A Phase II Study of Ibrutinib Plus Rituximab Followed by Venetoclax and Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma: Window II Protocol
Overview
- Phase
- Phase 2
- Intervention
- Cyclophosphamide
- Conditions
- Mantle Cell Lymphoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 51
- Locations
- 1
- Primary Endpoint
- Efficacy of ibrutinib plus rituximab combination followed by venetoclax
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
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 that may interfere with the ability of cancer cells to grow and spread. 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. Giving ibrutinib, rituximab, and venetoclax together with combination chemotherapy may work better in treating patients with mantle cell lymphoma.
Detailed Description
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. Developing a novel biomarker for minimal residual disease (MRD) assay using the circulating tumor deoxyribonucleic acid (DNA) (ctDNA) assay on a customized capture sequencing gene panel for MCL using serial plasma samples collected in this trial. 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. 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. 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. GROUP III: Patients receive maintenance therapy as in group I. 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy
- •MCL patients must have a clinical indication to start systemic therapy. Symptoms and features of MCL include any of the following: a) B-symptoms, b) Mantle Cell Lymphoma International Prognostic Index (MIPI) \> 3, c) Ki 67 \>= 30%, d) bulky tumors \> 10 cm or in case of \>= 2 tumors, each \>= 5 cm in diameter, e) disease threatening organ function, f) elevated lactate dehydrogenase (LDH), g) peripheral blood (PB) white blood cell (WBC) \> 50,000, h) pancytopenia due to bone marrow MCL, i) patient's choice due to anxiety; j) pain due to lymphoma; k) somatic mutations in the TP53, NSD2 or NOTCH genes; l) size of spleen \>= 20 cm
- •Newly diagnosed MCL with no prior therapy
- •Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study
- •Bi-dimensional measurable disease using both computed tomography (CT) scan and/or positron emission tomography (PET)-CT or gastrointestinal biopsies, CT gastrointestinal, bone marrow or spleen only patients are allowable
- •Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
- •Absolute neutrophil count (ANC) \>= 1000/mm\^3 independent of growth factor support
- •Platelets \>= 100,000/mm\^3 or \>= 50,000/mm\^3 if bone marrow involvement without necessitating transfusion
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x upper limit of normal (ULN)
- •Total bilirubin =\< 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
Exclusion Criteria
- •Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion, places the patient at unacceptable risk or would prevent the subject from signing the informed consent form
- •Pregnant or breast-feeding females
- •Known human immunodeficiency virus (HIV) infection (HIV testing is not required)
- •Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
- •Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
- •Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface \[HBs\] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core \[HBc\] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
- •Treatment with any of the following within 7 days prior to the first dose of study drug:
- •Steroid therapy for anti-neoplastic intent
- •Moderate or strong cytochrome P450 3A (CYP3A) inhibitors
- •Moderate or strong CYP3A inducers
Arms & Interventions
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Cyclophosphamide
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Cytarabine
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Dexamethasone
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Doxorubicin Hydrochloride
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Ibrutinib
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Methotrexate
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Rituximab
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Venetoclax
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Doxorubicin Hydrochloride
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as described in part 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 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.
Intervention: Vincristine Sulfate
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Cyclophosphamide
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Cytarabine
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Dexamethasone
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Ibrutinib
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Methotrexate
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Rituximab
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Venetoclax
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)
Patients receive ibrutinib, rituximab, and venetoclax as in part I. 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.
Intervention: Vincristine Sulfate
Group III (ibrutinib, rituximab, venetoclax)
Patients receive ibrutinib, rituximab, venetoclax as in part I. Patients then receive maintenance therapy as in group I.
Intervention: Ibrutinib
Group III (ibrutinib, rituximab, venetoclax)
Patients receive ibrutinib, rituximab, venetoclax as in part I. Patients then receive maintenance therapy as in group I.
Intervention: Rituximab
Group III (ibrutinib, rituximab, venetoclax)
Patients receive ibrutinib, rituximab, venetoclax as in part I. Patients then receive maintenance therapy as in group I.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Efficacy of ibrutinib plus rituximab combination followed by venetoclax
Time Frame: Up to cycle 12
Determined by complete response (CR). The complete response after 4 cycles of venetoclax combined with ibrutinib plus rituximab and toxicity within first cycle of venetoclax combination will be monitored simultaneously using the Bayesian stopping boundaries calculated based on beta-binomial distributions. The prior probabilities of response and toxicity are modeled by beta distributions. Complete response and its 95% confidence interval will be calculated. Logistic regression will be utilized to assess the effect of patient prognostic factors on the CR rate and the toxicity rate.
Secondary Outcomes
- Progression-free survival (PFS)(Up to 5 years)
- Incidence of adverse events(Up to 5 years)