Ibrutinib, Rituximab, Venetoclax, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma
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| ClinicalTrials.gov Identifier: NCT03710772 |
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Recruitment Status :
Active, not recruiting
First Posted : October 18, 2018
Last Update Posted : December 7, 2020
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Sponsor:
M.D. Anderson Cancer Center
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
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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. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy such as, venetoclax, 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Mantle Cell Lymphoma | Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Hydrochloride Drug: Ibrutinib Drug: Methotrexate Biological: Rituximab Drug: Venetoclax Drug: Vincristine | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 54 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | May 1, 2019 |
| Estimated Primary Completion Date : | April 22, 2021 |
| Estimated Study Completion Date : | May 22, 2021 |
| 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 twice daily (BID) on days 2-4, and doxorubicin hydrochloride IV over 24 hours and vincristine IV over 15-30 minutes on day 5 of odd-numbered courses (1, 3, 5, and 7). 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 courses (2, 4, 6, and 8). Treatment repeats every 28 days for up to 8 courses 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. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Ibrutinib Given PO
Other Names:
Drug: Methotrexate Given IV
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Venetoclax Given PO
Other Names:
Drug: Vincristine Given IV
Other Names:
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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 4 courses in the absence of disease progression or unacceptable toxicity. Patience also receive maintenance therapy as in group I. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Ibrutinib Given PO
Other Names:
Drug: Methotrexate Given IV
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Venetoclax Given PO
Other Names:
Drug: Vincristine Given IV
Other Names:
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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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Drug: Ibrutinib
Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Venetoclax Given PO
Other Names:
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Primary Outcome Measures :
- Efficacy of ibrutinib plus rituximab combination followed by venetoclax [ Time Frame: Up to course 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 Outcome Measures :
- Incidence of adverse events [ Time Frame: Up to 5 years ]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.
- Progression-free survival (PFS) [ Time Frame: Up to 5 years ]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.
Other Outcome Measures:
- Circulating tumor deoxyribonucleic acid (ctDNA) levels [ Time Frame: Up to 5 years ]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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| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy
- MCL must be symptomatic and need immediate therapy. Symptoms and nature of MCL include any of the following: a) B-symptoms, b) Mantle Cell Lymphoma International Prognostic Index (MIPI) larger than 3, c) Ki 67 larger than or equal to 30%, d) bulky tumors larger than 10cm or in case of larger than or equal to 2 tumors, each larger than or equal to 5cm in diameter, e) disease threatening organ function, f) elevated lactate dehydrogenase (LDH), g) peripheral blood (PB) white blood cell (WBC) larger than 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, c-MYC or NOTCH genes; l) size of spleen larger than or equal to 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 gastrointestinal, bone marrow or spleen only patients are allowable
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
- Absolute neutrophil count (ANC) larger than or equal to 1000/mm^3 independent of growth factor support
- Platelets larger than or equal to 100,000/mm^3 or larger than or equal to 50,000/mm^3 if bone marrow involvement without necessitating transfusion
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x upper limit of normal (ULN)
- Total bilirubin less than or equal to 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
- Creatinine clearance (CLcr) larger than 50 mL/min
- Cardiac ejection fraction larger than or equal to 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 larger 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 30 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
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: a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal) b. 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
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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
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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] larger than 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate less than 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03710772
Locations
| United States, Texas | |
| M D Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Luhua (Michael) Wang | M.D. Anderson Cancer Center |
Additional Information:
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT03710772 |
| Other Study ID Numbers: |
2018-0447 NCI-2018-02137 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2018-0447 ( Other Identifier: M D Anderson Cancer Center ) |
| First Posted: | October 18, 2018 Key Record Dates |
| Last Update Posted: | December 7, 2020 |
| Last Verified: | December 2020 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Lymphoma Lymphoma, Mantle-Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Cytarabine Dexamethasone Dexamethasone acetate Cyclophosphamide Rituximab Doxorubicin |
Liposomal doxorubicin Methotrexate Vincristine Venetoclax Antineoplastic Agents, Immunological Ichthammol Antibodies Immunoglobulins Antibodies, Monoclonal BB 1101 Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating |