Comparison between rituximab plus zanubrutinib versus rituximab monotherapy in untreated splenic marginal zone lymphoma patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Association International Extranodal Lymphoma Study Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 May 2024 → ongoing

Decision date (initial)

2024-04-29

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

BeOne Medicines

External identifiers

EU CT number

2023-503755-10-00

ClinicalTrials.gov

NCT05735834

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of the trial is to evaluate the efficacy of the addition of zanubrutinib to rituximab versus rituximab monotherapy in subjects with previously untreated SMZL in terms of Progression free Survival (PFS).

Secondary objectives 2

1. To evaluate the activity of the addition of zanubrutinib to rituximab vs rituximab monotherapy in subjects with previously untreated SMZL in terms of Overall Response Rate (ORR), Duration of Response (DoR), and Overall Survival (OS).
2. To evaluate the safety profile of the addition of zanubrutinib to rituximab versus rituximab monotherapy in subjects with previously untreated SMZL.

Conditions and MedDRA coding

Splenic marginal zone lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Ability to understand and willingness to sign a written informed consent in accordance with ICH/GCP regulations before registration and prior to any trial-specific procedures.
2. Female subjects who are of non-reproductive potential and female subjects of childbearing potential with a negative serum pregnancy test upon study entry.
3. Male and female subjects who agree to use highly effective methods of birth control during the period of therapy and for 12 months after the last dose of rituximab and 30 days after the last dose of zanubrutinib.
4. Confirmed diagnosis of SMZL, including Matutes immunophenotype score <3. Evaluation of the following features is desirable: absence of CD103, expression by flow cytometry, absence of Cyclin D1, BCL6, and CD10 expression by immunohistochemistry, and absence of the MYD88 L265P mutation. Patients with prominent splenomegaly and involvement of the splenic hilar and/or extra hilar lymph nodes are eligible.
5. Previously untreated disease. Patients with prior hepatitis C virus (HCV) infection who underwent HCV eradication and have persistent SMZL after 3 months post-eradication can be included.
6. Treatment needs according to the ESMO guideline criteria.
7. Measurable lesions
8. Age ≥ 18 years.
9. European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
10. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, platelet count ≥ 50 x 109/L, Hb > 7.5 g/dl. Values below such thresholds are allowed if attributable to the underlying lymphoma. Transfusions are allowed if clinically indicated during screening.
11. Adequate hepatic and renal function and coagulation parameters
12. Patient able and willing to swallow trial drugs as whole tablet/capsule.

Exclusion criteria 15

1. Previous splenectomy
2. Any uncontrolled active systemic infection requiring intravenous antimicrobial treatment, known human immunodeficiency virus (HIV) infection, active COronaVIrus Disease 19 (COVID-19) infection, presence of viral hepatitis B surface antigen (HBsAg) or viral hepatitis B core antibody (HBcAb), Presence of HCV antibody
3. Active, uncontrolled autoimmune phenomenon
4. Concomitant treatment with strong CYP3A inducers or inhibitors.
5. Any systemic therapy for SMZL.
6. Patients with central nervous system (CNS) involvement.
7. Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer.
8. Clinically significant cardiovascular disease
9. History of cerebrovascular accident or intracranial hemorrhage within 6 months before registration and known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
10. History of confirmed progressive multifocal leukoencephalopathy
11. Concomitant diseases that require anticoagulant therapy with warfarin or phenprocoumon or other vitamin K antagonists and patients treated with dual anti-platelet therapy. Patients being treated with factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e. dabigatran) low molecular weight heparin (LMWH), or single anti-platelet agents (eg. aspirin, clopidogrel) can be included but must be properly informed about the potential risk of bleeding
12. Malabsorption syndrome or other condition that precludes the enteral route of administration
13. Other sever acute or chronic medical or psychiatric condition or laboratory abnormalities which may increase the risk associates with trial participation and/or would make the patient inappropriate for enrolment into this trial.
14. Pregnancy or breastfeeding.
15. Concurrent participation in another therapeutic clinical trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Investigator-assessed PFS rate at 3 years according to the Lugano 2014 criteria

Secondary endpoints 8

1. Investigator-assessed complete remission rates achieved at 12 and 24 months of treatment, assessed according to the Lugano 2014 criteria.
2. Investigator-assessed best response achieved at any time during the treatment period (24 months) assessed according to the Lugano 2014 criteria
3. Investigator-assessed complete remission rates achieved at 12 and 24 months of treatment, assessed according to the Matutes criteria
4. Investigator-assessed best response achieved at any time during the treatment period (24 months) assessed according to the Matutes criteria
5. Investigator-assessed Time to next anti-lymphoma treatment (TTNT) according to the Lugano 2014 criteria
6. Investigator-assessed duration of response according to the Lugano 2014 criteria
7. Overall Survival according to the Lugano 2014 criteria
8. Analysis of type and severity of adverse events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Association International Extranodal Lymphoma Study Group

Sponsor organisation

Association International Extranodal Lymphoma Study Group

Address

Via Vincenzo Vela 6

City

Bellinzona

Postcode

6500

Country

Switzerland

Scientific contact point

Organisation

Association International Extranodal Lymphoma Study Group

Contact name

IELSG Operation Office

Public contact point

Organisation

Association International Extranodal Lymphoma Study Group

Contact name

IELSG Operation Office

Third parties 1

Locations

7 EU/EEA countries · 42 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 95 files

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

Application history

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