| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pancreatic neuroendocrine tumors (NET) comprise only 1-2% of all pancreatic tumors. The annual incidence is approx. 3.5 to 4 per million population. The hormones secreted by pancreatic NET depend upon the cell of origin and are physiologically involved in a network of autocrine, paracrine, endocrine and neurotransmitter communication. While hormone secretion is not observed in all cases, the “nonfunctioning” pancreatic NET tend to be more aggressive and present with symptoms of tumor bulk. |
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| MedDRA Classification |
| 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 determine the objective response rate (ORR) (including complete response and partial response) of RAD001 10 mg po qd monotherapy in patients with advanced (unresectable or metastatic) pancreatic NETs after the failure of cytotoxic chemotherapy (stratum 1). |
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| E.2.2 | Secondary objectives of the trial |
To determine:
• response duration of RAD001 10 mg po qd monotherapy (stratum 1).
• objective response rate (ORR) and response duration of RAD001 10 mg po qd plus Sandostatin LAR Depot therapy in patients whose tumors have progressed while receiving Sandostatin LAR Depot therapy and after the failure of cytotoxic chemotherapy (stratum 2).
• safety and tolerability of RAD001 monotherapy (10 mg/d) in patients with Pancreatic NET (stratum 1).
• safety and tolerability of the combination of RAD001 (10 mg/d) plus Sandostatin LAR Depot in patients with Pancreatic NET (stratum 2).
• progression free survival (PFS) and the overall survival (OS) of patients receiving RAD001 10 mg per day in combination with Sandostatin LAR and of patients receiving RAD001 10 mg per day monotherapy.
• To assess the steady state exposure to RAD001 and to estimate the effect of co-administering Sandostatin LAR® Depot on RAD001 exposure. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Inclusion criteria for both strata:
1. Adult male or female patients (≥18 years of age).
2. Advanced (unresectable or metastatic) biopsy-proven pancreatic NET documented as follows:
• Radiologic, operative, or pathology reports should document a pancreatic location of tumor at some point in the patient’s history;
• Patients must have confirmed low-grade or intermediate-grade neuroendocrine carcinoma. Pathology report should state one of the following: carcinoid, islet cell carcinoma, pancreatic endocrine tumor, low-grade or well-differentiated neuroendocrine carcinoma, atypical carcinoid, intermediate-grade or moderately differentiated neuroendocrine carcinoma;
• Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma are not eligible.
3. Documented objective progression of disease by RECIST criteria while receiving cytotoxic chemotherapy or documented progression at any time after receiving an adequate course of cytotoxic chemotherapy (i.e., at least 3 consecutive cycles or months of treatment with the same cytotoxic drug or regimen). Previous therapy with alpha interferon or tyrosine kinase inhibitors are allowed but would not be considered to be prior chemotherapy.
Objective progression of disease must be documented by RECIST criteria. Any of the following would be sufficient according to RECIST:
• a 20% increase in the sum of unidimensionally measured target lesions;
• a new lesion;
• unequivocal increase in non-measurable disease.
4. At screening, a triphasic CT or MRI scan must demonstrate measurable disease by RECIST criteria, i.e., the presence of at least one measurable lesion. Measurable disease lesions must be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness)
5. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL.
6. Adequate liver function as shown by:
• serum bilirubin ≤ 1.5 x ULN;
• INR < 1.3 x ULN (or < 3 ULN on anticoagulants);
• ALT and AST ≤ 2.5x ULN ( ≤ 5x ULN in patients with liver metastases).
7. Adequate renal function: serum creatinine ≤ 1.5 x ULN.
8. Fasting serum cholesterol ≤300 mg/dL OR 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In cases where one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
9. Women using an acceptable form of contraception prior to receiving RAD001 or women who meet the protocol definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy. Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, hysterectomy, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap).
10. WHO Performance Status 0-2.
11. Signed informed consent to participate in the study must be obtained from patients after they have been fully informed of the nature and potential risks by the investigator (or his/her designee) with the aid of written information.
Inclusion criteria for Stratum 2 only:
1. Meet all inclusion criteria defined for Stratum 1.
2. Receiving treatment (at least 3 consecutive months) with Sandostatin LAR® Depot.
3. In addition to documentation of progressive disease on or after chemotherapy, patients in stratum 2 must have documented objective progression of disease while receiving Sandostatin LAR® Depot. The initial and follow-up scans documenting progression must have been obtained during continual monthly therapy with Sandostatin LAR® Depot, with at least 2 months separating the initial and follow-up scans. Progression must be documented by RECIST criteria as described above. |
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| E.4 | Principal exclusion criteria |
1. Anticancer therapy within 3 weeks of enrollment including chemotherapy, hormonal therapy, immunotherapy, surgery or radiotherapy. Investigational agents used solely for imaging purposes are permissible if deemed safe and acceptable by local review authorities. Sandostatin LAR® Depot is allowed in stratum 2.
2. Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation of hepatic metastasis within 2 months of enrollment.
3. Prior therapy with RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus).
4. Patients with uncontrolled diabetes mellitus as defined by fast blood sugar > 1.5 x ULN.
5. Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.
6. Serious intercurrent infections, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy.
7. No other prior or concurrent malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for five years.
8. Known history of immunocompromise, including a positive HIV test. An HIV test will not be required; however, previous medical history will be reviewed.
9. Pregnant or nursing (lactating) women. Unless demonstrated to be post-menopausal (see inclusion criteria), pregnancy should be excluded by serum pregnancy test.
10. Concomitant medications known to inhibit, induce or be a substrate to isoenzyme CYP3A are excluded unless the drugs are medically necessary and no substitutes are available. If there are no acceptable substitutes, special precautions should be taken in these patients.
Additional Exclusion Criteria for Stratum 1 only:
1. Received treatment with Sandostatin LAR® Depot or any other long-acting somatostatin analogue in the 60 days prior to enrollment or any short-acting somatostatin analogue in the two weeks prior to enrollment. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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| 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 | 1 |
| 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 | 4 |
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