Study to Determine the Maximum Tolerated Dose, Safety and Tolerability of a Single Dose of Lanreotide Prolonged Release Formulation (PRF) in Subjects With Acromegaly

Study Overview
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Brief Summary
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The objectives of the protocol is to determine the maximum tolerated dose and to investigate the pharmacokinetics of a single dose of lanreotide PRF in subjects with acromegaly.

Official Title
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Phase IIa, Open Label, Dose Ascending Study to Determine the Maximum Tolerated Dose, Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of Lanreotide PRF in Subjects With Acromegaly Previously Treated and Controlled With Either Octreotide LAR or Lanreotide Autogel

Conditions
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Acromegaly

Intervention / Treatment
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* Drug: Lanreotide PRF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of acromegaly. Provided written informed consent prior to any study related procedures. Between 18 and 75 years of age inclusive. Female of non-childbearing potential or male. Non-childbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired). Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use a medically accepted, effective method of contraception (i.e. condom) for the duration of the study (maximum of 7.5 months). Treatment with a stable dose of either octreotide LAR or lanreotide Autogel for at least 3 months immediately prior to study entry, with confirmation of disease control during this treatment period (documentation of age adjusted IGF 1 <1.3 x upper limit of normal (ULN), based on local laboratory results, during screening period). If the subject is receiving treatment for hypertension, the dose has been stable for at least 1 month prior to study entry. Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol. Exclusion Criteria: Has undergone radiotherapy within 2 years prior to study entry. Has been treated with a dopamine agonist and/or GH receptor antagonist or has undergone pituitary surgery within 3 months prior to study entry. Is anticipated to require pituitary surgery or radiotherapy during the study. Has clinically significant hepatic abnormalities and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3 x ULN and/or alkaline phosphatase (AP) ≥2.5 x ULN and/or total bilirubin ≥1.5 x ULN and/or gamma-glutamyl transpeptidase (GGT) ≥2.5 x ULN during the Screening period (central laboratory results) or a history of these findings when on somatostatin analogue (SSTa) treatment. Has clinically significant pancreatic abnormalities and/or amylase and/or lipase ≥1.5 x ULN during the Screening period (central laboratory results). Has any significant renal abnormalities and/or creatinine ≥1.5 x ULN during the screening period (central laboratory results). Has uncontrolled diabetes (glycosylated haemoglobin (HbA1c) ≥9%, centrally assessed during the Screening period), or has diabetes treated with insulin for less than 6 months prior to study entry. Has any known uncontrolled cardiovascular disease or had any of the following within 6 months of Screening: ventricular or atrial dysrhythmia ≥grade 2, bradycardia ≥grade 2, electrocardiogram (ECG) QT interval corrected (QTc) prolonged ≥grade 2, myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications. Use of any hormone replacement therapy (HRT) with oestrogens. Has symptomatic gallstones/ sludge at the Screening Visit echography (local assessment) OR is asymptomatic but has echography showing clear evidence of impending inflammation such as localised mucosal thickening suggesting the subject is at high risk of developing acute disease. Subjects with asymptomatic gallstones/ sludge and otherwise normal echography may be entered at the discretion of the investigator. Has abnormal findings during the Screening period, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject's safety. Has been treated with any other investigational medicinal product (IMP) prior to the first study visit without undergoing a washout period of seven times the elimination half-life of the investigational compound. Has a known hypersensitivity to any of the test materials or related compounds. Is likely to require treatment during the study with drugs that are not permitted by the study protocol. Has a history of, or known current, problems with alcohol or drug abuse. Has any mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lanreotide PRF<br>One single dose of lanreotide PRF (via subcutaneous injection) either 180mg or 270mg or 360mg. | Drug: Lanreotide PRF<br> <br> * Other names: Lanreotide acetate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs. | The MTD was defined based on the DLTs observed in each cohort. A DLT was defined as an adverse event (AE) (excluding anorexia and fatigue) or an abnormal laboratory value occurring within the first week (up to Week 2) following lanreotide PRF administration and during the entire study duration, assessed as unrelated to acromegaly, intercurrent illness or concomitant medications and which met any of the pre-established toxicity criteria. If no DLTs were reported then no MTD could be defined. | From Day 1 up to Week 25. | 
| PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). | Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide Cmax values were determined using non-compartmental analysis. | From Baseline (pre-dose) up to Week 25. | 
| PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). | Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Median serum lanreotide Tmax values were determined using non-compartmental analysis. | From Baseline (pre-dose) up to Week 25. | 
| PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). | Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide t1/2 values were determined using non-compartmental analysis. Only values fulfilling the determination rules for t1/2 were analysed. | From Baseline (pre-dose) up to Week 25. | 
| PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85). | Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Sample were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-85 values were determined using non-compartmental analysis. | From Baseline (pre-dose) up to Day 85 | 
| PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). | Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-∞ values were determined using non-compartmental analysis. Only values fulfilling the accuracy determination rules for AUC0-∞ were analysed. | From Baseline (pre-dose) up to Week 25. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Summary of Number of Subjects With AEs. | AEs reported by the investigators using the National Cancer Institute-Common Toxicity Criteria (NCI CTCAE) classification (Version 4.03) and incidence of all reported treatment emergent AEs (TEAEs) and serious AEs (SAEs) are presented by dose cohort. AEs were assigned to a NCI CTCAE Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. TEAEs were defined as any AE that occurs during the active phase of the study (between the start of the 3 month treatment period and 3 months after the end of study treatment). The worst intensity of TEAES at each grade are reported for all and for related TEAES. In the event of multiple occurrences of the same AEs being reported by the same subject, the maximum intensity and the most serious causality were reported. | From Day -42 up to Week 25. | 
| PK Analysis of Glycofurol Excipients: Cmax. | Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Mean serum N1-glycofurol and N2-glycofurol Cmax values were determined using non-compartmental analysis. | From Baseline (pre-dose) up to Day 5. | 
| PK Analysis of Glycofurol Excipients: Tmax. | Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Median serum N1-glycofurol and N2-glycofurol Tmax values were determined using non-compartmental analysis. | From Baseline (pre-dose) up to Day 5. | 
| PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). | Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Mean serum N1-glycofurol and N2-glycofurol AUC0-∞ and AUC0-t values were determined using non-compartmental analysis. Only AUC0-∞ values fulfilling the accuracy determination rules were analysed. | From Baseline (pre-dose) up to Day 5. | 
| PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Blood samples were collected for the determination of IGF-1 in serum at Baseline (pre-dose), 6 hours post-dose and at Weeks 5, 9 and 13. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Serum concentrations of IGF-1 were calculated using the Immulite 2000 Platform for all subjects in the safety population. The production of the reagent kits was stopped by the vendor during the study. The old reagent kits were used for Cohorts 1 and 2 until their expiry date and then the kits were switched to a new reagent and used for remaining subjects in Cohorts 2 and 3. Summary data for serum concentrations of IGF-1 were obtained using both methods (old and new reagent) and the mean change from Baseline at each time point is presented. | From Baseline (pre-dose) up to Week 25. | 
| PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | GH cycle assessments were performed by taking 5 samples in the morning (with a sample taken every 30 minutes for 2 hours) at Baseline (pre-dose), Week 5 and Week 13. Summary data for the mean of the 5 samplings of the GH cycle were generated and the mean change from Baseline at each time point is presented. | From Baseline (pre-dose) up to Week 13. | 
| PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | Blood samples were collected for the determination of FT3 and FT4 in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentrations of FT3 and FT4 were calculated and the mean change from Baseline at each time point is presented. | From Baseline (pre-dose) up to Week 25. | 
| PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Blood samples were collected for the determination of TSH in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentrations of TSH were calculated and the mean change from Baseline at each time point is presented. | From Baseline (pre-dose) up to Week 25. | 
| PD Analysis: Mean Change From Baseline in Prolactin. | Blood samples were collected for the determination of prolactin in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentration of prolactin were calculated and the mean change from Baseline at each time point is presented. | From Baseline (pre-dose) up to Week 25. |