Date: 2014-07-16
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in the New England Journal of Medicine
Company: Ipsen (France)
Product: Somatuline® Autogel® (lanreotide) 120mg
Action mechanism:
Disease: gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: CLARINET (Controlled study of Lanreotide Antiproliferative Response in NET) is a 96-week,multinational study that was conducted in collaboration with UKI NETS and ENETS in patients (n=204) with well or moderately differentiated non-functioning GEP-NETs and a proliferation index (Ki67) of <10%. A total of 265 patients from 44 centres across 14 countries were enrolled, with 204 patients with well or moderately differentiated non-functioning GEP-NETs and a proliferation index (Ki67) of <10%, subsequently randomly allocated to treatment (n=101 in Somatuline® Autogel® 120 mg group and n=103 in placebo group). At enrollment, primary tumor locations were pancreas (44%), midgut (36%), hindgut (7%) and unknown (13%). Most patients had stable tumors (96%) and were treatment-naïve (84%). 30% of patients had Ki67 3%–10% (WHO grade 2), 33% had hepatic tumor load >25%.
The primary endpoint of efficacy was time to either disease progression (using Response Evaluation Criteria In Solid Tumors, RECIST) or death. Two baseline computed tomography scans were performed, followed by additional scans at 12 weeks intervals during the first year and 24 weeks intervals during the second year up to 96 weeks.Patients were randomized to either Somatuline® Autogel® 120 mg or placebo. The primary endpoint of efficacy was time to either disease progression (using Response Evaluation Criteria In Solid Tumors, RECIST) or death. Two baseline computedtomography scans were performed, followed by additional scans at intervals up to 96 weeks. Secondary endpoints included proportion of patients alive and without tumor progression at 48 and 96 weeks, time to progression, overall survival, safety, quality of life, plasma chromogranin A levels, tumor markers, and pharmacokinetic parameters. (NCT00353496).
Latest
news: The data gathered from 204 GEP-NET patients over the 96-week study showed that placebo-treated patients had a median PFS of 18.0 months and 33.0% had not progressed or died at 96 weeks, whereas the median PFS for Somatuline® treated patients was not reached and 65.1% had not progressed or died at 96 weeks (stratified logrank test, p<0.001). This represented a 53% reduction in risk of disease progression or death based on a hazard ratio of 0.47 (95% CI: 0.30–0.73). These statistically and clinically significant antiproliferative effects of Somatuline® were observed in a large population of patients with grade G1 or G2 (World Health Organization classification) GEP-NETs, and independent of hepatic tumor volume (≤25% or >25%). Quality of life measures were not different between the Somatuline® and placebo groups. Safety data generated from the study are consistent with the known safety profile of Somatuline®. * On September 28, 2013, Ipsen has announced that results from CLARINET® Phase III clinical trial presented at the 2013 European Cancer Congress showed the antiproliferative effect of Somatuline® (lanreotide) 120 mg injection in the treatment of non-functioning gastroentero and pancreatic neuroendocrine tumors (“GEP-NETs”). The results were presented in the LBA3 abstract: “A randomized, double-blind, placebo-Controlled study of Lanreotide Antiproliferative Response in patients with gastroenteropancreatic NeuroEndocrine Tumors (CLARINET)”. CLARINET® met its primary endpoint by demonstrating that treatment with Somatuline® Autogel® / Somatuline® Depot® (lanreotide) Injection 120 mg (referred to as Somatuline®) was associated with a statistically significant reduction of the risk of disease progression or death by 53% vs. placebo (hazard ratio 0.47, 95% CI: 0.30–0.73; p=0.0002). This result is based on the observation that 62% of GEP-NET patients treated with Somatuline® had not progressed or died versus 22% with placebo over the follow-up period (Kaplan-Meier estimates). The median progression free survival was not reached (beyond 2 years) in the Somatuline® group versus 18 months in the placebo group.
