Zanubrutinib With Pemetrexed to Treat Relapsed/Refractory Primary and Secondary Central Nervous System (CNS) Lymphomas

NCT05681195 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2021-LIN-001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being conducted to evaluate the safety and efficacy of the combination of pemetrexed and zanubrutinib (called induction therapy) followed by zanubrutinib treatment alone (also called maintenance therapy) in people who have relapsed or refractory (RR) primary central nervous system lymphoma (PCNSL) or isolated central nervous system relapse of B cell lymphoma (SCNSL). Assessments include how well people respond to this treatment, whether their disease gets better or worse, and their survival. Safety of this treatment and its side effects also will be assessed.

Conditions

Primary Central Nervous System Lymphoma; Secondary Central Nervous System Lymphoma; Relapsed Cancer; Refractory Cancer

Outcome Measures

Primary Outcomes (1)

• Best Overall Response Rate (ORR) to Induction Therapy

  Best ORR to induction therapy is defined as the best response between the start of induction therapy until the end of induction therapy based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

  6 months

Secondary Outcomes (10)

• Best Overall Response Rate (ORR) after transplant, WBRT + zanubrutinib maintenance, or zanubrutinib maintenance alone

  5 years

• Complete Response (CR) Rate to induction therapy

  6 months

• Complete Response (CR) Rate after transplant, WBRT + zanubrutinib maintenance, or zanubrutinib maintenance alone

  5 years

• Duration of Response (DOR)

  5 years

• Duration of Complete Response (DOCR)

  5 years

Study Arms (1)

Induction Therapy + SOC Treatment

EXPERIMENTAL

Participants will receive the induction therapy (oral zanubrutinib + IV pemetrexed) and be placed into one of the cohorts according to standard of care (SOC) treatment: Cohort 1: Induction Therapy + Autologous Stem Cell Transplant (ASCT) After completion of the induction therapy, ASCT candidates will undergo transplant as per SOC. If the transplant is delayed and 8 induction cycles have been completed, oral zanubrutinib maintenance will proceed until transplant, but will not occur after transplant. Cohort 2: Induction Therapy + Whole Brain Radiation Therapy (WBRT) After completion of the induction therapy, WBRT candidates will undergo WBRT as per SOC. Oral zanubrutinib maintenance will start 7-10 days after the completion of WBRT. 28-d maintenance cycles will continue until disease progression. Cohort 3: Induction Therapy Alone After completion of the induction therapy, 28-day oral zanubrutinib maintenance cycles will begin and continue until disease progression

Drug: Pemetrexed; Drug: Zanubrutinib; Procedure: Autologous Stem Cell Transplant (ASCT); Radiation: Whole Brain Radiation Therapy (WBRT)

Interventions

Pemetrexed DRUG

Participants will receive 900 mg/m\^2 via IV infusion over 10 minutes every 3 weeks x 4-8 induction cycles (21 days per cycle) as part of the induction therapy.

Also known as: Alimta

Induction Therapy + SOC Treatment

Zanubrutinib DRUG

Participants will receive 320 mg PO daily or dose-adjusted when given concomitantly with CYP3A4 inhibitor on Days 3-19 of each induction cycle x 4-8 cycles (21 days per cycle) as part of the induction therapy. For those on maintenance therapy, participants will receive 320 mg PO daily or dose-adjusted when given concomitantly with CYP3A4 inhibitor on Days 1-28 of each maintenance cycle (28 days per cycle) until the transplant (if applicable) or disease progression.

Also known as: Brukinsa

Induction Therapy + SOC Treatment

Autologous Stem Cell Transplant (ASCT) PROCEDURE

ASCT will occur in participants who are candidates for this procedure according to standard of care institutional protocols

Induction Therapy + SOC Treatment

Whole Brain Radiation Therapy (WBRT) RADIATION

WBRT will occur in participants who are candidates for this procedure but not candidates for ASCT according to standard of care institutional protocols

Induction Therapy + SOC Treatment

Eligibility Criteria

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

You may qualify if:

