E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse Large B-Cell Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Diffuse Large B-Cell Lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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-chemotherapy 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 longest 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-chemotherapy treatment. Radiation therapy (RT) during or after R-chemotherapy is acceptable provided: 1) it ends 4 weeks prior to start of study drug and, 2) in case of consolidation RT targeted at initial bulky tumor mass administered after R-chemotherapy, patient is already in CR before initiating RT. Complete remission from R-chemotherapy must be confirmed by clinical and radiologic evaluation along with bone marrow confirmation (if bone marrow was involved by lymphoma before the R-chemotherapy treatment). Local pathology report on the bone marrow biopsy is acceptable. If bone marrow was not involved by lymphoma before R-chemotherapy treatment, then another bone marrow confirmation after R-chemotherapy is not required.
5. Patients who received a minimum 5 cycles of R-chemotherapy treatment and maximum 8 cycles of R-chemotherapy treatment. Any variation of R-CHOP interval (R-CHOP-14, R-CHOP-21) is acceptable. Liposomal doxorubicin, epirubicin, or pirarubicin (also known as therarubicin) is acceptable. R-EPOCH is acceptable.
6. Patients’ last treatment cycle with R-chemotherapy must be 6 to 14 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 (may 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
• Serum creatinine ≤ 2 x ULN
10. Women of childbearing potential must have had a negative serum pregnancy test 14 days prior to the start of study drug plus a negative local urine pregnancy test on Day 1, Cycle 1 prior to treatment and must be willing to use highly effective methods of contraception during the study and for 8 weeks after study drug administration.
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-chemotherapy treatment, prior to study entry.
2. Patients receiving ongoing radiation therapy or who received radiation therapy to the residual tumor masses <4 weeks from start of study drug.
3. Patients who have previously received systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus, etc).
4. Patients with evidence of current central nervous system (CNS) involvement with lymphoma. Patients who have only had prophylactic intrathecal 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 from start of study drug.
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 ≤ 5 mg of dexamethasone per day, if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency or asthma.
9. Patients with active, bleeding diathesis.
10. Patients with a known history of HIV seropositivity.
11. Patients with known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to any of its 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 02 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 or decompensated liver disease
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 of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 8 weeks after study drug administration. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
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.5.1.1 | Timepoint(s) of evaluation of this end point |
All DFS events to be included up to 31-Dec-2015 |
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E.5.2 | Secondary end point(s) |
1. Overall survival (OS): Overall survival is defined as the time from date of randomization to date of death due to any cause. If the patient is not known to have died, survival will be censored at the date of the last contact
2. Lymphoma-specific survival (LSS): Lymphoma-specific survival is defined as time from randomization to death as a result of lymphoma, which means that death must be recorded as a result of lymphoma.
3. Number of adverse events in patients who recieve RAD001 in comparison to matching placebo. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•If Final DFS analysis is significant: Interim OS analysis will be done at the time of revised final DFS analysis (31-Dec-2015 cutoff date). If this OS analysis is not significant, OS will be tested again at the final OS analysis at the pre-defined fixed cut-off date of 31-Dec-2018 (5 years after last patient was randomized).
•If Final DFS analysis is Not significant: OS will not be tested and the study close-out activities will be initiated.
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 |
Argentina |
Australia |
Austria |
Brazil |
Canada |
China |
Colombia |
Czech Republic |
Egypt |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Lebanon |
Mexico |
New Zealand |
Norway |
Peru |
Poland |
Russian Federation |
Saudi Arabia |
Singapore |
Slovakia |
Spain |
Switzerland |
Thailand |
Turkey |
United States |
Venezuela, Bolivarian Republic of |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |