A Phase Ib Trial of Zanubrutinib in Combination With R-PolaCHP (ZaR-PolaCHP) for Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Cyclophosphamide
- Conditions
- Diffuse Large B-Cell Lymphoma
- Sponsor
- Yazeed Sawalha
- Enrollment
- 38
- Locations
- 6
- Primary Endpoint
- Incidence of adverse events
- Status
- Suspended
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase Ib trial seeks to find out the best dose and possible side effects and/or benefits of zanubrutinib in combination with the R-PolaCHP in treating patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Zanubrutinib is designed to block a protein called Bruton Tyrosine Kinase in order to stop cancer growth. R-CHOP is the acronym for the combination of five drugs: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. It is the most widely used chemoimmunotherapy regimen for DLBCL and is considered the standard-of-care treatment for patients with DLBCL. Three of the drugs in R-CHOP (cyclophosphamide, doxorubicin and vincristine) are chemotherapy drugs. Rituximab is a type of immunotherapy and prednisone is a type of steroids.
Detailed Description
PRIMARY OBJECTIVE: I. Determine the safety, toxicity profile and recommended phase 2 dose (RP2D) of zanubrutinib in combination with ZaR-PolaCHP (ZaR-PolaCHP) for patients with previously untreated diffuse large B-cell lymphoma (DLBCL). SECONDARY OBJECTIVES: I. Determine the objective response rate (ORR) (complete and partial responses), progression-free survival (PFS) and overall survival (OS) of ZaR-CHOP in patients treated at the RP2D. II. Provide descriptive data on treatment exposure to zanubrutinib and R-CHOP including treatment discontinuation rate and relative dose intensity. EXPLORATORY OBJECTIVES: I. Examine archival tumor samples attained before starting treatment on trial to determine the clinical outcomes of molecularly defined DLBCL subtypes in patients treated with ZaR-Pola-CHP or ZaR-CHOP. II. Measure circulating tumor deoxyribonucleic acid (DNA) (ctDNA) to correlate its presence with response by positron emission tomography (PET) imaging. OUTLINE: This is a dose de-escalation study of zanubrutinib and fixed-dose R-CHOP regimen followed by a dose-expansion study. Patients receive zanubrutinib orally (PO) once or twice daily on days 1-21, rituximab intravenously (IV) on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months for 2 years.
Investigators
Yazeed Sawalha
Principal Investigator
Ohio State University Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed DLBCL, irrespective of cell-of-origin. Patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are eligible only if they have not previously been treated for indolent lymphoma except for local radiation for early-stage disease
- •Patients may have received brief treatment with glucocorticoids (up to 250 mg/day prednisone or equivalent for a maximum of 10 days) and/or 1 cycle of chemotherapy such as R-CHOP (or some component\[s\] thereof) for the diagnosis of B-cell lymphoma provided they had staging computed tomography (CT) and/or positron emission tomography (PET)/CT scans prior to chemotherapy. Treatment must occur within 28 days prior to enrollment
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of zanubrutinib in combination with R-CHOP in patients \<18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =\<
- •Performance status of 3 will be accepted if the impairment is caused by DLBCL complications and improvement is expected once therapy is initiated
- •Measurable disease (defined as \>= 1.5cm in diameter) or at least one PET fludeoxyglucose F-18 (FDG) avid area of disease
- •Patients must have adequate hematologic, hepatic, and renal function as defined below:
- •Hemoglobin \>= 7.0 g/dL
- •Absolute neutrophil count (ANC) \> 1,000/mcL
- •Platelet count \> 75,000/mcL
Exclusion Criteria
- •Major surgery within 4 weeks before Day 1, Cycle 1 of treatment
- •Prior anthracycline use \>= 150 mg/m\^2
- •Known central nervous system (CNS) involvement. Patients at high risk for secondary CNS involvement but without neurologic symptoms suspected to be due to lymphoma are allowed to be enrolled and receive intrathecal chemotherapy with methotrexate, cytarabine, and/or glucocorticoids. Concurrent (during treatment with ZaR-polaCHP) CNS prophylaxis with IV methotrexate is NOT permitted in this study. CNS prophylaxis with IV methotrexate after completing ZaR-PolaCHP treatment and obtaining end-of-treatment response assessment is allowed. Patients who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on the study at the discretion of the principal investigator
- •Active systemic bacterial, fungal or viral infection except for localized fungal infections of skin or nails. Patients with resolving infections such as urinary tract, respiratory, or skin infections may be enrolled if clinically improving. NOTE: patients may be receiving prophylactic antiviral or antibacterial therapies at the investigator's discretion
- •Evidence of current uncontrolled or symptomatic cardiovascular conditions, including, uncontrolled cardiac arrhythmias, history of or symptomatic congestive heart failure (New York Heart Association \[NYHA\] Class III or greater), unstable angina, or myocardial infarction within the past 6 months. Poorly controlled or clinically significant atherosclerotic vascular disease including angioplasty, cardiac or vascular stenting within 6 months of enrollment
- •History of cerebrovascular accident or transient ischemic attack within the 6 months before Day 1, Cycle 1 of treatment
- •Any prior history of intracranial hemorrhage
- •Known bleeding diatheses or platelet dysfunction disorders
- •Known gastrointestinal (GI) disease or gastrointestinal procedure that will significantly interfere with the oral absorption or tolerance of zanubrutinib including the inability to swallow pills/capsules
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
Arms & Interventions
Treatment (zanubrutinib, R-CHOP)
Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Treatment (zanubrutinib, R-CHOP)
Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin Hydrochloride
Treatment (zanubrutinib, R-CHOP)
Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone
Treatment (zanubrutinib, R-CHOP)
Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab
Treatment (zanubrutinib, R-CHOP)
Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine Sulfate
Treatment (zanubrutinib, R-CHOP)
Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Zanubrutinib
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to 24 months
Measured by the Common Terminology Criteria for Adverse Events version 5.0.
Secondary Outcomes
- Objective response rate (ORR)(Up to 5 years)
- Progression-free survival(From the start of treatment to time of progression or death, whichever occurs first, assessed up to 5 years)
- Overall survival (OS)(From start of treatment to death from any cause, assessed up to 5 years)
- Zanubrutinib duration of treatment(Up to 6 cycles (each cycle is 21 days in length))
- Zanubrutinib average daily dose(Up to 6 cycles (each cycle is 21 days in length))
- Zanubrutinib discontinuation rate(Up to 6 cycles (each cycle is 21 days in length))
- Zanubrutinib relative dose intensity(Up to 6 cycles (each cycle is 21 days in length))
- Number of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) cycles received(Up to 6 cycles (each cycle is 21 days in length))
- R-CHOP discontinuation rates(Up to 6 cycles (each cycle is 21 days in length))
- R-CHOP relative dose intensity(Up to 6 cycles (each cycle is 21 days in length))