| 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 |
| The primary study objective is to compare the efficacy of BBR 2778 to a selection of single agents in terms of complete response (CR) and unconfirmed complete response (CRu) rate according to the report of the international workshop to standardize response criteria for Non Hodgkin's Lymphoma |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to compare efficacy as demonstrated by overall survival, CR and CRu rate in histologically confirmed patients, objective overall response lasting at least 4 months, and progression-free survival. Additional pre specified analyses will be overall response rate, time to initial response, time to complete response, duration of response, dose intensity, cardiac function, safety and evaluation of BBR2778 pharmacokinetics in a subset of patients according to a Limited Sampling Model. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed aggressive [de novo or transformed] NHL according to REAL/WHO classification. The histological specimen used to determine eligibility must be the most recently obtained specimen. If the histology sample is more than 2 years old, the case must be discussed with the medical monitor before enrolling the patient. Clear documentation of transformation from indolent lymphoma is needed, if applicable. Lymph node biopsy slides or tissue blocks suitable for review must be available. • transformed indolent lymphoma (areas of follicularity allowed) • diffuse large B-cell lymphoma mediastinal large B-cell lymphoma primary effusion lymphoma (includes previously called immunoblastic lymphoma) • peripheral T-cell lymphoma, not otherwise characterized (encompasses diffused mixed cell lymphoma) • anaplastic large cell lymphoma, T/null cell, primary systemic type Note: patients with any Ann Arbor stage, International Prognostic Index (IPI) score or bone marrow status are eligible.
2. Patients must have received rituximab in prior regimens in those countries where it is the standard of care and available at the patient’s institution, and when neoplastic cells express CD20.
3. At least one objectively measurable lesion as demonstrated by CT, spiral CT, or MRI that can be followed for response as a target lesion. Patients with the following sites of disease are NOT eligible: • Patients with only skin lesions or only palpable lymph nodes. • Patients with spleen or bone marrow as only site of disease.
4. Relapse (with evidence of disease progression) after 2 or more prior regimens of chemotherapy, including: first line treatment with a standard anthracycline-containing regimen such as CHOP or equivalent • at least one additional combination chemotherapy regimen. High dose chemotherapy or chemoradiotherapy with autologous stem cell support counts as one prior regimen. • Allogeneic transplant counts as one prior regimen. In patients with a previous allo-transplant, there cannot be any serious or active graft-versus-host disease (GvHD) requiring immunosuppressive therapy. (See Section 6.3 of the protocol for a list of exclusionary medications).
5. Patients must be sensitive to the last anthracycline/anthracenedione containing regimen. Sensitive is defined as: • Previously responded (confirmed or unconfirmed PR or CR) to anthracycline/anthracenedione, and • Relapsed after a response duration ≥ 6 months.
6. Age ≥ 18 years.
7. ECOG performance status of ≤ 2.
8. Life expectancy ≥ 3 months according to investigator opinion.
9. Hb ≥ 8g/dL, neutrophils ≥1.5 x 109/L and platelets ≥ 50 x109/L. • If there is bone marrow involvement, then neutrophils > 0.5 x 109/L, platelets > 10 x 109/L and the ability to provide platelet transfusion, is acceptable.
10. Serum bilirubin ≤ 1.5 x the institution’s upper limit normal (ULN) and creatinine ≤ 1.5 ULN and alkaline phosphatase ≤2.0 x the institution’s ULN and AST or ALT ≤ 2.0 x the institution’s ULN. If hepatic involvement by lymphoma is present, AST or ALT may be ≤ 5.0 x the institution’s ULN.
11. Patients previously treated with one of the comparative agents must be sensitive to that agent, if it will be used in this trial. Sensitive is defined as: • Previously responded to that agent, and • Relapsed after a response duration ≥ 6 months.
12. Patients must have recovered from all acute toxicities from prior therapy (except alopecia and grade 1 peripheral neuropathy).
13. LVEF ≥ 50% determined by MUGA scan.
14. Ability to comply with the visit schedule and assessments required by the protocol.
15. Signed approved informed consent, with understanding of study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with a cumulative dose of doxorubicin or equivalent (see Section 17.2 of the protocol) exceeding 450 mg/m² according to the following calculation index: X/450 + Y/160 > 1 where X is the doxorubicin dose in mg/m² and Y the mitoxantrone dose in mg/m².
2. Histological diagnosis of Burkitt lymphoma, lymphoblastic lymphoma or Mantle cell lymphoma.
3. Active CNS lymphoma involvement based on clinical evaluation (if the patient requires a diagnostic lumbar puncture due to high risk criteria i.e. sinus involvement, high LDH, high IPI, or bone marrow involvement, it will be acceptable to administer intrathecal chemotherapy, which can include methotrexate, cytarabine and corticosteroids, according to institutional standards).
4. HIV-related lymphoma.
5. Any chemotherapy, radiotherapy, or other anticancer treatment (including corticosteroid, 10 or more mg/day of prednisone or equivalent) within the 2 weeks before randomization. For radioimmunoconjugate therapy, there must be 8 weeks since last dose or platelet recovery to ≥ 50 x 109/L prior to randomization.
6. Major thoracic and/or abdominal surgery within the 2 weeks before randomization from which the patient has not fully recovered. Patients who have had minor surgery may be enrolled after a ≥1 week recovery period.
7. Clinically significant cardiovascular abnormalities (equal to NYHA grade III- IV), myocardial infarction within the prior 6 months, severe arrhythmia or uncontrolled hypertension or uncontrolled angina.
8. Serious (NCI CTCAE grade 3-4) intercurrent infection at randomization or deep seated or systemic mycotic infections.
9. History of or clinical symptoms suggesting HIV infection. Patients with a previous history of Hepatitis B (HBV) or Hepatitis C (HCV) infection without clinical symptoms and whose hepatic parameters comply with inclusion criterion number 10 (serum bilirubin, creatinine alkaline phosphatase, ALT and AST levels) and patients with seropositivity presumed to be due to prior vaccination against HBV will not be excluded.
10. History of another malignancy except: curatively treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in remission, or any other cancer from which the patient has been disease-free for 5 years.
11. Any condition which, in the judgment of the Investigator, would place the subject at undue risk, interfere with the results of the study, or make the subject otherwise unsuitable.
12. Participation in any other investigational drug study within 2 weeks before randomization. Patient must have recovered from all side effects of other investigational therapy. For radioimmunoconjugate therapy, there must be 8 weeks since last dose, or platelet recovery to ≥ 50 x 109/L prior to randomization.
13. Known hypersensitivity to the excipients or the study drug that the patient will receive.
14. Pregnant women or nursing mothers.
15. Potentially fertile men and women not willing to use adequate contraception during the study and for 6 months after the last day of study drug administration. 16. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete response (CR) and unconfirmed Complete response (CRu) rate: The total proportion of patients with CR or CRu.CR and CRu will be defined according to the report of the international workshop to standardize response criteria for NHL and can be found in apendix 17 of the protocol. |
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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 | 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 | 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) | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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
| |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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