Edda Gomez-Panzani

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

OBJECTIVE To evaluate the efficacy and safety of lanreotide depot/autogel 120 mg for the control of carcinoid syndrome (CS) symptoms in patients with neuroendocrine tumors (NETs). METHODS This was a 16-week, randomized, double-blind, phase 3 trial (Clinicaltrials.gov: NCT00774930). Patients with/without prior somatostatin analog (SSA) use were randomized to lanreotide depot/autogel 120 mg or placebo every 4 weeks, with access to short-acting octreotide as rescue medication. The primary endpoint was the percentage of days in which short-acting octreotide was used, which was assessed from daily diaries using an analysis of covariance including the stratification variables baseline short-acting octreotide use and frequency of diarrhea/flushing. The proportions of patients experiencing treatment success was a supportive analysis. Adverse events were recorded at all visits. RESULTS A total of 115 patients were enrolled (lanreotide, n = 59; placebo, n = 56). The adjusted mean (95% confidence interval [CI]) percentage of days with rescue octreotide use (primary endpoint) was significantly lower in the lanreotide (33.7%; 95% CI, 25.0%-42.4%) versus the placebo group (48.5%; 95% CI, 39.6%-57.4%), representing an absolute difference of -14.8% (95% CI, -26.8% to -2.8%; P = .017). The odds ratio of full/partial treatment success (≤3 days short-acting octreotide use weeks 12 to 15) was significantly greater with lanreotide than placebo (2.4; 95% CI, 1.1-5.3; P = .036). No new safety concerns were identified, and lanreotide was well tolerated. CONCLUSION Lanreotide depot/autogel is effective for the control of CS symptoms in patients (SSA-naïve or experienced) with NETs. ABBREVIATIONS AE = adverse event BMI = body mass index CS = carcinoid syndrome ELECT = Evaluating Lanreotide Efficacy and safety as a Carcinoid-syndrome Treatment HRQoL = health-related quality of life LTOLE = long-term open-label extension NET = neuroendocrine tumor OL = open label SSA = somatostatin analog.

1135PDQUALITY OF LIFE (QOL) ASSOCIATED WITH LANREOTIDE AUTOGEL (LAN) TREATMENT FOR CARCINOID SYNDROME (CS) IN GASTROENTEROPANCREATIC NEUROENDOCRINE TUMOUR (GEPNET) PATIENTS: RESULTS OF THE ELECT STUDY

ABSTRACT Aim: QoL is an important consideration for CS treatment. This analysis evaluated QoL in GEP-NET patients treated for CS in the ELECT study. Methods: ELECT was a 16-week, randomised, double-blind (DB) phase III study (NCT00774930). Patients with GEP-NETs and a history of CS were treated with LAN 120 mg (n = 59) or placebo (n = 56) every 4 weeks. It was followed by 32-week and ≥2-year open-label extensions (OLEs). The primary endpoint was % of days of rescue medication use (SC octreotide) during DB study. Safety evaluations focused on adverse events (AEs). QoL was assessed using the EORTC QLQ-C30 and the EORTC QLQ-GI.NET21. Scores for global health status score (QLQ-C30) and endocrine and gastrointestinal subscales (QLQ-GI.NET21) were secondary endpoints; other scores were exploratory. Results: Mean [95% CI] % of days of rescue medication use was significantly lower with LAN (34% [25, 42%]) than placebo (49% [40, 57%]); difference –15% [–27, –3%], p = 0.02. Treatment-related AEs occurred in 15 (26%) LAN vs. 11 (19%) placebo patients: most common AEs were gastrointestinal. The global health status score (QLQ-C30) remained similar after 12 weeks of DB treatment with LAN and placebo. Treatment differences in endocrine and gastrointestinal subscale scores are shown in the table. For all functional scales of the QLQ-C30, scores remained stable/slightly improved in the LAN group, while there were small deteriorations in the placebo group; however CIs were wide. For the other subscales of the QLQ-GI.NET21, changes in scores were similar in both treatment groups. Conclusions: LAN 120 mg treatment for CS symptoms was not associated with a deterioration in QoL in GEP-NET patients. In fact, despite the relatively short duration of the study, there was evidence of initial improvements in some aspects of QoL. Results of QoL scores in OLE may provides more information. Table: Effect of LAN on QoL secondary endpoints. Values are mean (SD) unless otherwise stated. P-value tested at a significance level of 0.05. A hierarchical testing procedure was applied for secondary endpoints. Data shown are for the transformed scores, which can range from 0 to 100. A higher transformed score for global health status represents a better QoL. A higher transformed score for Endocrine and GI symptoms represents a higher level of symptomatology/problems Lanreotide Autogel Placebo LS mean treatment difference in change from baseline [95% CI] p-value QLQ-C30 Global health status/QoL Baseline 59.89 (20.15) [n = 59] 62.58 (20.28) [n = 55] 4.05 [–2.09, 10.20] 0.1931 Week 12 64.93 (19.37) [n = 48] 61.19 (18.07) [n = 35] 4.05 [–2.09, 10.20] 0.1931 QLQ-GI.NET21 Endocrine symptoms Baseline 25.89 (22.83) [n = 59] 33.54 (23.92) [n = 53] –7.04 [–14.80, 0.73] 0.0750 Week 12 18.06 (20.06) [n = 48] 29.84 (22.51) [n = 35] –7.04 [–14.80, 0.73] 0.0750 QLQ-GI.NET21 Gastrointestinal symptoms Baseline 22.40 (16.95) [n = 59] 24.84 (20.09) [n = 53] –4.68 [–9.63, 0.26] 0.0632 Week 12 17.64 (14.32) [n = 48] 23.62 (15.45) [n = 35] –4.68 [–9.63, 0.26] 0.0632 Disclosure: E. Gomez-Panzani: Ipsen: employee; A.I. Vinik: Ipsen: Research grant, advisory board member; E.M. Wolin: Research grant from Ipsen. Advisory board member for Ipsen, Novartis and Celgene; H. Audry: Received consulting fee (contract statistician) from Ipsen.

United States Regulations

Publisher Summary The United States Regulations on Food and Drug Administration is explained in this chapter. In the USA, one of the first attempts to regulate foods was an Act passed in Massachusetts on March 8, 1785. The origin of the Food and Drug Administration (FDA) dates to 1862 when a single chemist, Dr Charles M. Wetherill, was appointed to the US Department of Agriculture. In April 2008, the FDA published a regulatory change ending the need for clinical trials conducted outside the USA to comply with the Declaration of Helsinki. In September 2009, the FDA and the European Medicines Agency (EMA) entered into the agreement known as the EMA-FDA GCP Initiative. The initiative is a confidentiality arrangement in effect through 2010 that allows the sharing of advance drafts of legislation and/or regulatory guidance documents, information related to the authorization and supervision of medicinal products, information, including inspection reports, about GCP inspections for specific products. The FDA also committed to trending data to determine whether there is a difference in data integrity and human subject protection between domestic and foreign clinical trial sites. With respect to expanding its oversight of foreign clinical trials, if the agreement with the EMA proves to be successful, it would indeed leverage this partnership with other regulatory bodies. These recommendations and the FDAs response mean that sponsors can expect more FDA oversight of foreign clinical trial.