This phase II trial studies how well ibrutinib and rituximab given together with venetoclax and combination chemotherapy work in treating patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Drugs used in chemotherapy such as, cyclophosphamide, vincristine, doxorubicin, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s DNA and may kill cancer cells. It may also lower the body’s immune response. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell’s DNA and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving ibrutinib, rituximab, and venetoclax together with combination chemotherapy may work better in treating patients with mantle cell lymphoma.
Additional locations may be listed on ClinicalTrials.gov for NCT03710772.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To determine the complete response rate of the ibrutinib plus rituximab combination followed by venetoclax in newly diagnosed young mantle cell lymphoma (MCL) patients.
SECONDARY OBJECTIVES:
I. To determine the safety profile of the ibrutinib plus rituximab combination followed by venetoclax in newly diagnosed young MCL patients.
II. To evaluate the progression-free survival and overall survival time of the ibrutinib plus rituximab combination followed by venetoclax and hyper-fractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in newly diagnosed young MCL patients.
EXPLORATORY OBJECTIVE:
I. Identifying the biomarker for response and resistance, using whole exome, ribonucleic acid (RNA) sequencing, immune profile and cytokine/chemokine analysis and serial minimal residual disease (MRD), clonal evolution using the serial RNA sequencing for B cell receptor clonotypes.
OUTLINE:
PART I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and receive rituximab intravenously (IV) over 4-8 hours on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3-12. Patients also receive venetoclax PO QD on days 1-28 of cycles 5-12. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening, and undergo the collection of blood samples, computed tomography (CT), and chest x-ray throughout the trial. Patients may undergo bone marrow biopsy (BMB) and bone marrow aspiration (BMA), colonoscopy or endoscopy, and positron emission tomography (PET)/CT throughout the trial as clinically indicated.
PART II: Patients are assigned to 1 of 3 groups depending on risk status.
GROUP I:
COMBINATION CHEMOTHERAPY: Patients receive rituximab IV over 6 hours on day 1, dexamethasone PO or IV on days 1-4, cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4, and doxorubicin hydrochloride IV over 24 hours and vincristine sulfate IV over 15-30 minutes on day 5 of odd-numbered cycles (1 and 3). Patients also receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours BID on days 3-4 of even-numbered cycles (2 and 4). Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive ibrutinib and venetoclax PO QD on days 1-28, and rituximab IV over 4-8 hours on day 1 of every other month. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA at screening, and undergo the collection of blood samples, CT, and chest x-ray throughout the trial. Patients may undergo BMB and BMA, colonoscopy or endoscopy, and PET/CT throughout the trial as clinically indicated.
GROUP II: Patients receive combination chemotherapy as in group I. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive maintenance therapy as in group I. Patients also undergo ECHO or MUGA at screening, and undergo the collection of blood samples, CT, and chest x-ray throughout the trial. Patients may undergo BMB and BMA, colonoscopy or endoscopy, and PET/CT throughout the trial as clinically indicated.
GROUP III: Patients receive maintenance therapy as in group I. Patients also undergo ECHO or MUGA at screening, and undergo the collection of blood samples, CT, and chest x-ray throughout the trial. Patients may undergo BMB and BMA, colonoscopy or endoscopy, and PET/CT throughout the trial as clinically indicated.
After completion of study treatment, patients are followed up at 30 days, every 4 months for 2 years, every 6 months for 2 years, and then annually for up to 5 years.
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorLuhua (Michael) Wang