* On July 16, 2014, Ipsen announced that the New England Journal of Medicine has published clinical trial results showing that Somatuline® Autogel® / Somatuline® Depot® (lanreotide) Injection 120 mg (referred to as Somatuline®) achieved statistically significant prolongation of progression free survival (PFS) over placebo in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). CLARINET®, an investigational Phase III randomized, double-blind, placebo-controlled study of the antiproliferative effects of Somatuline® was conducted in 48 centers across 14 countries. The article titled “Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors” has been published in the July 17th edition (N. Engl. J. Med. 2014; 371: 224-233).
The effect of Somatuline® on disease progression was observed across certain pre-specified subgroups of patients. Statistically significant results were obtained in patients with midgut tumors, in patients with G1 and G2 (proliferation index Ki67 <10%) tumors, and in patients with moderate (? 25%) and high (>25%) hepatic tumor load. The data on Somatuline® with respect to progression free survival showed a clinically relevant difference vs placebo in patients with pancreatic NETs, although the subgroup analysis did not reach statistical significance.
The results per subgroup are disclosed in the table below:
Subgroups
Midgut NETs(n=73)
Progression free survival (PFS)
Median PFS:
• Somatuline®: > 2 years
• Placebo: 21.1 months
Statistical results
• hazard ratio 0.35• 95% CI: 0.16 -0.80
• p=0.0091
Pancreatic NETs (n=91)
Progression free survival (PFS)
Median PFS:• Somatuline®: > 2 years
• Placebo: 12.1 months
Statistical results
• hazard ratio 0.58• 95% CI: 0.32 -1.04
• p=0.0637
WHO grade tumors: G1 (n=141)
Progression free survival (PFS)
Median PFS:• Somatuline®: > 2 years
• Placebo: 18.3 months
• hazard ratio 0.43
• 95% CI: 0.25 -0.74
• p=0.0016
WHO grade tumors: G2 (n=61)
Median PFS:
• Somatuline®: > 2 years
• Placebo: 12.1 months
Statistical results
• hazard ratio 0.45• 95% CI: 0.22 -0.91
• p=0.0235
Hepatic tumor load (< 25%) (n=133)
Progression free survival (PFS)
Median PFS:• Somatuline®: > 2 years
• Placebo: 21.1 months
Statistical results
• hazard ratio 0.34• 95% CI: 0.18 -0.62
• p=0.0002
Hepatic tumor load (> 25%) (n=67)
Progression free survival (PFS)
Median PFS:• Somatuline®: 24.1 months
• Placebo: 9.4 months
Statistical results
• hazard ratio 0.45• 95% CI: 0.23 - 0.88
• p=0.0170
Safety profile
Safety data generated from the CLARINET® study were consistent with the known safety profile of Somatuline®. Treatment-related adverse events occurred in 50% of patients treated with Somatuline® versus 28% in the placebo arm, and very few of these were serious (3% with Somatuline® versus 1% with placebo). The most frequent treatment-related adverse events included diarrhea (26% with Somatuline® versus 9% with placebo), abdominal pain (14% with Somatuline® vs 2% with placebo) and gallstone formation (10% with Somatuline® vs 3 % with placebo).
The data from CLARINET® is considered investigational, as Somatuline® is not approved specifically to treat non-functioning GEP-NETs in any market. Somatuline® is approved for treatment of symptoms associated with neuroendocrine tumors, which can include the treatment of GEP-NETs patients experiencing symptoms from carcinoid syndrome, in many markets where it is marketed as Somatuline® Autogel®. Somatuline® is not approved in the US to treat neuroendocrine tumors or symptoms thereof, where it is marketed as Somatuline® Depot®.
* On July 11, 2013, Ipsen has announced results from the primary endpoint of the CLARINET study, assessing the effect of Somatuline® Autogel® 120 mg on tumor progression-free survival in patients with GEP-NETs. Treatment with Somatuline® Autogel® 120mg was found to be statistically significantly superior to placebo in extending time to either disease progression or death. The safety profile observed in the study is consistent with the known safety profile of Somatuline®. Comprehensive results from this study will be disclosed at the annual meeting of the European Society of Medical Oncology (ESMO) (Sept. 27 – Oct. 1, 2013).
CLARINET provides medically important results as it is the first large scale placebo-controlled randomized study to demonstrate the antitumoral activity of a somatostatin analog in non-functioning GEP-NETs.
