Zanubrutinib in Combination With R-PolaCHP (ZaR-PolaCHP) for Newly Diagnosed Diffuse Large B-Cell Lymphoma

NCT ID: NCT04850495

Last Updated: 2025-11-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-16
• Study Completion Date: 2026-06-15

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.

Conditions

Diffuse Large B-Cell Lymphoma; Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma; Transformed Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Given IV

Doxorubicin Hydrochloride

Intervention Type: DRUG

Given IV

Prednisone

Intervention Type: DRUG

Given PO

Rituximab

Intervention Type: BIOLOGICAL

Given IV

Vincristine Sulfate

Intervention Type: DRUG

Given IV

Zanubrutinib

Intervention Type: DRUG

Given PO

Interventions

Cyclophosphamide

Given IV

Intervention Type: DRUG

Doxorubicin Hydrochloride

Given IV

Intervention Type: DRUG

Prednisone

Given PO

Intervention Type: DRUG

Rituximab

Given IV

Intervention Type: BIOLOGICAL

Vincristine Sulfate

Given IV

Intervention Type: DRUG

Zanubrutinib

Given PO

Intervention Type: DRUG

Other Intervention Names

(-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI); ADM; Adriacin; Adriamycin; Adriamycin Hydrochloride; Adriamycin PFS; Adriamycin RDF; ADRIAMYCIN, HYDROCHLORIDE; Adriamycine; Adriblastina; Adriblastine; Adrimedac; Chloridrato de Doxorrubicina; DOX; DOXO-CELL; Doxolem; Doxorubicin HCl; Doxorubicin.HCl; Doxorubin; Farmiblastina; FI 106; FI-106; hydroxydaunorubicin; Rubex; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltasone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Orasone; Panafcort; Panasol-S; Paracort; Perrigo Prednisone; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisone Intensol; Prednisonum; Prednitone; Promifen; Rayos; Servisone; SK-Prednisone; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; MabThera; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituxan; Rituximab ABBS; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar JHL1101; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; Rituximab Biosimilar SIBP-02; rituximab biosimilar TQB2303; rituximab-abbs; RTXM83; Truxima; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Oncovin; Vincasar; Vincosid; Vincrex; Vincristine, sulfate; BGB-3111; Brukinsa; BTK-InhB

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 =< 2. 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
• Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) (unless due to Gilbert's disease)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) < 2.5 x institutional ULN
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 2.5 x institutional ULN
• Creatinine clearance > 40 mL/min calculated by Cockcroft-Gault
• Adequate cardiac function with a left ventricular ejection fraction (LVEF) >= 50% as assessed by echocardiogram or MUGA (Multigated acquisition scan)
• 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 3 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 90 days after the last dose of zanubrutinib
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study
• Patients must have the ability to understand and the willingness to sign a written informed consent document and Health Insurance Portability and Accountability Act (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
• International Prognostic Index must be documented:

• ECOG performance status >= 2 (1 point)
• Age >= 60 (1 point)
• >= 2 extranodal sites (1 point)
• Lactate dehydrogenase measurement (LDH) > upper limit of normal (1 point)
• Ann Arbor Stage III or IV (1 point)
• Is there evidence of transformation from indolent lymphoma?

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
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
• 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
• 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
• Known history of human immunodeficiency virus (HIV), active hepatitis C infection (HCV ribonucleic acid [RNA] polymerase chain reaction [PCR]-positive) and/or active hepatitis B infections (HBV deoxyribonucleic acid [DNA] PCR-positive). If hepatitis B virus core (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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Yazeed Sawalha

OTHER

Sponsor Role: lead

Responsible Party

Yazeed Sawalha

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Yazeed Sawalha, MD

Role: PRINCIPAL_INVESTIGATOR

Ohio State University Comprehensive Cancer Center

Locations

Cleveland Clinic

Cleveland, Ohio, United States

Site Status: RECRUITING

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Site Status: RECRUITING

MUSC

Charleston, South Carolina, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

The Ohio State University Comprehensive Cancer Center

Role: CONTACT

OSUCCCClinicaltrials@osumc.edu

800-293-5066

Anna Krivenko

Role: CONTACT

Anna.Krivenko@osumc.edu

614-366-3872

Facility Contacts

Cancer Answer Line (Taussig)

Role: primary

216-444-7923

Yazeed Sawalha, MD

Role: primary

Yazeed.sawalha@osumc.edu

614-293-0837

Shanta Salzer

Role: primary

salzers@musc.edu

843-792-4271

Related Links

http://cancer.osu.edu

The Jamesline

Other Identifiers

NCI-2021-01332

Identifier Type: REGISTRY

Identifier Source: secondary_id

OSU-20189

Identifier Type: -

Identifier Source: org_study_id