data available for analysis are presented.

Primary

From baseline up to Week 53.

CTC Presence at Baseline v No CTC Presence at Baseline

48

Pre-specified

0.87

2-sided

The effect of lanreotide Autogel on the symptoms of diarrhoea and flushing in subjects was assessed through patient reporting of NET symptoms. Subjects recorded 24-hour symptom severity for the 7 days prior to treatment (baseline), for the first 16 weeks and on days 11 to 17 of each subsequent injection interval until Week 49. After the final study drug injection at Week 49, subjects provided 24-hour symptom frequency on days 11 to 28. Symptom frequency was recorded by answering predetermined questions on the IVRS. Mean change from baseline in frequency (number of episodes) of diarrhoea and flushing are described at Week 1 (Visit 2) and at Week 49 (Visit 14) by CTC presence at baseline and overall. A negative change indicates an improvement in symptoms from baseline. Subjects in the ITT population with data available for analysis, according to CTC presence and overall, are presented for each time point.

Secondary

From baseline up to Week 53.

The effect of lanreotide Autogel on the mode severity of flushing was assessed through patient reporting of NET symptoms. Subjects recorded 24-hour symptom severity for the 7 days prior to treatment (baseline), for the first 16 weeks and on days 11 to 17 of each subsequent injection interval until Week 49. After the final study drug injection at Week 49, subjects provided 24-hour symptom severity on days 11 to 28. Symptom severity was recorded by answering predetermined questions on the IVRS. Severity of flushing was recorded using a three-point system (mild, moderate or severe). The mode (most frequent) intensity of flushing are reported at baseline and at Week 49 (Visit 14). Percentages of subjects in each severity category are based on the number of subjects in the analysis set with available responses. Subjects in the ITT population with data available for analysis, according to CTC presence and overall, are presented at each time point.

Secondary

From Baseline up to Week 53.

The effect of lanreotide Autogel treatment on QoL was assessed using the EORTC QLQ-C30 at baseline, Weeks 13 (Visit 5), 25 (Visit 8) and 53 (Visit 15/end of study). The 30 item scale is divided into 9 multi-item scales (including 5 functional scales, 1 global health status/QoL scale and 3 general symptom scales) and 6 single items. Possible answers to the first 28 items (all items except the 2 concerning global quality of life) go from 1 (Not at all) to 4 (Very much). The answers for the 2 last questions (Q29-30) go from 1 (Very poor) to 7 (Excellent). All of the scales and single-item measures range in score from 0 to 100. For multi-item scales, the raw score will be calculated by the addition of item responses divided by the number of items. Higher scores for global health and functional domains indicate a better QoL, while higher symptom scores indicate worse symptoms. The mean change from baseline at each time point is reported for each of the category subscores.

Secondary

From baseline up to Week 53.

The effect of lanreotide Autogel treatment on QoL was assessed using the EORTC QLQ-G.I.NET21 at baseline, Weeks 13 (Visit 5), 25 (Visit 8) and 53 (Visit 15/end of study).The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 – Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 – Q51 scores range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the subscores were generated. Higher scores indicate worse symptoms or more problems. The mean change from baseline at each time point is reported for each of the category subscores. Subjects in the ITT population with data available for analysis is presented.

Secondary

From baseline up to Week 53.

Subjects underwent CT or MRI scans at baseline and Week 53. Progression was assessed by investigators using RECIST v1.1. The best overall response to study treatment is the highest time point response achieved by the subject and was assessed as a complete response, partial response, stable disease, progressive disease or non evaluable. For analysis of PFS, event dates were assigned to the first time that progressive disease was noted or the date of death. In case of progressive disease followed by death, the first event was considered in the analysis. Censoring dates were defined in subjects with no progressive disease or death before end of study. Median, minimum and maximum PFS time at one year was analysed by CTC presence at baseline and overall and estimated using the Kaplan-Meier method. Subjects in the ITT population with data available for analysis are presented.

Secondary

From baseline up to Week 53.

From baseline to Week 53 (approximately 1 year).

Treatment emergent adverse events are reported and defined as any adverse event that occurred from the first study drug injection until 28 days after the last study drug injection.

18.0

Lanreotide Autogel