| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
|
| 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 evaluate the efficacy of lenalidomide as maintenance therapy after completion of first-line combination chemotherapy in patients with mantle cell lymphoma (MCL) who are not candidates for transplantation and have achieved partial response (PR) or complete response (CR). |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety of lenalidomide as maintenance therapy after completion of first-line combination chemotherapy in patients with MCL who are not candidates for transplantation and have achieved partial or complete response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must understand and voluntarily sign an informed consent form
2. Must be ≥ 18 years of age at the time of signing the informed consent form
3. Must be able to adhere to the study visit schedule and other protocol requirements
4. Histologically-proven mantle cell non-Hodgkin’s lymphoma, including evidence of cyclin D1 overexpression by immunohistochemistry. In patients whose tumors are negative for the cyclin D1 overexpression, evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable
5. Must have received one of the following first-line induction chemotherapy regimens with rituximab:
a. A combination regimen containing all of the following components: cyclophosphamide, vincristine, adriamycin and a glucocorticoid. For example: R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), R-CHOP 14, R-CHOP 21; (minimum of 6 full dosed cycles up to maximum 8 cycles). Regimens containing cytarabine, or methotrexate are not allowed.
b. Fludarabine containing regimen such as FC (fludarabine, cyclophosphamide) (minimum of 6 full dosed cycles)
c. Patients who have been treated with less than 6 cycles of R-CHOP or R-FC, but received ≥4 cycles, can be considered eligible if dose reduction or treatment discontinuation occurred due to severe drug related toxicity, including, but not limited to: cardiac insufficiency, neurotoxicity, drug induced or worsened diabetes mellitus, repetitive febrile neutropenia and severe infections despite appropriate growth factor support, life threatening allergic reactions and the physician considers that adequate treatment has been delivered
d. Clinically appropriate dose modifications of vincristine or prednisone in the first-line induction chemotherapy regimen will be allowed if occurred in cycles ≥4
6. Must have completed the first-line induction chemotherapy regimen and achieved a PR or better response as assessed by 2007 Revised Response Criteria for Malignant Lymphoma (Cheson, 2007)
7. Must have completed last dose of first-line induction chemotherapy no less than 4 weeks (28 days) and no later than 12 weeks (84 days) prior to randomization
8. Patients whom the physician considers ineligible for transplant at the time of enrollment because of one of the following reasons:
a. Age ≥ 65 years
b. Comorbidity for patients < 65 years
Comorbidity is defined as any condition including laboratory abnormalities or clinical symptoms such as e.g. cardiac insufficiency and severe pulmonary diseases that places the patient at an unacceptable risk if he/she undergoes transplant
c. Patient declines transplant
9. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2 at the time of screening
10. Female of child bearing potential must:
a. Have two negative medically supervised urine pregnancy test prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the patient practices complete and continued sexual abstinence
b. Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy
11. Male patients must:
a. Agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy
b. Agree to not donate semen during study drug therapy and for a period after end of study drug therapy
12. All patients must:
a. Have an understanding that the study drug could have a potential teratogenic risk
b. Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy
c. Agree not to share study medication with another person
d. Be counseled about pregnancy precautions and risks of fetal exposure. |
|
| E.4 | Principal exclusion criteria |
1. Histology other than MCL, for example transformed lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma
2. Patients who do not have archival tumor samples and who do have no tumor accessible for biopsy are not eligible into the study
3. Patients who have received more than 1 line of induction chemotherapy
4. Patients who received 1st line induction therapy other than those specified in inclusion criteria or had treatment modification as follows:
a. Addition of new drugs to the first-line induction chemotherapy specified in inclusion criteria will not be allowed. For example, addition of cytarabine or methotrexate to R-CHOP/R-CHOP-like etc will not be allowed
b. Switching of regimens in the middle of induction treatment will not be allowed. For example, CHOP to FC or CHOP to CVP (cyclophosphamide, vincristine, and prednisone), etc will not be allowed
c. Use of any agents as "maintenance" following completion of initial combination chemotherapy are not allowed
5. Patients who have received less than 4 cycles of R-CHOP, R-CHOP-like, or R-FC are ineligible
6. Patients who achieved stable disease or progressive disease as best response with first line-induction chemotherapy
7. Any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L)
b. Platelet count < 60,000/mm3 (60 x 109/L)
c. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT)) > 3.0 x upper limit of normal (ULN), except in patients with documented liver involvement by lymphoma
d. Serum bilirubin > 1.5 x ULN, except in case of Gilbert's Syndrome and documented liver involvement by lymphoma
8. Calculated creatinine clearance (i.e. Cockcroft-Gault formula) of < 30 mL /min
9. Active or any history of central nervous system (CNS) lymphoma or leptomeningeal involvement by lymphoma
10. Patients should not be receiving corticosteroids except for prednisone ≤ 10 mg/day or equivalent for purposes other than treating MCL
11. Patients at high risk for deep vein thrombosis (DVT) not willing to take DVT prophylaxis
12. Prior history of malignancies other than MCL unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:
a. Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c. Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e. Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
13. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form
14. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible
15. Pregnant or lactating females
16. Uncontrolled intercurrent illness including, but not limited to:
a. Ongoing or active infection requiring parenteral antibiotics
b. Uncontrolled diabetes mellitus as defined by the investigator
c. Chronic symptomatic congestive heart failure (Class III or IV of the New York Heart Association Classification for Heart Disease)
d.Unstable angina pectoris, angioplasty, stenting, or myocardial infarctions within 6 months
e. Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia. Patients with controlled atrial fibrillation that is asymptomatic are eligible
17. Prior ≥ Grade 3 allergic reaction/hypersensitivity to thalidomide
18. Desquamating (blistering) rash while taking thalidomide
19. Prior use of lenalidomide
20. Use of any standard or experimental anti-cancer drug therapy or radiation within 3 weeks of the initiation (Day 1) of study drug therapy
21. Participation in another clinical trial during the screening/baseline phase and treatment phase of the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) |
|
| 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 | 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 | 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) | 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 | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| 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 |
|
| 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
|
Study will be terminated when either 80% of patients have died or 5-years after last patient is randomised, whichever comes first
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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