E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced progressive pancreatic neuroendocrine tumors (PNET) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067517 |
E.1.2 | Term | Pancreatic neuroendocrine tumour |
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 |
To estimate the treatment effect of everolimus in combination with pasireotide LAR relative to everolimus alone on progression-free survival (PFS) in patients with advanced PNET and to assess the predictive probability of success in a possible subsequent phase III study once 80 PFS events have been observed. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability profile of everolimus alone or in combination with pasireotide LAR
• To evaluate the Objective Response Rate (ORR) and Disease Control Rate (DCR)
• To evaluate the duration of response (DoR)
• To evaluate overall survival (OS)
• To estimate the treatment effect on PFS and to assess the predictive probability of success
in a possible subsequent phase III study once 105 PFS events have been observed
• To assess pharmacokinetic (PK) exposures of everolimus and pasireotide LAR
• To assess potential PK drug-drug interactions between everolimus and pasireotide LAR |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Advanced (unresectable or metastatic), histologically confirmed well differentiated (low to intermediate grade) pancreatic neuroendocrine tumor (PNET).
2. Radiological documentation of progressive disease within the last 12 months prior to randomization.
3. Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT.
4. Adult patients (male or female) ≥ 18 years of age.
5. WHO performance status ≤ 2
6. Adequate bone marrow function:
• WBC ≥ 2.5 x 109/L,
• ANC ≥ 1.5 x 109/L,
• Platelets ≥ 100 x 109/L,
• Hb ≥ 9 g/dL
7. No evidence of significant liver/pancreas disease:
• Serum total bilirubin ≤ 1.5 x ULN,
• INR < 1.3,
• ALT or AST ≤ 3 x ULN
• Serum lipase and amylase ≤ 2 x ULN
8. Serum creatinine ≤ 2.0 mg/dl and estimated glomerular filtration rate (eGFR) > 30
ml/min/m2 (calculated with MDRD formula).
9. Written informed consent is to be obtained prior to any screening procedures. |
|
E.4 | Principal exclusion criteria |
1. Patients currently requiring SSA treatment.
2. Patients who received prior therapy with mTOR inhibitors or pasireotide.
3. Patients who received any cytotoxic chemotherapy, targeted therapy, SSAs, or biotherapy within the last 4 weeks.
4. Patients with more than 2 prior systemic treatment regimens
5. Patients with a known hypersensitivity to SSAs.
6. Patients with a known hypersensitivity to any component of the pasireotide LAR or s.c. formulations, everolimus or other rapamycin analogs (sirolimus, temsirolimus) or to their excipients.
7. Prior treatment with radiolabeled SSAs within the last 12 months.
8. Patients with hepatic artery embolization, cryoablation or radiofrequency ablation of hepatic metastasis within the last 3 months prior to randomization.
9. Patients who have received radiotherapy of target lesions. Patients who have received local radiotherapy of non-target lesions for local symptom control within the last 4 weeks must have recovered from any adverse effects of radiotherapy prior to randomization.
10. 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 prior to randomization.
11. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent.
12. Patients with symptomatic cholelithiasis.
13. Patients who are not biochemically euthyroid. Patients with history hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy for at least 3 months.
14. Patients with abnormal coagulation (PT [INR] or aPTT elevated by 30% above normal limits).
15. QT-related exclusion criteria:
• Patients with a baseline QTcF > 450 ms,
• History of syncope or family history of idiopathic sudden death, Long QT syndrome,
• Sustained or clinically significant cardiac arrhythmias,
• Patients with risk factors for torsades de pointes: Potassium < 3.0 mmol/L,
magnesium < 0.4 mmol/L or, calcium < 1.75 mmol/L at baseline. If the electrolyte abnormalities are corrected prior to start of study drug, the patient may become eligible for the trial. Cardiac failure, clinically significant/symptomatic bradycardia or
high-grade AV block,
• Concomitant medications known to prolong the QT interval (see Appendix 2).
• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes mellitus or Parkinson’s disease), HIV, liver cirrhosis, uncontrolled
hypothyroidism or cardiac failure.
16. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
• Uncontrolled diabetes as defined by HbA1c ≥ 8% despite adequate therapy,
• Fasting serum cholesterol > 300 mg/dL (7.75 mmol/L) OR fasting triglycerides > 2.5
x ULN despite appropriate lipid lowering medication.
• Severely impaired lung function defined as spirometry and DLCO that is 50% of the
normal predicted value and/or O2 saturation that is 88% or less at rest on room air. DLCO should be adjusted to hemoglobin value and patient lung volumes.
• Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result
(ELISA and Western blot). A HIV test will not be required; however, previousmedical history will be reviewed.
• Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment.
• History or active liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis.
• Quantifiable HBV-DNA or positive hepatitis B surface antigen(HbsAg).
• Quantifiable HCV-RNA.
• History of, or current alcohol misuse/abuse within the past 12 months.
• Known gallbladder or bile duct disease, acute or chronic pancreatitis.
• Life-threatening autoimmune and ischemic disorders.
• Patients who have a history of another primary malignancy within the last 3 years,
with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix.
• Symptomatic CNS metastases requiring corticosteroid therapy.
• 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 Medical Monitor.
17. 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.
18. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing.
19. Pregnant or lactating women (see protocol for definition).
20. Women of child-bearing potential (see protocol for definition). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
PFS per RECIST 1.0. PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first |
|
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 | No |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | No |
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
| Information not present in EudraCT |
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 | 28 |
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 |
Australia |
Brazil |
Japan |
Thailand |
Turkey |
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 | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |