Joëlle Blumberg

Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors

BACKGROUND Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors

OBJECTIVE:Somatostatin analogs are the first-line drugs for controlling hormone-mediated symptoms of carcinoid tumors. Prospective and retrospective studies have suggested that somatostatin analogs also have antiproliferative activity. The octapeptide lanreotide is available in sustained-release form, obviating the need for daily injections.METHODS:A total of 46 patients were enrolled in this open, prospective, phase II trial. They received lanreotide 30 mg i.m. every 14 days for 6 months when they had symptomatic carcinoid tumors, and lanreotide 30 mg i.m. every 10 days if they had nonsymptomatic tumors. Nonsymptomatic tumors were progressive before the start of the study. Tumor size was assessed every 3 months by means of computed tomography. The assessment was centralized and was made by an external panel.RESULTS:In all, 30 patients had symptomatic neuroendocrine tumors and 16 had asymptomatic neuroendocrine tumors. Five patients in the group with symptomatic tumors and two in the group with nonsymptomatic tumors were considered not to be evaluable. The mean duration of treatment was 12 months in the group with symptomatic tumors and 13 months in the other group. Among the 39 evaluable patients, two objective responses were obtained, giving an objective response rate of 5% (one in the group with symptomatic tumors and one in the other group). Nineteen patients had no significant increase in their tumor size for a mean of 9.5 months.CONCLUSIONS:Lanreotide is safe and well tolerated in patients with carcinoid tumors. It seems to have both symptomatic and antitumoral effects in this setting.

Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly

Background  An essential criterion for control of acromegaly is normalization of IGF‐I levels. Somatostatin analogues act to suppress IGF‐I and GH levels.

Efficacy and Tolerability of the Long-Acting Somatostatin Analog Lanreotide in Acromegaly. A 12-Month Multicenter Study of 58 Acromegalic Patients

Objective: To determine the effects of the new somatostatin analogue, lanreotide, in its prolonged released form (PR), in patients with acromegaly.Design: Prospective open multicenter non comparative study.Setting: Thirty-three university-affiliated medical centers.Patients: One hundred sixteen acromegalic patients with active disease, of whom 58 patients complied with the protocol and completed the 12-month period treatment.Intervention: Lanreotide PR treatment was started at a dose of 30 mg intramuscularly every 14 days. If integrated mean plasma GH levels were not below 5 μg/L and/or IGF-I levels were not normalized after one month of treatment, injections were given every 10 days. The duration of the study was 12 months.Results: After one month of treatment mean plasma GH and IGF-I levels had fallen from 10.7 ± 11.1 μg/L (mean ± SD; range, 2.6 – 74.8 μg/L; median, 7 μg/L) and 718 ± 270 μg/L (range 338 – 1440 μg/L; median, 645 μg/L), respectively, to 7.8 ± 10.1 μg/L and 575 ± 252 μg/L, respectively. Thirty patients (22%) had plasma GH levels below 2.5 μg/L, and 8 patients (16%) had age-adjusted normal plasma IGF-I levels. At the sixth month of treatment mean plasma GH levels of 2.5 μg/L or less, and normal plasma IGF-I levels were observed in 33%, and 33% of patients, respectively. At the twelvth month of treatment, these percentages were 41%, and 41%, respectively. The interval between two injections was shortened (one injection every 10 days) in 8 of the 58 patients (13%) at the second month of treatment, and at the end of the study, 70% of patients required 3 injections per month. The most frequent adverse event elicited by enquiry was transient diarrhea (76% of patients), followed by abdominal pain (62%) and pain at the injection site (59%). Based on the analysis of a subgroup of 46 patients who had at least a measurement of fecal fat content after day 0 of the study, a non significant increase (from 4.2 ± 3.4 to 5.1 ± 4.3 g/24h, p = 0.3) in mean steatorrhea was observed during treatment. Before treatment, steatorrhea was present in 9 (19%) patients. During the study, 15 additional patients (32%) developed persistent steatorrhea, and there was a transient increase in fecal fat content above 6 g/24 h in another 11 patients. After exclusion of the 7 patients (12%) with gallstones at enrolment, new gallstones were diagnosed in 6 out of 50 patients (12%) during the study.Conclusion: Two or three monthly injections of lanreotide PR decreased GH concentration to less than 2.5 μg/L and normalized IGF-I levels in 41% of patients treated during 12 months. The good tolerability of this treatment, and the reduction in the frequency of injections, plus the sustained drug serum concentrations, confirm the usefulness of this new somatostatin analog formulation.

