IRB Study Number 24-573
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objective:
Determine the RP2D and safety of zanubrutinib in combination with ZaR-PolaCHP (ZaR-PolaCHP) for patients with previously untreated DLBCL.
Secondary Objectives:
Determine the objective response rate, progression-free survival and overall survival for patients at the RP2D.
Provide descriptive data on treatment exposure to zanubrutinib and R-PolaCHP including treatment discontinuation rate and relative dose intensity.
Inclusion Criteria
4.1.1. Patients with CD20-positive DLBCL, including one of the following diagnoses by 2016 WHO classification of lymphoid neoplasms: DLBCL, not otherwise specified (NOS) irrespective of cell-of-origin; T-cell/histiocyte-rich large B-cell lymphoma; Epstein-Barr virus-positive DLBCL, NOS. Patients with previously diagnosed indolent lymphoma (follicular lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma but not small lymphocytic lymphoma/chronic lymphocytic leukemia) 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 with High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) and High-grade B-cell lymphoma, NOS are excluded.
4.1.2. Patients must have an International Prognostic Index score ≥ 2 and deemed to require 6 cycles of chemotherapy.
4.1.3. 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 R-PolaCHP [or some component(s) thereof] for the diagnosis of B-cell lymphoma provided they had staging CT and/or PET/CT scans prior to chemotherapy. Treatment must occur within 28 days prior to enrollment. A treatment cycle that contains both cyclophosphamide and doxorubicin will count towards the 6 cycles on therapy (i.e. the cycle off study will count as Cycle 1).
4.1.4. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of zanubrutinib in combination with R-PolaCHP in patients <18 years of age, children are excluded from this study.
4.1.5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix I). Performance Status of 3 will be accepted if the impairment is caused by DLBCL complications and improvement is expected once therapy is initiated.
4.1.6. Measurable disease (defined as ≥ 1.5cm in diameter) or at least one PET FDG avid area of disease
4.1.7. Patients must have adequate hematologic, hepatic, and renal function as defined below.:
4.1.7.1. Hemoglobin ≥ 7.0 g/dL
4.1.7.2. Absolute neutrophil count (ANC) > 1,000/mcL
4.1.7.3. Platelet count > 75,000/mcL
4.1.7.4. Total bilirubin 1.5 x the upper limit of the normal range (ULN) [unless due to Gilbert’s disease]
4.1.7.5. AST (SGOT) < 2.5 x institutional ULN
4.1.7.6. ALT (SGPT) < 2.5 x institutional ULN
4.1.7.7. Creatinine clearance >40 mL/min calculated by Cockcroft-Gault (see Appendix II: Cockcroft-Gault estimation of CrCl):
Patients on dialysis are not eligible.
4.1.7.8. Adequate cardiac function with a left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or MUGA (Multi Gated Acquisition Scan).
4.1.7.9. The effects of zanubrutinib on the developing human fetus are unknown. For this reason and because chemotherapeutic agents used in this study are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks prior to initiation of treatment, for the duration of study participation and for 6 months after completing treatment. Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately. Men must agree to refrain from sperm donation for at least 6 months after the last dose of zanubrutinib.
4.1.7.10. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
4.1.7.11. Patients must have the ability to understand and the willingness to sign a written informed consent document and HIPAA consent document. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
4.1.7.12. International Prognostic Index must be documented:
ECOG performance status ≥2 (1 point)
Age ≥60 (1 point)
≥2 extranodal sites (1 point)
LDH > upper limit of normal (1 point)
Ann Arbor Stage III or IV (1 point)
Is there evidence of transformation from indolent lymphoma? _Yes _No
Exclusion Criteria
4.2.1. Patients planned for dose-attenuated or “mini”-CHOP due to age or other reasons are excluded.
4.2.2. Major surgery within 4 weeks before Day 1, Cycle 1 of treatment.
4.2.3. Prior anthracycline use ≥150 mg/m2
4.2.4. 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. CNS prophylaxis with IV methotrexate is NOT permitted in this study. 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.
4.2.5. 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.
4.2.6. Evidence of current uncontrolled or symptomatic cardiovascular conditions, including, uncontrolled cardiac arrhythmias, history of or symptomatic congestive heart failure (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.
4.2.7. History of cerebrovascular accident or transient ischemic attack within the 6 months before Day 1, Cycle 1 of treatment.
4.2.8. Any prior history of intracranial hemorrhage.
4.2.9. Known bleeding diatheses or platelet dysfunction disorders.
4.2.10. 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.
4.2.11. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
4.2.12. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
4.2.13. Evidence of prior malignancy except for: adequately treated non-melanoma skin cancer, adequately treated in situ carcinoma, low-grade prostate carcinoma (Gleason grade ≤ 6) managed with observation that has been stable for at least 6 months, or any malignancy treated with curative intent and continuously disease-free for at least 3 years.
4.2.14. Participation in other interventional clinical trials, including those with other investigational agents not included in this trial, within 21 days of Day 1, Cycle 1 of this trial. Also excluded are patients who are receiving any other investigational agents outside of a clinical trial.
4.2.15. Known history of HIV, active hepatitis C infection (HCV RNA PCR-positive) and/or active hepatitis B infections (HBV DNA PCR-positive). If HBc antibody is positive, the patient must be evaluated for the presence of HBV DNA by PCR. If HCV antibody is positive, the patient must be evaluated for the presence of HCV RNA by PCR. Patients with positive HBc antibody and negative HBV DNA by PCR are eligible. Patients with positive HCV antibody and negative HCV RNA by PCR are eligible.
4.2.16. Pregnant or breastfeeding women are excluded from this study. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with zanubrutinib, breastfeeding should be discontinued if the mother is treated with zanubrutinib. These potential risks may also apply to other agents used in this study.
4.2.17. Ongoing systemic treatment with a moderate or strong CYP3A inhibitor or inducer. Treatment with any moderate or strong CYP3A inhibitor or inducer needs to be stopped for 5 half-lives prior to starting treatment on trial
