Ibrutinib and Rituximab for the Treatment of Treatment Naive Marginal Zone Lymphoma
This phase III trial studies how well ibrutinib and rituximab work compared with rituximab alone in treating patients with marginal zone lymphoma who have not received prior treatment for the disease (treatment naive). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving ibrutinib and rituximab may work better in treating patients with marginal zone lymphoma compared to rituximab alone.
Inclusion Criteria
- Histologically documented marginal zone lymphoma, including splenic, nodal, and extranodal sub-types at the enrolling institution
- No prior systemic therapy for MZL with the exception of the following: * Prior antibiotic therapy for Helicobacter (H.) pylori, Chlamydophila (C.) psittaci, and Borrelia (B.) burgdorferi * Prior antiviral therapy for hepatitis C virus (HCV) * Note: Subjects are eligible if they had prior splenectomy or other local surgical treatment or local radiation therapy without systemic therapy and now require their first ever systemic therapy
- Men and women >= 18 years of age
- Patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma must be H. pylori negative or have failed a trial of H. pylori eradication
- Patients with gastric MALT lymphoma who are H. pylori negative or who have relapsed/refractory disease after H. pylori eradication must be ineligible for, have refused or failed gastric radiation therapy
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- >= 1 measurable lesion on computed tomography (CT) scan (> 1.5 cm in longest dimension) unless bone marrow disease only including those with hemolytic anemia. Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by magnetic resonance imaging (MRI) instead. Patients with splenomegaly without other measurable disease must have splenomegaly of > 15 cm in the craniocaudal direction
- Life expectancy of > 3 months, in the opinion of the investigator
- Female subjects must be of non-reproductive potential (i.e., post-menopausal by history - no menses for >= 2 years; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
- Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 12 months (females) and 90 days (males) after the last dose of study drug
- Documented evidence of need for treatment, including, but not limited to, threatened end-organ function, bulky disease (> 5 cm), symptoms, requirement for transfusion or growth factor support, or medically significant need for intervention
- For subjects with presumptive evidence of transformation based on clinical assessment of factors such as, but not limited to, increasing lactate dehydrogenase (LDH), rapidly worsening disease, or frequent B-symptoms, both a pre-treatment tumor biopsy and bone marrow biopsy are required to rule out large cell transformation. For all subjects, results of both the tumor biopsy and bone marrow biopsy must be known prior to enrollment and randomization
Exclusion Criteria
- Medically apparent central nervous system lymphoma or leptomeningeal disease
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible
- Subject who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to first dose of ibrutinib/placebo or subject who requires continuous treatment with a strong CYP3A inhibitor
- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration of > 20 mg/day of prednisone) within 28 days of the first dose of study drug
- Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmias or class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification; or a history of unstable angina, acute coronary syndrome, or myocardial infarction within 6 months of prior to screening
- Recent infection requiring systemic anti-infective treatment that was completed =< 14 days before the first dose of study drug
- Any uncontrolled active systemic infection
- Known bleeding diathesis (e.g., von Willebrand’s disease) or hemophilia
- Hepatitis B (hepatitis B virus [HBV]): All subjects must be screened for hepatitis B and C. Subjects with a positive polymerase chain reaction for hepatitis B must be on entecavir or equivalent therapy as per institutional standard of care. (Hepatitis [Hep] C patients may be enrolled if other parameters precluding hepatic impairment are met. And they are not undergoing active therapy for hepatitis C)
- Human immunodeficiency virus (HIV): NOTE: HIV is a contraindication if the subject has an active opportunistic infection (OI) within 12 months and CD4 count is below the normal range
- Absolute neutrophil count (ANC) < 750 cells/mm^3 (0.75 x 10^9/L) unless there is documented bone marrow involvement
- Platelet count < 50,000 cells/mm^3 (50 x 10^9/L) independent of transfusion support unless there is documented bone marrow involvement
- Serum aspartate transaminase (AST) or alanine transaminase (ALT) >= 3.0 x upper limit of normal (ULN)
- Creatinine > 2.0 x ULN or estimated glomerular filtration rate (GFR) (Cockcroft-Gault) < 30 mL/min
- Hemoglobin < 8.0 g/dL unless secondary to hemolysis or documented bone marrow involvement
- Bilirubin > 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
- Prothrombin time (PT)/international normalized ratio (INR) > 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) > 1.5 x ULN unless factor XI deficiency or lupus anticoagulant
- Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction
- Major surgery within 4 weeks prior to the first dose of study drug
- Any life-threatening illness, medical condition, including uncontrolled diabetes mellitus (DM), or organ system dysfunction that, in the opinion of the investigator, could compromise the subject’s safety or put the study outcomes at undue risk
- Lactating or pregnant
- Unwilling or unable to participate in all required study evaluations and procedures
- Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
- Subjects with chronic liver disease with hepatic impairment Child-Pugh class B or C
Additional locations may be listed on ClinicalTrials.gov for NCT04212013.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To compare the efficacy of rituximab and ibrutinib versus (vs) rituximab and placebo in subjects with treatment naive marginal zone lymphoma (MZL) using complete response rate at 30 months after randomization as assessed by investigator response per Response Evaluation Criteria In Lymphoma (RECIL).
SECONDARY OBJECTIVES:
I. To compare efficacy parameters such as the overall response rate (ORR), including the complete response (CR) and partial response (PR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) to rituximab and ibrutinib vs rituximab and placebo in subjects with treatment naive MZL.
II. To evaluate the safety (frequency, severity and relatedness of adverse events [AE’s]); frequency of AE’s requiring discontinuation of study drug or dose reductions and tolerability of rituximab and ibrutinib vs rituximab and placebo in subjects with treatment naive MZL.
EXPLORATORY OBJECTIVES:
I. To evaluate prognostic and predictive biomarkers relative to treatment outcomes.
II. Evaluate quality of life using the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L) instrument.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response at 30 months discontinue ibrutinib. Patients also receive rituximab intravenously (IV) on days 1, 8, 15, 22 of cycle 1 (or beginning on day 8, rituximab and hyaluronidase human subcutaneously [SC] over 5 minutes instead of rituximab) in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive placebo PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response at 30 months discontinue placebo. Patients also receive rituximab IV on days 1, 8, 15, 22 of cycle 1 (or beginning on day 8, rituximab and hyaluronidase human SC over 5 minutes instead of rituximab) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months until progressive disease or use of alternative antineoplastic therapy, and then every 6 months for up to 5 years.
Trial PhasePhase III
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorAriela Noy
- Primary ID19-243
- Secondary IDsNCI-2019-08879
- ClinicalTrials.gov IDNCT04212013