| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated and symptomatic patients with histologically proven CD20-positive marginal zone B-cell lymphoma (MZL) in need of systemic treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously untreated marginal zone 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076596 |
| E.1.2 | Term | Marginal zone 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Aim of the study is to assess the efficacy of the combination of rituximab and ibrutinib in EMZL patients and to explore its activity in SMZL and NMZL as exploratory subset. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the safety of the combination and to evaluate further efficacy parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for inclusion, each patient must fulfill all of the following criteria:
Chemotherapy and immunotherapy-naïve, symptomatic and in need of treatment patients, with histologically proven CD20-positive MZL, not eligible for local therapy, including:
1. EMZL (MALT Lymphoma) patients with MALT- IPI score 1-2 in need of systemic therapy. Either de novo or relapsed following local therapy (including surgery, radiotherapy and antibiotics for H. pylori-positive gastric lymphoma) arisen at any extranodal site with MALT-international prognostic index (IPI) score 1-2 at the time of study entry.
1.1. The following patients with gastric MALT Lymphoma can be entered:
a) H. pylori-negative cases, either de novo (non pretreated) or at relapse following local therapy (i.e., surgery, radiotherapy or antibiotics).
b) H. pylori-positive cases at diagnosis, who either first line antibiotics or further local treatment (surgery or radiotherapy), including patients with:
- clinical (endoscopic) and histological evidence of disease progression at any time post H. pylori eradication;
- clinical (endoscopic) and histological relapse (without H. pylori re-infection), after a remission patients;
- persistent (stable) lymphoma at = 1 year post H. pylori eradication.
1.2. Similar consideration may be applied to patients with ocular adnexal lymphoma treated with antibiotics.
2. SMZL patients in need of therapy.
Either de novo or relapsed following local therapy [including surgery and antiviral therapy for Hepatitis C virus (HCV)]. Patient must have a symptomatic disease requiring treatment and be not eligible for splenectomy or not willing to undergo splenectomy.
2.1. Patients with SMZL can be entered if any of the following criteria is present:
a) bulky progressive or painful splenomegaly;
b) enlarged lymph nodes or involvement of extranodal sites with or without cytopenias, i.e. involvement of ≥3 nodal sites, each with a diameter of ≥3 cm. Any nodal tumor mass with a diameter of ≥7 cm (GELG criteria, as adopted in follicular lymphoma;
c) one of the following symptomatic/progressive cytopenias:
- Hgb < 10 g/dL;
- ANC < 1000/μL:
- PLT< 80 000/μL whatever the reason (autoimmune or hypersplenism or bone marrow infiltration).
2.2. Splenectomised patients with rapidly raising lymphocyte counts, lymphadenopathy or
involvement of extranodal sites can be entered.
2.3. SMZL with concomitant HCV infection who have not responded to or are relapsed after
antiviral therapy can be entered
3. NMZL patients in need of therapy
Either, de novo presenting with disseminated disease or relapsed after local radiotherapy or following antiviral therapy for HCV. Localized nodal MZL is not eligible.
4. Measurable or evaluable disease.
5. Ann Arbor II-IV. Stage I disease may be eligible only if not
candidate to local therapy (surgery or radiotherapy).
6. Age = 18.
7. Life expectancy of at least 1 year.
8. ECOG Performance status 0-2 (see Appendix C).
9. Adequate bone marrow function.
10. Adequate kidney function
11. 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.
12. Fertile male or female patients of childbearing potential and their partners must use higly effective contraception methods during the study and for at least 12 months after the last dose of subcutaneous rituximab and 3 months after the last dose of ibrutinib. In case hormonal methods of birth control is used a barrier method must be added;
13. Ability to understand and the willingness to sign a written informed consent document |
|
| E.4 | Principal exclusion criteria |
1. Any type of lymphoma other than MZL (including MZL with histologic transformation to high-grade lymphoma).
2. Localized (stage IE and IIE) gastric, ocular and cutaneous MALT lymphoma that may benefit from local therapy only (surgery or radiotherapy).
3. Known CNS involvement of MZL.
4. Any previous systemic treatment with immunotherapy or chemotherapy or with BTK inhibitors.
5. Major surgery within 4 weeks prior to registration.
6. History of stroke or intracranial bleeding within 6 months.
7. Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia.
8. Concurrent use of warfarin of other vitamin K antagonists.
9. Concurrent use of strong cytochrome P450 (CYP)3A4/5 inhibitors.
10. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
11. International normalized ratio (INR) or prothrombin time (PT) =1.5 ULN. Partial thromboplastin time (PTT) or activated PTT (aPTT) =1.5 ULN unless due to lupus anticoagulant.
12. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
13. Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions to the compound of ibrutinib and/or rituximab themselves or to the excipients in their formulation).
14. Active HCV or Hepatitis B virus (HBV) infections.
15. HIV infection or immunodeficiency.
16. Pregnancy or breastfeeding.
17. Clinically significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
18. Any serious medical or psychiatric illness likely to interfere with participation in this clinical study.
19. Prior history of malignancies other than MZL within 3 years.
20. Current enrolment or participation in another therapeutic clinical trial within 28 days prior to treatment start. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
a) Complete Response (CR) rate at 12 months
b) PFS at 5 years assessed by the investigators, according to revised response criteria for malignant lymphomas, from study entry to death from any cause or PD |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
a) 12 months after treatment start
b) 5 years after treatment start |
|
| E.5.2 | Secondary end point(s) |
a) Acute and long-term safety evaluated by assessment of laboratory parameters and adverse events coded with NCI Common Toxicity Criteria, version 4.0
b) Complete Response rate at 24 months
c) Overal Response Rate (ORR) at 12 and 24 months
d) Overall Survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) From Informed Consent signature until 28 days after treatment end
b) 24 months after treatment start
c) 12 and 24 months after treatment start
d) From the date of treatment start to the date of death for any cause until 5 years from treatment start |
|
| 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 | No |
| E.6.4 | Safety | No |
| 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 | No |
| 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 | No |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| Belgium |
| France |
| Italy |
| Portugal |
| Switzerland |
|
| 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 | 8 |
| 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 | 8 |
| 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 |
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