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 | 15.1 |
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 bilirubin ≤ 1.5 x ULN,
• INR < 1.3,
• ALT and AST ≤ 3 x ULN
• Serum lipase ≤ 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 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 clinically 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 QTcF > 470 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.Cardiac failure, clinically significant/symptomatic bradycardia
or high-grade AV block
•Concomitant medications known to prolong the QT interval
•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
•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
•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 nursing (lactating) women
20.Women of child-bearing potential UNLESS they are using adequate
highly effective birth control methods during dosing and for 8 weeks
after stopping study treatment
21. Sexually active males must use a condom during intercourse while
taking the drug and
for 8 weeks after stopping treatment and should not father a child in this
period. Female partners of male patients must also be advised to use one
of the contraception methods presented in the protocol
For more details,please refer to the protocol |
|
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 | Information not present in EudraCT |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
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 |