E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare disease-free survival (DFS) in poor risk patients with DLBCL after achieving CR following first-line R-CHOP who receive RAD001 versus patients who receive matching placebo. |
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E.2.2 | Secondary objectives of the trial |
? To compare overall survival (OS) and lymphoma-specific survival (LSS) in patients who receive RAD001 versus patients who receive matching placebo. ? To describe the safety profile of RAD001 in comparison to the matching placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with previous histologically-confirmed Stage III-IV (or Stage II bulky disease defined as any tumor mass more than 10 cm in largest diameter), at time of original diagnosis, diffuse large B cell lymphoma (pathology report based on original tumor tissue/lymph node is acceptable for meeting inclusion criteria, but tumor tissue (slides/block) must be available to be sent for central pathology to confirm diagnosis). 2. Patients defined as poor risk with IPI of 3, 4, or 5 at time of original diagnosis. 3. Patients age ? 18 years old. 4. Patients must have achieved complete remission (CR) based on the revised IWRC (Cheson et al 2007) following first line R-CHOP treatment. Radiation therapy in combination with R-CHOP is acceptable if the radiation therapy ended by the time of RCHOP completion. Complete remission from R-CHOP must be confirmed by clinical and radiologic evaluation along with bone marrow confirmation (if bone marrow was involved by lymphoma before the R-CHOP treatment). Local pathology report on the bone marrow biopsy is acceptable. If bone marrow was not involved by lymphoma before R-CHOP treatment, then bone marrow confirmation after R-CHOP is not required. 5. Patients who received a minimum 6 cycles of R-CHOP treatment and maximum 8 cycles of R-CHOP treatment. Any variation of CHOP (R-CHOP-14, R-CHOP-21) is acceptable. Liposomal doxorubicin is acceptable. 6. Patients? last treatment with R-CHOP must be 6 to 12 weeks prior to start of study drug. 7. Patients with ECOG performance status (PS) 0, 1, or 2. 8. Patients willing to provide a portion of his/her tumor tissue from original diagnosis or lymph node to confirm diagnosis. 9. The following laboratory values obtained ? 21 days prior to start of study drug: ? Absolute neutrophil count ? 1000/mm3 (or 1.0 GI/L, SI units) ? Platelet count ? 100,000/mm3 (or 100 GI/L, SI units) ? Hemoglobin ? 9 g/dL (can be achieved by transfusion) ? Total bilirubin ? 2 x ULN (if >2 x ULN direct bilirubin is required and should be ?1.5 x ULN) ? AST ? 3 x ULN (? 5 x ULN if liver involvement is present) ? Serum creatinine ? 2 x ULN 10. Women of childbearing potential must have had a negative serum pregnancy test 7 days prior to the start of study drug. 11. Patients who give a written informed consent obtained according to local guidelines. 12. Patients capable of swallowing intact study medication tablets and following directions regarding taking study drug, or have a daily caregiver who will be responsible for administering study drug. |
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E.4 | Principal exclusion criteria |
1. Patients with evidence of disease according to the revised IWRC (Cheson et al 2007) after completion of the first-line R-CHOP treatment, prior to study entry. 2. Patients receiving ongoing radiation therapy or who received radiation therapy to the residual tumor masses after R-CHOP. 3. Patients who have previously received systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus, etc). 4. Patients with evidence of current central nervous system (CNS) involvement. Patients who have only had prophylactic intrathecal or intravenous chemotherapy against CNS disease are eligible. 5. Patients with transformed follicular lymphoma. 6. Patients who received ibritumomab tiuxetan (Zevalin®), in order, to avoid potential delayed kidney toxicities. 7. Patients who had myelosuppressive chemotherapy or biologic therapy < 3 weeks. 8. Patients receiving chronic systemic immunosuppressive agents. Inhaled and topical steroids are acceptable. Patients may be receiving stable (not increased within the last month) chronic doses of corticosteroids with a maximum dose of 20 mg of prednisone or 10 mg of dexamethasone per day, if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica or adrenal insufficiency or asthma. 9. Patients with active, bleeding diathesis. 10. Patients with a known history of HIV seropositivity, chronic hepatitis, or other active viral infections. 11. Patients with known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to any of the excipients. 12. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: ? unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ? 6 months prior to first study drug, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ? 6 months before study drug start ? severely impaired lung function as 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 ? poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN ? any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study ? nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study drug, such as severe hypertension that is not controlled with medical management and thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication ? liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis. 13. Patients who have a history of another primary malignancy ? 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine cervix. 14. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Oral contraceptives are not acceptable. 15. Patients who are using other investigational agents or who had received investigational drugs ? 4 weeks prior to study drug start. 16. Patients unwilling to or unable to comply with the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease-free survival (DFS): Disease-free survival (DFS) is the time from date of randomization to the date of event defined as the first documented recurrence of the disease or death due to any cause. |
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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 | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 | 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
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 | 25 |