Clinical study of ibrutinib and rituximab in untreated marginal zone lymphomas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Association International Extranodal Lymphoma Study Group (IELSG)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Sep 2019 → ongoing

Decision date (initial)

2024-06-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F. Hoffmann La Roche Ltd · Janssen Pharmaceutica NV

External identifiers

EU CT number

2023-507886-25-00

EudraCT number

2018-002364-44

ClinicalTrials.gov

NCT03697512

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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

Secondary objectives 1

1. To assess the safety of the combination and to evaluate further efficacy parameters

Conditions and MedDRA coding

Previously untreated and symptomatic patients with histologically proven CD20-positive marginal zone B-cell lymphoma (MZL) in need of systemic treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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 1-3 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 (see Appendix B). 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
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 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

Exclusion criteria 21

1. Any type of lymphoma other than MZL (including MZL with histologic transformation to high-grade lymphoma)
2. Any previous systemic treatment with immunotherapy or chemotherapy or with BTK inhibitors.
3. Major surgery within 4 weeks prior to registration
4. History of stroke or intracranial bleeding within 6 months
5. Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia.
6. Concurrent use of warfarin of other vitamin K antagonists
7. Concurrent use of strong cytochrome P450 (CYP)3A4/5 inhibitors
8. Positive test results for hepatitis C. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
9. HIV infection or immunodeficiency
10. Active, severe infections
11. Pregnancy or breastfeeding
12. 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.
13. 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
14. Any serious medical or psychiatric illness likely to interfere with participation in this clinical study
15. Prior history of malignancies other than MZL within 3 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
16. Current enrolment or participation in another therapeutic clinical trial within 28 days prior to treatment start
17. 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).
18. Active HCV or Hepatitis B virus (HBV) infections. Positive test results for chronic HBV infection (defined as positive HBsAg serology).
19. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing and taking specific antiviral prophylaxis, according to local policy. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination are eligible
20. Localized (stage IE and IIE) gastric, ocular and cutaneous MALT lymphoma that may benefit from local therapy only (surgery or radiotherapy).
21. Known CNS involvement of MZL.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 4

1. Acute and long-term safety evaluated by assessment of laboratory parameters and adverse events coded with NCI Common Toxicity Criteria, version 4.0
2. Complete Response rate at 24 months
3. Overal Response Rate (ORR) at 12 and 24 months
4. Overall Survival

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Association International Extranodal Lymphoma Study Group (IELSG)

Sponsor organisation

Association International Extranodal Lymphoma Study Group (IELSG)

Address

Via Vincenzo Vela 6

City

Bellinzona

Postcode

6500

Country

Switzerland

Scientific contact point

Organisation

Association International Extranodal Lymphoma Study Group (IELSG)

Contact name

IELSG Operations Office

Public contact point

Organisation

Association International Extranodal Lymphoma Study Group (IELSG)

Contact name

IELSG Operations Office

Third parties 2

Locations

4 EU/EEA countries · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications