Zanubrutinib in Combination With Pola-R-CHP and High-dose Methotrexate in Patients With Secondary CNS Lymphoma

NCT06730542 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 20240458
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to is to determine the effects (good and bad) of Zanubrutinib in Combination with Pola-R-CHP and High-dose Methotrexate in patients with Secondary Central Nervous System (CNS) Lymphoma.

Conditions

CNS Lymphoma

Outcome Measures

Primary Outcomes (1)

• Number of participants experiencing dose-limiting toxicities (DLTs)

  The number of participants experiencing dose-limiting toxicities (DLTs) after starting study therapy. Toxicity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, per physician discretion.

  Up to 21 days

Secondary Outcomes (6)

• Overall Response Rate (ORR)

  Up to 5 years

• Number of Patients achieving conversion from PR to CR

  Up to 5 years

• Progression-Free Survival (PFS)

  Up to 5 years

• Overall Survival (OS)

  Up to 5 years

• Number of participants experiencing treatment-related adverse events (AEs)

  Up to 42 months

Study Arms (1)

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

EXPERIMENTAL

Participants will be in this group for up to 2 years

Drug: Zanubrutinib; Drug: Methotrexate; Drug: Polatuzumab Vedotin; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Prednisone

Interventions

Zanubrutinib DRUG

Zanubrutinib capsules will be self-administered orally by participants at a starting dose of 160 mg twice a day (BID) or 320 mg once a day (QD)\* at the beginning of Cycle 2 of Pola-R-CHP therapy.

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Methotrexate DRUG

Participants will receive Methotrexate as per standard of care (SOC).

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Polatuzumab Vedotin DRUG

Participants will receive Polatuzumab Vedotin as per standard of care (SOC).

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Rituximab DRUG

Participants will receive Rituximab as per standard of care (SOC), as part of combination standard of care Pola-R-CHP therapy.

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Cyclophosphamide DRUG

Participants will receive Cyclophosphamide as per standard of care (SOC), as part of combination standard of care Pola-R-CHP therapy.

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Doxorubicin DRUG

Participants will receive Doxorubicin as per standard of care (SOC), as part of combination standard of care Pola-R-CHP therapy.

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Prednisone DRUG

Participants will receive Prednisone as per standard of care (SOC), as part of combination standard of care Pola-R-CHP therapy.

Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women ≥ 18 years of age on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).
• Patients must have histologic confirmation of large B-cell lymphoma (LBCL) defined by the World Health Organization (WHO) classification. All LBCL subtypes are acceptable. Note: Patients with prior treatment for indolent lymphoma are still eligible for participation as long as they did not receive anthracycline-based therapy.
• Baseline 18-fluorodeoxyglucose (FDG)-positron emission tomography scan/computed tomography (PET/CT) must demonstrate FDG avid lesions compatible with CT-defined anatomical tumor sites (Note: FDG-PET/CT is not mandatory, and patients with CT scans only will be eligible for study entry as well). Patients should have at least 1 measurable site of disease per Lugano classification in FDG-PET/CT or CT scans.
• Presence of systemic and CNS involvement (brain, cerebellum, brainstem, meninges, cranial nerves, eyes, spinal cord, or a combination of these) at presentation.
• Determination of CNS involvement can be by brain biopsy, cerebrospinal fluid (CSF) evaluation by cytology and/or flow cytometry, neuroimaging, or strong clinical suspicion by Investigator for which CNS targeted therapy is recommended (ie, numb chin syndrome in patients with high CNS involvement risk).
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, except due to lymphoma involvement.
• Life expectancy of greater than ≥ 3 months.
• Women should avoid becoming pregnant while taking zanubrutinib and for up to 90 days after ending treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures while taking zanubrutininb and for up to 90 days after stopping treatment. It is currently unknown whether zanubrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Pregnancy testing is recommended for women of reproductive potential prior to initiating therapy.
• Agreement to use contraception during study participation.
• Female patients of childbearing potential must use highly effective methods of contraception. Recommended acceptable contraception methods are included in Section 5.12.
• Patients using hormonal contraceptives (eg, birth control pills or devices) must use a barrier method of contraception (eg, condoms) as well.
• A woman is considered of childbearing potential, ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
• A post-menopausal state is defined as no menses for 12 months without an alternative medical cause.
• Male patients with a female partner of childbearing potential are eligible if they abstained, are vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for 90 days after the last dose of zanubrutinib.
• Patients must have normal organ and marrow function as defined below:

You may not qualify if:

• Primary CNS lymphoma without evidence of systemic lymphoma.
• Prior systemic lymphoma therapy (Note: 1 cycle of an anthracycline based regimen, such as rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP), polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP), dose-adjusted etoposide phosphate, prednisone, oncovin, cyclophosphamide, hydroxydaunorubicin, and rituximab (EPOCH-R), or rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-Codox-M), and/or 1 dose of intrathecal therapy, will be allowed before enrollment \[Section 5.9\]). Note: Patients with prior treatment for indolent lymphoma are still eligible for participation as long as they did not receive anthracycline-based therapy.
• Any uncontrolled or clinically significant cardiovascular disease including the following:
• Myocardial infarction within 6 months before screening;
• Unstable angina within 3 months before screening;
• New York Heart Association class III or IV congestive heart failure;
• History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
• Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure measurements showing systolic blood pressure \> 170 mm Hg and/or diastolic blood pressure \> 105 mm Hg at screening.
• QT interval corrected with Fridericia's formula (QTcF) \> 450 msec or other significant electrocardiogram (EKG) abnormalities, including second-degree atrioventricular block Type II or third-degree atrioventricular block.
• Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
• Uncontrolled intercurrent illness such as liver cirrhosis, autoimmune disorder requiring immunosuppression or long-term corticosteroids (\> 10 mg daily prednisone equivalent), or any other serious medical condition, laboratory abnormality, or psychiatric illness which would compromise ability to comply with study procedures.
• Severe or debilitating pulmonary disease.
• Concurrent malignancy requiring active therapy.
• Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.
• Active fungal, bacterial and/or viral infection requiring systemic therapy.

Sponsors & Collaborators

• Juan P. Alderuccio, MD: lead
• BeiGene: collaborator

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

RECRUITING

MeSH Terms

Interventions

zanubrutinib; Methotrexate; polatuzumab vedotin; Rituximab; Cyclophosphamide; Doxorubicin; Prednisone

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Study Officials

• Juan P Alderuccio, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Juan P Alderuccio, MD

CONTACT

+1 (347) 9312272; jalderuccio@med.miami.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Clinical

Study Record Dates

• First Submitted: December 9, 2024
• First Posted: December 12, 2024
• Study Start: April 17, 2025
• Primary Completion (Estimated): April 30, 2030
• Study Completion (Estimated): April 30, 2030
• Last Updated: May 8, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)