Three-Month Sustained-Release Form of Triptorelin in Patients with Advanced Prostatic Adenocarcinoma: Results of an Open Pharmacodynamic and Pharmacokinetic Multicenter Study

The pharmacodynamics and the pharmacokinetic characteristics of a new longer-acting formulation containing 11.25 mg of triptorelin (Decapeptyl) to be administered every 3 months were evaluated in 14 patients with advanced prostate carcinoma. After one single injection, the mean time to reach the surgical castration testosterone range is 22 days, and this effective testosterone suppression is maintained for the 3-month therapy. After a first plasma surge (35.70 ng/ml) occurring 2.5 h after injection and a rise between day 17 and day 31 (maximum on day 24: 0.32 ng/ml), the mean triptorelin plasma level is stable (0.06 ± 0.05 ng/ml) and maintained until day 91. This new formulation was well tolerated both locally and systemically.

Pharmacodynamic equivalence of a decapeptyl 3-month SR formulation with the 28-day SR formulation in patients with advanced prostate cancer

Aims: The objective of the study was to assess the pharmacodynamic equivalence of LHRH analogue triptorelin 3-month and 28-day SR formulations. Methods: Patients with documented locally advanced or metastatic prostate cancer were randomized to receive one injection of the 3-month formulation (n = 63) or three injections at 28-day intervals of the 28-day formulation (n = 68). Group-chemical castration rates defined as the percentage of patients reaching a testosterone plasma level ≤0.5 ng/ml were compared at D84 (i.e., 3 × 28 days). Testosterone, LH and triptorelin plasma profiles, and change from baseline in plasma PSA were assessed over 3 months (from baseline to D91). Results: Chemical castration rates were 98 and 96% in the 3-month and 28-day formulation groups, respectively, with confidence interval (two-sided 94.2% CI) of [–8.1%; 9.6%]. Median times to reach chemical castration were 18.8 and 18.5 days (p = 0.86, log rank), respectively. Ratios for mean peak plasma levels and AUC91 of the two formulations for both testosterone and LH fell within the [0.80; 1.25] equivalence interval. Mean PSA decreases from baseline at D91 were 91.0 and 91.7%, respectively (p = 0.73). Conclusion: Treatments with the two triptorelin formulations over 3 months are pharmacologically equivalent.

Efficacy of Lanreotide 30 mg on Prevention of Pain Relapse after Oral Refeeding in Patients with Necrotizing Acute Pancreatitis

Background: Pain relapse after oral refeeding occurs in 21% of the patients with acute pancreatitis, and in 35% of those with CT Balthazar’s score ≧D [Gut 1997;40:262]. Somatostatin analogues may decrease the pain relapse rate by inhibiting exocrine pancreatic secretion. Aims, Patients and Methods: To assess the frequency of pain relapse in patients with acute necrotizing pancreatitis after treatment with one intramuscular injection of lanreotide 30 mg on the day before refeeding. The refeeding procedure was standardized and progressive. Results: 23 patients were included in 4 centres. Acute pancreatitis was alcoholic (n = 11), biliary (n = 7), other (n = 5). Twelve patients had ≧3 Ranson’s criteria. Balthazar’s score (1985) was D or E in 7 and 16 patients, respectively. Median duration of pain and of interruption of oral feeding were 11 (3–23) and 16 (5–34) days, respectively. Median hospital stay was 22 (9–41) days. Only 1 patient (4.3 %) had pain occurring 3 days after refeeding. Conclusion: Pain relapse occurred in 4.3% of patients pretreated with the somatostatin analogue lanreotide, and this figure is lower than the expected 35% rate which was previously reported without preventive treatment. This suggests that one intramuscular injection of lanreotide 30 mg on the day before refeeding could decrease pain relapse in patients with acute necrotizing pancreatitis, but has to be confirmed in a phase III study.

Long-acting lanreotide in adolescent girls with constitutional tall stature.

