E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse large B-cell lymphoma |
|
E.1.1.1 | Medical condition in easily understood language |
Diffuse large B-cell lymphoma |
|
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 | 17.0 |
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) |
|
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 |
Evaluate the efficacy and safety of the Zevalin Regimen compared with observation alone in patients who are in PET-negative complete response per Revised Response Criteria for Mlignant Lymphoma, after first line CHOP. |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is 60years of age or older at time of randomisation 2. Histologically confirmed Ann Arbor stage II, III, or IV DLBCL; or FL Grade 3B according to the WHO classification 2008 (from initial diagnosis made prior to starting Rchemotherapy). 3. An H&E stained slide and unstained slides must be available for confirmatory pathology review, as per the separate Pathology Guidance document. Patients may be randomized based on the local diagnosis. 4. Presence of at least one IPI risk factor. The aaIPI is defined by one point for each factor: a. LDH > upper limit of normal (ULN); b. Stage III or IV; and c. WHO/ECOG performance status >1. 5. Firstline treatment must have been 6 cycles of standard RCHOP or RCHOPlike chemotherapy (e.g. RCHOP21, RCHOP14, or DAEPOCHR). Patients who received prephase therapy for the purpose of improving performance status prior to initiating RCHOP are eligible. Standard dose reductions for toxicity are allowed. 6. Complete remission (CR) according to the Revised Response Criteria for Malignant Lymphoma [22] (Appendix 2) after firstline treatment. a. Diagnostic CT scans with contrast of chest, abdomen, and pelvis must have been performed within 8 weeks after the first dose of the last cycle of Rchemotherapy. PETCTs obtained elsewhere before and after RCHOP are acceptable for evaluating response to RCHOP, but a diagnostic CT prerandomization is requested as reference for post randomization interval change. A neck CT will be applicable if the patient had involvement of the neck region by palpation / physical examination at initial diagnosis. The CT portion of an FDG PET that includes the neck will be acceptable if the neck had involvement. b. A negative FDGPET scan performed within 8 weeks after the first dose of the last cycle of Rchemotherapy and confirming CR, with negative defined as a score of 13 on the Deauville 5point scale (Appendix 3) used to quantify radionucleotide density in PET scans as determined locally [23]. PET positive/indeterminate lesions which are confirmed on biopsy to harbor no active lymphoma will be considered negative for determination of CR status. c. If positive bone marrow involvement at initial diagnosis the patient must have a negative bone marrow biopsy following Rchemotherapy to confirm the CR. 7. WHO/ECOG performance status of 0, 1 or 2. 8. Adequate hematopoietic functions unsupported by transfusion within the last 2 weeks: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Hemoglobin (Hgb) ≥ 9 g/dL, Platelets ≥ 100 x 109/L. Patients with blood counts close to recovery towards these values after RCHOP should be discussed with the study Medical Monitor prior to randomization, but blood counts must have met these thresholds prior to treatment with Y90 Zevalin. 9.In patients who had a post Rchemotherapy bone marrow biopsy performed, the marrow must show cellularity > 15%. For patients without a post Rchemotherapy bone marrow biopsy (i.e. those patients with negative marrow at diagnosis), a repeat biopsy to assess bone marrow cellularity of > 15% will be required only for patients randomized to the Zevalin Regimen. 10.Life expectancy of 6 months or longer. 11.Written informed consent obtained according to local guidelines. |
|
E.4 | Principal exclusion criteria |
1. Presence of any other malignancy or history of prior malignancy within 5 years of study entry. Within 5 years, patients treated with curative intent for Stage I or II cancers are eligible provided they have a life expectancy of > 5 years. The 5-year exclusion rule does not apply to-non melanoma skin tumors and in situ cervical cancer. 2. Prior radioimmunotherapy, including radiation therapy for NHL, or any other NHL therapy. 3. Presence of central nervous system (CNS) involvement, or testicular lymphoma at first diagnosis. 4. DLBCLas histological transformation of previously diagnosed indolent B-cell lymphoma. Patients with De Novo Transformed DLBCL, defined as DLBCL on lymph node biopsy and a “discordant marrow” with small cells at initial diagnosis, are eligible. 5. Known seropositivity for hepatitis C virus (HCV) or hepatitis B surface antigen (HbsAg). Patients who are positive for HbsAg but without active disease (Hep B PCR below the limits of detection) and who receive adequate prophylaxis may be enrolled, but should continue prophylaxis for at least 6 months after the last dose of rituximab or Zevalin. 6. Known history of HIV infection. 7. Abnormal liver function: total bilirubin > 2 × ULN unless secondary to Gilbert disease. 8. Abnormal renal function: serum creatinine > 2.0 × ULN. 9. Ongoing toxic effects of chemotherapy > grade 2 and expected to interfere with Zevalin treatment. 10. Known hypersensitivity to murine or chimeric antibodies or proteins. 11. Colony stimulating factor therapy administered more than 8 weeks after last dose of R-chemotherapy or within 4 weeks prior to planned administration of Zevalin. 12. Concurrent severe and/or medically uncontrolled disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months of study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study. 13. Treatment with investigational drugs less than 4 weeks prior to randomization. 14. Major surgery less than 4 weeks prior to randomization. 15. Concurrent systemic corticosteroid use for any reason except as premedication in case of known or suspected allergies to contrast media or as premedication for potential side effects of rituximab treatment. Patients on a chronic dose of prednisone for a medical condition (e.g. Asthma or autoimmune disease) less than or equal to 20mg daily, stable for 4 weeks, are permissible. 16. Unwillingness or inability to comply with the protocol. 17. Pregnant women or women who are breastfeeding
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall survival - assessed throughout the period of the study. |
|
E.5.2 | Secondary end point(s) |
24-month overall-survival rate post-randomisation
Progression-free survival |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
24-month overall-survival rate post-randomisation - proportion of all randomised patients who die within 24 months of randomisation.
Progression-free survival - assessed throughout the period of the study. |
|
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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
Observation, no Zevalin administered |
|
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Australia |
Austria |
Belgium |
Canada |
France |
Germany |
Ireland |
Israel |
Italy |
Netherlands |
Portugal |
Spain |
United Kingdom |
United States |
|
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
|
|
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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |