| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic carcinoid tumors whose disease-related symptoms are inadequately controlled by somatostatin analogues |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007271 |
| E.1.2 | Term | Carcinoid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Compare the long term efficacy of pasireotide LAR vs. octreotide LAR at month 6 in controlling diarrhea and/or flushing in patients with metastatic carcinoid tumors whose disease-related symptoms are inadequately controlled by the maximum approved dose of a somatostatin analogue. |
|
| E.2.2 | Secondary objectives of the trial |
Main Secondary Objectives:
• Assess the effect of pasireotide LAR vs. octreotide LAR on objective tumor response rate (CR or PR) at month 6 based on RECIST criteria.
• Assess the effect of pasireotide LAR vs. octreotide LAR on disease control rate (CR, PR or SD) at month 6 based on RECIST criteria.
• Assess the proportion of patients who achieved at least 30% reduction in frequency of bowel movements at month 6.
• Assess the effect of pasireotide LAR vs. octreotide LAR on:
- improvement in the individual components of the primary endpoints (i.e., percent change in daily bowel movement and/or total number of flushing)
- time to symptom response
- duration of symptom response
- time to symptom progression
- Quality of Life
• Assess the overall safety and tolerability of pasireotide LAR vs. octreotide LAR |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female patients aged 18 years or greater.
• Patients with histopathologically confirmed (from primary or metastatic lesion biopsy) metastatic carcinoid tumors of the digestive system with extent of disease determined by Computer Tomography (CT) scan or Magnetic Resonance Imaging (MRI).
• Patients must have inadequate control of symptoms (i.e. diarrhea and/or flushing) while receiving treatment with a maximum approved dose of a currently available somatostatin analogue for at least 3 months prior to study entry (as specified in Table 4-1). Inadequate control is defined by the groups below:
• Diarrhea and Flushing group (D+F): patients with a daily mean of ≥ 4 bowel movements and a total of ≥ 5 flushing episodes over a two-week period (14 days) while receiving treatment with a maximum approved dose of a currently available somatostatin analogue for at least a 3 month period prior to study entry (as specified in Table 4-1).
• Predominantly Diarrhea group (D): patients with a daily mean of ≥ 4 bowel movements and a total number of < 5 flushing episodes over a two-week period (14 days) while receiving treatment with a maximum approved dose of a currently available somatostatin analogue for at least a 3 month period prior to study entry (as specified in Table 4-1).
• Predominantly Flushing group (F): patients with ≥ 14 flushing episodes and a daily mean of < 4 bowel movements over a twoweek period (14 days)while receiving treatment with a maximum approved dose of a currently available somatostatin analogue for at least a 3 month period prior to study entry (as specified in Table 4-1).
• Patients with measurable or evaluable disease per RECIST criteria
• Karnofsky Performance Status ≥ 60 (requires occasional assistance, but is able to care for most of their personal needs, or better).
• Patients must observe the following intervals between the last injection of their previous treatment and the first injection of study drug:
• Octreotide LAR = 28 days (4 weeks)
• Octreotide s.c. = 8 hours
• Lanreotide Autogel = 28 days (4 weeks)
• Lanreotide SR = 14 days (2 weeks)
• Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary (see Section 6.6.2.1)
• Female patients of child bearing potential must have a negative pregnancy test at baseline.
• Patients for whom written informed consent to participate in the study has been obtained
• Baseline lab values for adequate organ function:
• Absolute neutrophil count ≥1.5 × 10^9/L
• Hemoglobin ≥9 g/dL
• Platelets ≥100 × 10^9/L
• Hepatic: Serum bilirubin ≤ 1.5 X upper limit of normal (ULN), Aspartate aminotransferase and alanine aminotransferase, ≤3 × ULN without liver metastases, ≤5 × ULN if documented liver metastases.
• Renal: Serum creatinine ≤2 mg/dL, calculated creatinine clearance ≥30 mL/min
•Potassium: Serum potassium ≥ 3.5 mEq/L |
|
| E.4 | Principal exclusion criteria |
•Patients who have received a somatostatin analogue higher than the maximum approved dose within 3 months of Visit 1. (This exclusion criteria is not applicable to patients who are receiving short acting formulation.)
•Patients receiving radiolabeled somatostatin analogue therapy within the 3 months or any cytotoxic chemotherapy or interferon therapy within the 4 weeks prior to recording baseline symptoms
• Patients who have undergone major surgery/surgical therapy for any cause within 1 month or surgical therapy of loco-regional metastases within the last 3 months before recording baseline symptoms
• Patients with hepatic artery embolization, chemoembolization or radioembolization (ytrium 90 microsphere) treatment within the last 6 months (1 month if there are
other sites of measurable disease), or patients who have undergone cryoablation or
radiofrequency ablation of hepatic metastasis within the last 2 months before recording baseline symptoms
• Patients who have received radiotherapy for any reason within the last 4 weeks and must have recovered from any side effects of radiotherapy before recording baseline symptoms
• Patients who are unwilling to follow dietary restrictions (see Section 7.4.2.7) within 3 days of urinary 5-HIAA sample collection or require medications that would interfere with urinary 5-HIAA measurement (e.g. Reserpine, mephenesin carbamate, Lugol’s solution)
• Patients with known malabsorption syndrome, short bowel or chologenic diarrhea not controlled by specific therapeutic means
• Patients who are not biochemically euthyroid
• Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly
controlled as indicated by HbA1C > 8%
• Patients with symptomatic cholelithiasis
• Any of the following cardiac abnormalities:
• QTcF at screening > 470 msec
• History of syncope or family history of idiopathic sudden death
• Sustained or clinically significant cardiac arrhythmias
• Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac
failure, clinically significant/symptomatic bradycardia, or high-grade AV block
• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused
by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or
cardiac failure
• Concomitant medication(s) known to increase the QT interval
• Patients with additional active malignant disease within the last five years (with the
exception of basal cell carcinoma or carcinoma in situ of the cervix)
• Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunocompromise, including a positive HIV test result (ELISA and Western blot). A HIV test will not be required; however, previous medical history will be reviewed
• Patients with abnormal coagulation (PT or APTT elevated by 30% above normal limits)
• Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the Investigator or the Sponsor’s Study physician
• Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. Female patients must use barrier contraception with condoms. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to enrollment and must agree to continue the oral contraceptive throughout the course of the study, and for three months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a
precautionary measure (available data do not suggest any increased reproductive risk with the study drugs).
• Patients who are currently part of or have participated in any clinical investigation with an
investigational drug (other then pasireotide) within 1 month prior to dosing
• Known hypersensitivity to somatostatin analogues or any component of the pasireotide or
octreotide LAR or s.c. formulations (see section 6.1.1)
• Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study
• Patients who have been previously treated with Pasireotide
• Any of the following hepatic related exclusion criteria:
• History of liver disease, such as cirrhosis or chronic active hepatitis B and C
• Presence of Hepatitis B surface antigen (HbsAg)
• Presence of Hepatitis C antibody (anti-HCV)
• History of, or current alcohol misuse/abuse within the past 12 months
• Known gallbladder or bile duct disease, acute or chronic pancreatitis
• Baseline ALT or AST > 3 x ULN
• Baseline total bilirubin > 1.5 x ULN |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is based on the mean number of bowel movements and/or total number of flushing episodes at month 6.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| exploratory Biomarker objective |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Egypt |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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