E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with MALT Lymphoma treated with chlorambucil and rituximab followed by maintenance treatment with subcutaneous rituximab |
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E.1.1.1 | Medical condition in easily understood language |
Treatment with chlorambucil and rituximab followed by treatment with subcutaneous rituximab in patients with a diagnosis of a particular type of lymphoma called MALT 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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060707 |
E.1.2 | Term | MALT lymphoma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Aim of the study is to assess the therapeutic safety and activity of the combination of Chlorambucil and Rituximab given for 6 months, followed by 2 years maintenance treatment with subcutaneous Rituximab alone in MALT lymphomas. |
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E.2.2 | Secondary objectives of the trial |
Efficacy and safety of study treatment |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically proven diagnosis of CD20-positive marginal zone B-cell lymphoma of MALT type either de novo, or relapsed following local therapy (including surgery, radiotherapy and antibiotics for H. pylori-positive gastric lymphoma) arisen at any extranodal site
1.1 The following patients with gastric MALT Lymphoma can be entered:
a. H. pylori-negative cases, either de novo (non pre-treated) or at relapse following local therapy (i.e., surgery, radiotherapy or antibiotics).
b. H. pylori-positive cases at diagnosis, who failed antibiotic therapy, including:
• Patients with clinical (endoscopic) and histological evidence of disease progression at any time post H. pylori eradication
• Stable disease with persistent lymphoma at ≥ 1 year post H. pylori eradication
• Relapse (without H. pylori re-infection), after a remission
• Patients who failed either first line antibiotics or further local treatment (surgery or radiotherapy)
1.2 Similar consideration may be applied to patients with ocular adnexal lymphoma treated with antibiotics.
2. Measurable or evaluable disease. Measurable disease in at least two perpendicular dimensions on an imaging scan is defined as: lymph node or nodal mass bi-dimensional measurement with > 1.5 cm in longest transverse diameter or the short diameter must measure > 10 mm regardless of the longest transverse diameter.
3. Any stage (Ann Arbor I-IV)
4. Age ≥ 18
5. Life expectancy of at least 1 year
6. ECOG performance status 0-2
7. Adequate bone marrow function (WBC >3.0x109/L, ANC >1.5x109/L, PLT >100x109/L), unless due to lymphoma involvement
8. Adequate kidney (serum creatinine <1,5x upper normal) and liver function (ASAT/ALAT <2,5 upper normal, total bilirubin <2,5x upper normal), unless due to lymphoma involvement
9. For women of childbearing potential only: negative serum pregnancy test done within 7 days prior to study drugs administration or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to the first study drugs administration
10. Fertile male or female patients of childbearing potential and their partners must use two forms of contraception during the study and for at least 12 months after the last dose of subcutaneous rituximab.
For appropriate methods of contraception considered acceptable, see Appendix C. Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately.
Female patients of childbearing potential are defined as follows:
• Pre-menopausal women (patients with regular menstruation, patients after menarche with amenorrhea or irregular cycles, patients using a contraceptive method that precludes withdrawal bleeding
• Women who have had tubal ligation
Female patients may be considered to NOT be of childbearing potential for the following reasons:
• The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
• The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months
11. Ability to understand and the willingness to sign a written informed consent document
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E.4 | Principal exclusion criteria |
1. Evidence of histologic transformation to a high grade lymphoma
2. Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer
3. Prior chemotherapy
4. Prior immunotherapy with any anti-CD20 monoclonal antibody
5. Prior radiotherapy in the last 6 weeks
6. Use of corticosteroids during the last 28 days, unless prednisone chronically administered at a dose <20 mg/day for indications other than lymphoma or lymphoma-related symptoms
7. Evidence of clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhytmias, congestive heart failure or myocardial infarction within 12 months before study entry
8. Evidence of symptomatic central nervous system (CNS) disease
9. Evidence of active opportunistic infections
10. Known HIV infection
11. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBV DNA test will be performed and if positive the subject will be excluded
12. Positive serology for hepatitis C (HC) defined as a positive test for HCAb, confirmed by HC RIBA immunoblot assay on the same sample.
13. Pregnant or lactating status
14. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
15. Fertile men or women of childbearing potential who do not agree to use a highly effective measure of contraception (such as oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) throughout the study and for at least 12 months after the last dose of subcutaneous rituximab
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E.5 End points |
E.5.1 | Primary end point(s) |
Complete Remission rate at 6 months |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Completion of induction phase II (6 months from study entry) |
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E.5.2 | Secondary end point(s) |
Response rate (Complete and partial remission rates) for all patients;
Progression-free-survival (PFS) (any case)
Event-free-survival (EFS) at 5 years for all patients;
Overall survival for all patients;
Response duration for responder patients;
Acute and long-term toxicity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of induction phase I, induction phase II, maintenance phase, end of follow up |
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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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 12 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 12 |
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 | 0 |