• Any of the following diseases histologically confirmed:
• Primary CNS lymphoma or isolated secondary CNS involvement by diffuse large B cell lymphoma with measurable disease
• Cytologic diagnosis of B cell non-Hodgkin's lymphoma with measurable disease
• Ocular lymphoma with histologic confirmation of ocular lymphoma and measurable intracranial tumor. Slit-lamp examination and vitreal or retinal biopsy will be done to confirm ocular lymphoma.
• Karnofsky performance status (KPS) ≥ 30% (≥ 50% for patients ≥ 60 years-old)
• Progressed during first-line chemotherapy and/or radiotherapy -OR- insufficient clinical response to previous therapy or relapsed after initial successful treatment OR unable to tolerate previous therapy defined as Grade 3+ acute kidney injury (AKI) and/or transaminase elevation according to CTCAE v 5.0 criteria preventing repeat treatment exposure OR prior glucarpidase use due to high dose methotrexate delayed clearance and/or toxicity OR those who would have been glucarpidase candidates due to delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered or toxic plasma methotrexate concentrations (\>1 micromole per liter) in patients with delayed methotrexate clearance) due to impaired renal function OR unable to receive high dose methotrexate induction on every 2 week +/- 3 days schedule due to deconditioning and/OR need for physical rehabilitation between the high dose methotrexate treatments
• No systemic lymphoma by positron emission tomography (PET) CT or CT scan of the chest, abdomen, and pelvis with contrast
• Adequate bone marrow and organ function demonstrated by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
• Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days prior to study enrollment
• Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study enrollment
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
• Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome
• Creatinine Clearance (CrCl)\> 45 mL/minute using Cockcroft-Gault formula
• Ability to understand and sign written informed consent prior to study entry unless the subject suffers from cognitive or physical impairment due to their CNS malignancy or due to a known underlying medical condition in which case consent could be signed by proxy

You may not qualify if:

• Serious uncontrolled concurrent illness or comorbid condition
• Other active systemic malignancy except for basal cell carcinoma of the skin, cervical carcinoma in situ or very low and low risk prostate cancer under observation. Patients with a remote history (3 years or more) of malignancy are eligible for the protocol in the absence of active disease
• Concurrent chronic systemic immune therapy, targeted therapy not indicated in this study protocol
• Unable to comprehend the study requirements or who are not likely to comply with the study protocol
• Prior participation in chemotherapy, cytotoxic therapy, immunotherapy, radiation therapy or therapeutic protocols within 2 weeks of protocol treatment
• Pregnant (confirmed by serum or urine β-HCG) or lactating
• Transaminases \> 3 times above the upper limits of the institutional normal
• Patients must not have pre-existing immunosuppression, concurrent immunosuppressive treatment with the exception of dexamethasone, or low dose prednisone with a total dose equivalent to 15 mg of prednisone a day or less for chronic conditions. Allogeneic stem cell transplant recipients as well as other organ transplant recipients are excluded. Autologous stem cell transplant recipients will qualify if relapse occurs at one year after the stem cell transplantation. Short course of dexamethasone up to 40 mg orally or intravenously daily with or without taper for CNS lymphoma symptom control is allowed.
• Patients should not have active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (e.g., idiopathic thrombocytopenia purpura).
• Non-healing wound, ulcer or bone fracture
• Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia
• Cerebrovascular accident or intracranial hemorrhage within 6 months of the study treatment; arterial or venous thrombotic or embolic event such as deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment. Patients with upper extremity catheter-related deep venous thrombosis will not be excluded.
• Concurrent use of warfarin or other vitamin K antagonists (need to be stopped 7 days prior to starting on trial drug)
• Infectious disease: HIV positive patients with positive viral load and CD4+ count \< 400 are excluded. HIV patients must have established and consistent infectious disease specialist care. HIV positive patients have to agree for every 12-week monitoring of viral load. Patients with the emergence of HIV viral load on the trial treatment will be referred to the infectious disease specialist and can continue on the trial treatment unless recommended to stop by the infectious disease specialist and PI. If the viral load reaches 100,000 copies per milliliter or above, the patient would be referred to an infectious disease specialist for and evaluation and would be taken off the trial.
• Patients with presence of HCV antibody are eligible if HCV RNA is undetectable and if they are willing to undergo monitoring for HCV reactivation every 12 weeks. HCV patients will be taken off trial if there is 1 log increase in viral load after the initial detection of HCV viral load regardless of liver function tests (LFTs). Patients will be referred promptly to hepatology specialist with the first detectable viral load.

Sponsors & Collaborators

• Baptist Health South Florida: lead
• BeiGene: collaborator

Study Sites (1)

Miami Cancer Institute at Baptist Health, Inc.

Miami, Florida, 33176, United States

RECRUITING

Related Links

• Miami Cancer Institute at Baptist Health, Inc.

MeSH Terms

Conditions

Recurrence; Neoplasms

Interventions

Pemetrexed; zanubrutinib

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Yuliya Linhares, M.D.

  Miami Cancer Institute at Baptist Health, Inc.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yuliya Linhares, M.D.

CONTACT

(786) 596-2000; YuliyaL@baptisthealth.net

Allison Miller

CONTACT

(786) 527-8519; Allison.Miller@baptisthealth.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 8, 2022
• First Posted: January 12, 2023
• Study Start: April 25, 2024
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2033
• Last Updated: March 3, 2026

Record last verified: 2026-03

Locations

US (1)