- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03710772
Ibrutinib, Rituximab, Venetoclax, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma
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
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Texas
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Houston, Texas, United States, 77030
- M D Anderson Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
- Creatinine clearance (CLcr) > 50 mL/min
- Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multigated acquisition (MUGA)
- Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated with life expectancy of greater than 3 years. Principal investigator (PI) can use clinical judgement in the best interest of patients
Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test (within 28 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug
- A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
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
Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
- Grapefruit or grapefruit products
- Seville oranges (including marmalade containing Seville oranges)
- Star fruit
- Patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum hepatitis B antibody). Known hepatitis C infection is allowed as long as there is no active disease and is cleared by gastrointestinal (GI) consultation
- Central nervous system with mantle cell lymphoma
- Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior to enrollment
- Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib
- Major surgery within 4 weeks of initiation of therapy or a wound that has not fully healed within 4 weeks of randomization. Clearance letter from primary physician required
- Requires anticoagulation with warfarin or equivalent vitamin K antagonist
- Requires chronic treatment with strong CYP3A inhibitors
- Patients with New York Health Association (NYHA) Class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 bpm), hypotension, light headedness and syncope, persistent and uncontrolled atrial fibrillation
- Recent placement of a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist
- Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of therapy
- Child-Pugh class B or C are excluded
- Vaccinated with live, attenuated vaccines within 4 weeks of randomization
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: 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. |
Given IV
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Given IV
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Given PO
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Given IV
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Given IV
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Given PO or IV
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Given IV
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Given IV
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Given PO
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Experimental: 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. |
Given IV
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Given IV
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Given PO
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Given IV
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Given IV
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Given PO or IV
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Given IV
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Given IV
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Given PO
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Experimental: Group III (ibrutinib, rituximab, venetoclax)
Patients receive ibrutinib, rituximab, venetoclax as in part I. Patients then receive maintenance therapy as in group I.
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Given PO
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Given IV
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Given PO
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Efficacy of ibrutinib plus rituximab combination followed by venetoclax
Time Frame: Up to cycle 12
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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.
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Up to cycle 12
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Incidence of adverse events
Time Frame: Up to 5 years
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Graded according to Common Terminology Criteria for Adverse Events (CTCAE).
The safety is measured by toxicity which is defined as grade 3-4 non-hematologic toxicities within first cycle treatment of venetoclax combined with ibrutinib plus rituximab.
Toxicity data by type and severity will be summarized by frequency tables.
Logistic regression will be utilized to assess the effect of patient prognostic factors on the CR rate and the toxicity rate.
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Up to 5 years
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Progression-free survival (PFS)
Time Frame: Up to 5 years
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The distribution of PFS will be estimated using the method of Kaplan and Meier.
Comparison of PFS by important subgroups will be made using the log-rank test.
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Up to 5 years
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Circulating tumor deoxyribonucleic acid (ctDNA) levels
Time Frame: Up to 5 years
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Descriptive statistics will be used to summarize the ctDNA levels.
Longitudinal analysis will be applied to evaluate the change of over time for each detected variant using mixed-effects model.
Dynamic prediction modeling with time-dependent covariate in survival analysis for PFS will be explored based on ctDNA levels and clinical covariates.
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Up to 5 years
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Luhua (Michael) Wang, M.D. Anderson Cancer Center
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Lymphoma, Non-Hodgkin
- Lymphoma
- Lymphoma, Mantle-Cell
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Antiviral Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Protease Inhibitors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Dermatologic Agents
- Antibiotics, Antineoplastic
- Reproductive Control Agents
- Abortifacient Agents, Nonsteroidal
- Abortifacient Agents
- Folic Acid Antagonists
- Dexamethasone
- Dexamethasone acetate
- BB 1101
- Cyclophosphamide
- Antibodies
- Immunoglobulins
- Venetoclax
- Rituximab
- Doxorubicin
- Liposomal doxorubicin
- Antibodies, Monoclonal
- Antineoplastic Agents, Immunological
- Cytarabine
- Methotrexate
- Vincristine
Other Study ID Numbers
- 2018-0447 (Other Identifier: M D Anderson Cancer Center)
- NCI-2018-02137 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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