Testing Zanubrutinib and Tislelizumab as Well as Standard of Care for the Treatment of Patients With Progressive Lymphoma Post Anti-CD19 CAR-T Cell Therapy (OZUHN-024)

University Health Network, Toronto

Status and phase

Not yet enrolling

Phase 2

Conditions

Progressive Lymphoma Post Anti-CD19 CAR-T Cell Therapy

Treatments

Drug: Tislelizumab

Study type

Interventional

Funder types

Other

Identifiers

NCT06919705

ZeTA

Details and patient eligibility

About

This study is designed to see how well two new drugs work, either alone or with the usual treatment, for patients whose lymphoma (a type of cancer) has gotten worse after they've already received a special type of immune therapy called anti-CD19 CAR-T cell therapy. It's a planned, multi-site clinical trial. This means that patients from several different medical centers will be involved in the study.

The study will test two specific drugs:

Zanubrutinib: A new drug that targets certain cancer cells and blocks a specific protein involved in cancer cell survival, known as a BTK inhibitor. Tislelizumab: Another new drug that helps the immune system attack cancer cells by blocking a protein that prevents immune cells from doing their job, known as a PD-1 inhibitor. We have already seen that this combination of drugs is safe and shows early promise in treating patients with aggressive B cell cancers that have come back or didn't respond well to previous treatments. Additionally, research in the lab suggests that adding either a BTK or a PD-1 inhibitor might make CAR-T therapy, a type of treatment where modified immune cells are used to target cancer, even more effective. Since there isn't much experience with using the drugs tislelizumab and zanubrutinib on their own for this specific group of patients, the first part of our trial will test each drug alone to make sure they're safe to use.

If these drugs are found to be safe when used by themselves, we'll then try a new treatment approach that combines both drugs together. Here's what we're hoping to achieve:

Combining zanubrutinib and tislelizumab might work well because:

Zanubrutinib helps to directly attack lymphoma cells (a type of cancer cell). Tislelizumab helps the immune system (or CAR-T therapy) work better against cancer cells. We want to see if this combination is effective and safe for patients whose lymphoma has continued to progress or come back after they've already had anti-CD19 CAR-T therapy.

Enrollment

76 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

1. Age ≥ 18 years 2. Able and willing to provide written informed consent and to comply with the study protocol 3. Radiologically measurable disease (≥ 1 nodal lesion > 2.0 cm in the longest diameter, and/or extranodal lesion > 1.0cm in the longest diameter) 4. Intervention arm: Radiological measurable disease per inclusion criterion #3 with more than one site of disease.
2. Relapse or refractory Large B Cell Lymphoma post-CD19 directed CAR-T cell therapy within 6 weeks prior to enrollment (histological confirmation highly recommended although not mandatory) 6. Intervention arm: Hemoglobin ≥ 80 g/L at screening 7. Intervention arm: Platelet count ≥ 75 x 109 at screening 8. Intervention arm: Neutrophil count ≥ 1.0 x 109/L at screening 9. Intervention arm: ECOG performance status 2 at screening 10. AST and ALT < 2.5x ULN at screening 11. Serum total bilirubin < 1.5x ULN, except in patients with documented Gilberts syndrome at screening 12. Creatinine clearance ≥ 30 mL/min (as estimated by Cockcroft-Gault equation) at screening
* Counts can be supported with growth factors or transfusions as per standard transfusion protocolhighly recommended although not mandatory) 6. Intervention arm: Hemoglobin ≥ 80 g/L at screening

Exclusion criteria

1. Life expectancy < 30 days at the time of enrollment 2. Prior exposure to BTK or PD-1 inhibitor at any time prior to enrollment 3. Prior anaphylactic reaction to monoclonal antibody therapy at any time prior to enrollment 4. On higher than physiologic doses (10mg daily) of prednisone daily at least 7 days prior to initiation of trial treatment 5. Uncontrolled autoimmune disease 6. Known active CNS involvement disease 7. History of prior allogeneic transplant or organ transplant 8. Active bleeding or history of bleeding diathesis including, but not limited to: - History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention - History of stroke or intracranial hemorrhage within 180 days before first dose of study drug 9. Difficulty with or unable to swallow oral medication, or known conditions that would significantly affect gastrointestinal function that would limit absorption of oral medication 10. History of chronic, or active, uncontrolled bacterial, or fungal infection; human T-cell lymphotropic virus type 1 seropositive status 11. Serologic status reflecting active viral hepatitis B or C infection as follows: (a) presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20IU), and if they are willing to be on appropriate prophylaxis and undergo monitoring for HBV reactivation if clinically indicated. (b) Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
2. Individuals with known active HIV infection are eligible if CD4 and viral titres are controlled 13. Any serious intercurrent illness, life threatening condition, or organ system dysfunction including:
(1) Clinically significant cardiovascular disease/history including: (a) prolonged QTc > 480ms, (b) history of Mobitz II second degree or third degree heart block without a permanent pacemaker in situ, (c) uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure reading on 2 separate occasions showing systolic BP > 170 mmHg and/or diastolic BP > 105mmHg at screening, (d) uncontrolled or history of symptomatic arrhythmias (ie. sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes), (e) congestive heart failure or NYHA class ≥ 3, (f) myocardial infarction within 6 months of screening. (2) History of significant cerebrovascular events including stroke or intracranial hemorrhage within 6 months prior to enrollment; History of other active malignancies within 2 years of prior to enrollment, with the exception of adequately treated in-situ carcinoma of cervix; localized basal cell or squamous cell carcinoma of skin; or previous malignancy confined and treated locally (surgery or other modality) with curative intent.
1. Female patients of childbearing potential must practice highly effective methods (Section 6.7.1.1) of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 120 days after the last dose of zanubrutinib or tislelizumab 15. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other highly effective methods during the study treatment period and for ≥ 120 days after the last dose of zanubrutinib or tislelizumab.
2. Major surgery within 4 weeks of the first dose of study drug 17. Vaccination with a live vaccine within 28 days prior to the first dose of study drug 18. Patient requires treatment with warfarin or other vitamin K antagonists 19. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of breath, congestive obstructive pulmonary disease).
3. History of interstitial lung disease or non-infectious pneumonitis or pulmonary fibrosis, except for those induced by radiation therapy.
4. Active and symptomatic fungal, bacterial, and/or viral infection; human T-cell lymphotropic virus type 1 seropositive status.
5. Any illness or condition that in the opinion of the investigator may affect safety of treatment or evaluation of any study endpoint.
6. Active autoimmune diseases or history of severe autoimmune diseases ; these include but are not limited to a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, or clinically manifest antiphospholipid syndrome. Note: Subjects are permitted to enroll if they have vitiligo, eczema, type I diabetes mellitus, or endocrine deficiencies, including thyroiditis managed with replacement hormones including physiologic doses of corticosteroids. Subjects with Sjögren's syndrome and psoriasis controlled with topical medication and subjects with positive serology, such as antinuclear antibodies or antithyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
7. A condition requiring systemic treatment with either corticosteroids (> 20 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration, except for PCNSL and SCNSL. Note: adrenal replacement doses ≤ 20 mg daily prednisone or equivalents are permitted in the absence of active autoimmune disease; subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).
8. Major surgery in the past 4 weeks prior to the first day of screening. 26. Patients with contraindications for zanubrutinib and Tislelizumab 27. Pregnant or lactating women. 28. Hypersensitivity to zanubrutinib and Tislelizumab or any of the other ingredients of the applicable study drugs 29. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or stabilized, except for AEs not constituting a likely safety risk 30. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia ≤ 14 days before randomization.