Background/Aims: The aim of the study was to evaluate the efficacy and safety of lanreotide prolonged release (PR) 30 mg (long-acting lanreotide) in girls with constitutional tall stature (CTS). Methods: This open label prospective study included 35 girls (mean age 12.6 years) with CTS and a predicted adult height of >180 cm. Intramuscular injections of lanreotide PR 30 mg were given every 14 days, for a minimum of 12 months and up to 36 months. Adult height was compared with pretreatment predicted height. Results: The mean predicted adult height was reduced by 3.8 cm (95% CI 3.7–4.9 cm) in the restricted intent-to-treat population. Mean growth velocity decreased from 7.9 ± 1.5 cm/year at preinclusion to 1.7 ± 2.3 cm/year at the last visit on treatment (n = 35). Gastrointestinal adverse events and cholelithiasis were reported in 35/37 patients and 5/37 patients, respectively. There was 1 withdrawal due to gastrointestinal disorders. Conclusions: Biweekly intramuscular lanreotide PR 30 mg given to girls with CTS after the onset of pubertal development reduced adult height as compared with predicted height. Treatment-associated adverse events were consistent with the overall safety profile of lanreotide 30 mg PR and did not deter most patients from long-term treatment.

A 6-Month Trial of the Efficacy and Safety of Triptorelin Pamoate (11.25 mg) Every 3 Months in Children with Precocious Puberty: A Retrospective Comparison with Triptorelin Acetate.

Background/Aims: To evaluate the efficacy and safety of a triptorelin pamoate (11.25 mg) 3-month formulation in the management of central precocious puberty (CPP) (TP Study) and to retrospectively compare it with a triptorelin acetate (11.25 mg) 3-month formulation (TA Study). Methods: We conducted two phase III, multicentre, single-stage, non-comparative, open-label studies. In the TP Study, patients with CPP received an intramuscular injection of triptorelin pamoate 11.25 mg at baseline and 3 months after baseline. Hormonal changes as well as safety and efficacy endpoints were measured at baseline, 3 months, and 6 months. Results: The baseline characteristics of the 37 patients in the TP Study were similar to those of the TA Study population. A suppressed luteinising hormone (LH) response (LH peak ≤3 IU/l) to the gonadotrophin-releasing hormone test at 3 months (primary endpoint) occurred in 83.8 and 82.8% of the cases in the TP and the TA Study, respectively. At 6 months, a suppressed LH response occurred in 86.5 and 96.8% of the cases in the TP and the TA Study, respectively. Pubertal development was slowed in both studies. Adverse events were mild to moderate and resolved without sequelae in the TP Study. Conclusion: Triptorelin pamoate 11.25 mg administered at 3-month intervals is an effective and well-tolerated treatment in patients with CPP. The efficacy and safety profiles appear similar to those reported in the literature for triptorelin acetate 11.25 mg.

Efficacy of lanreotide 30 mg as symptomatic treatment in patients with inoperable bowel obstruction due to peritoneal carcinomatosis: A randomized double-blind, placebo-controlled study.

242 Background: Somatostatin analogues in previous open label studies improved symptoms due to bowel obstruction in patients with peritoneal carcinomatosis. This study assessed the efficacy and safety of lanreotide microparticles 30 mg as treatment of clinical symptoms in inoperable patients. METHODS Eighty cancer patients with inoperable digestive obstruction of malignant origin (mean age 62.3 years, 82.5% female) were randomized to receive one intramuscular injection either of lanreotide microparticles 30 mg (N=43) or placebo (N=37). The primary location of cancer was mostly genital (ovary 37.5%, uterus 13.8%) or digestive (colon 16.3%, stomach 11.3%, pancreas 6.3%). Most patients were fed by central parenteral route (80%) and were severely impaired (63.8% ECOG 3 or 4). The primary endpoint was the response rate at day 7 (responders defined as patients with ≤ 1 vomiting episode per day or no vomiting recurrence after removal of the NGT, for at least 3 consecutive days) assessed in a diary card in the intention to treat (ITT) population. Per protocol (PP) population mainly excludes concomitant treatment and inclusion criteria deviations defined during a blinded data review meeting. RESULTS In the ITT analysis, 41.9% of lanreotide 30mg treated patients were responders versus 29.7% for placebo. This difference was not statistically significant (odds ratio (OR) = 1.75 (95% CI [0.68; 4.49], p = 0.24, logistic regression). The predefinedPP (n= 49) sub group analysis did show a statistically and clinically significantly higher response rate in the lanreotide group (OR 3.60 (95% CI [1.03, 12.62], p = 0.045). There was no significant difference between the 2 treatment groups in secondary efficacy endpoints assessment but there were significant differences in favor of lanreotide in well-being using a visual analogue scale at D3 (p = 0.04), D6 (p = 0.04) and D7 (p = 0.01). No drug-related serious adverse event (SAE) or unexpected event was reported. CONCLUSIONS Lanreotide 30 mg may decrease clinical symptoms and improve well-being in patients with inoperable bowel obstruction due to peritoneal carcinomatosis. [Table: see text].