| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| large-cell neuroendocrine carcinoma of the lung |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057270 |
| E.1.2 | Term | Neuroendocrine carcinoma |
| 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 |
The primary objective of this study is to evaluate the efficacy of RAD001 in patients with advanced (stage IV) Lung Cancer (Large Cell) with neuroendocrine differentiation treated with a combination of (RAD001) with paclitaxel and carboplatin.
The primary endpoint is the proportion of subjects progression-free at Month 3 (C4D21) according to RECIST. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate proportion of subjects progression-free at Month 6
• To evaluate overall response rate (ORR) at 3 months (C4D21) based on RECIST
• To evaluate disease control rate (DCR) at 3 months (C4D21) based on RECIST
• To evaluate progression-free survival (PFS)
• To evaluate overall survival (OS)
• To evaluate the safety and tolerability
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who give a written informed consent obtained according to local guidelines
2. Histologically confirmed diagnosis of lung cancer of LC-NEC type according to WHO classification:
a. Tumor must be stage IV at time of inclusion of patient
b. Neuroendocrine differentiation as shown by:
• Morphology: neuroendocrine
• Non-small cell cytological characteristics
• Positive for at least 1 of the following 3 markers: CD56, Synaptophysine, Chromogranine A
c. Increased proliferation rate assessed by a mitosis rate of > 11/10 HPF (and if available a Ki67 proliferation rate of > 50%)
3. Age ≥ 18 years
4. World Health Organisation (WHO) performance status grade ≤ 1
5. measurable disease as per RECIST Version 1.1 (see PTS 1)
6. Adequate bone marrow function as shown by:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin (Hb) > 9g/dL
7. Adequate liver function as shown by:
• Serum aspartate aminotransferase (AST) and alanine aminotransferase(ALT) ≤ 2.5 x upper limit of normal (ULN) (or ≤ 5 x ULN if hepatic metastases are present)
• Total bilirubin ≤ 1.5 x ULN
8. Adequate renal function as shown by:
• Serum creatinine < 1.5 x ULN or creatinine clearance ≥ 45 mL/min
|
|
| E.4 | Principal exclusion criteria |
1. History or clinical evidence of central nervous system (CNS) metastases. Note: Subjects who have previously-treated CNS metastases (whole brain radiotherapy, surgery ± radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:
• are asymptomatic and,
• have had no evidence of active CNS metastases for ≥ 3 months prior to enrollment and,
• have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC)Presence of SCLC cells
2. Presence of SCLC cells
3. Patients who have a history of another active primary malignancy ≤ 3 years, with the exception of inactive basal or squamous cell carcinoma of the skin or cervical cancer in situ, early stages of breast cancer (LCIS and DCIS) and prostate cancer (stage T1a)
4. prior chemotherapy for the treatment of advanced lung cancer and/or not having recovered from the side effects of any other therapy (adjuvant treatment for earlier stages I-III is allowed if finished at least one year before study entry as well as a multimodal chemotherapy treatment)
5. Patients who have received any investigational drug ≤ 28 days before starting study treatment or who have not recovered from side effects of such therapy
6. Patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia with the exception of diagnostic interventions or stent implantation; patients with surgery for advanced lung cancer are eligible, if surgery > 4 weeks before randomization) or patients that may require major surgery during the course of the study
7. Patients who have received wide field radiation therapy to >= 25 % of the bone marrow within 4 weeks prior to study treatment or limited radiation therapy for palliation (including cranial irradiation for non-active brain metastases) within 2 weeks
8. Patients receiving chronic systemic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisone equivalent) or another immunosuppressive agent. Inhaled and topical steroids are acceptable.
9. Known allergy or hypersensitivity to platinum-containing drugs, especially carboplatin.
10. Known allergy or hypersensitivity to taxanes, other drugs formulated in Cremophor EL (polyoxyethylated castor oil) or any known excipients of these drugs.
11. Known allergy or hypersensitivity to Rapamycin derivatives and other mTOR inhibitors.
12. Patients who have received prior therapy with RAD001 or other mTOR inhibitors
13. Patients currently being treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A (please refer to Table 6-5). Treatment with such drugs must be stopped at least 7 days prior to first dosing of study treatment
14. Having any severe and/or uncontrolled medical conditions such as:
• unstable angina pectoris, unstable angina, or symptomatic congestive heart failure (NYHA II, III, IV), ventricular arrhythmias, active ischemic heart disease, myocardial infarction ≤ 6 months prior to allocation, serious uncontrolled cardiac arrhythmia or uncontrolled hypertension
• uncontrolled diabetes as defined by fasting serum glucose >2 x ULN
• active or uncontrolled severe infection
• chronic liver or renal disease
• Having impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patients with pre-existing interstitial lung disease (ILD) / pneumonitis of grade > 1
• Severely impaired lung function with a resting 02 saturation that is 89% or less on room air
• Patients with active skin, mucosal, renal, neurological or ocular disorders of grade > 1
• Patients with peripheral neuropathie > grade 1
• Patients with grade 3 hypercholesterolemia / hypertriglyceridemia or grade 2 hypercholesterolemia / hypertriglyceridemia with history of coronary artery disease (despite lipid lowering treatment if given)
• Patients with a known history of Human Immunodeficiency Virus seropositivity
• Patients with known Hepatitis B/C positivity (screening is mandatory for patients as described in Section 4.1)
15. Women who are pregnant or breast feeding
16. Women of child bearing potential or sexually active males, unwilling or unable to use the required highly effective method(s) of contraception for both sexes while receiving treatment and for at least 6 months after the discontinuation of study treatment.
17. Positive serum pregnancy test at screening for all women of child-bearing potential
18. Patients who have a history of non-compliance to medical regimens or patients unwilling or unable to comply with the protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of this study is to evaluate the efficacy of RAD001 in patients with advanced (stage IV) Lung Cancer (Large Cell) with neuroendocrine differentiation treated with a combination of RAD001 with paclitaxel and carboplatin. The primary endpoint is the proportion of subjects progression-free at Month 3 (C4D21) as assessed by the central reviewer according to RECIST. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | No |
| 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
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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