Tafasitamab + Zanubrutinib for Chronic Lymphocytic Leukemia

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers

Disqualifiers: Hepatitis B, HIV, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well tafasitamab and zanubrutinib works in treating patients with newly diagnosed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Tafasitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Zanubrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of a protein that signals cancer cells to multiply. This may stop the growth and spread of cancer cells. Giving tafasitamab and zanubrutinib in combination may kill more cancer cells in patients with CLL/SLL than giving either treatment alone.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use certain medications like strong CYP3A4 inducers within 2 weeks before starting the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Tafasitamab and Zanubrutinib for treating Chronic Lymphocytic Leukemia?

Research shows that Zanubrutinib, one of the drugs in the combination, is effective in treating Chronic Lymphocytic Leukemia (CLL) by significantly improving progression-free survival and having a high overall response rate in patients. It is also noted for its improved safety profile compared to similar drugs. ^{1 2 3 4 5}

Is the combination of Tafasitamab and Zanubrutinib safe for treating chronic lymphocytic leukemia?

Zanubrutinib, a part of the combination treatment, has been shown to be generally well tolerated in patients with chronic lymphocytic leukemia, with common side effects including infections, bruising, and fatigue. Serious side effects like low white blood cell counts and pneumonia were less common. Tafasitamab's safety profile is not detailed in the provided research, but Zanubrutinib's safety data suggests it is generally safe for human use. ^{1 2 3 6 7}

How is the drug combination of Tafasitamab and Zanubrutinib unique for treating chronic lymphocytic leukemia?

The combination of Tafasitamab and Zanubrutinib is unique because Zanubrutinib is a next-generation Bruton tyrosine kinase inhibitor that offers improved selectivity and fewer side effects compared to older treatments like ibrutinib, while Tafasitamab is an antibody that targets CD19 on B-cells, potentially enhancing the treatment's effectiveness by working through different mechanisms. ^{1 2 3 6 8}

Research Team

Matthew Mei, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

Adults diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma who need treatment and can swallow pills. They should have no prior CLL treatments (except certain steroids/rituximab), stable organ function, and no severe bleeding disorders or liver disease. Participants must agree to use birth control and not be pregnant.

Inclusion Criteria

My kidneys work well enough, with a clearance rate of at least 30 mL/min.

My blood clotting measurements are within safe limits, with or without anticoagulants.

I can perform all my self-care activities and am up more than 50% of my waking hours.

Exclusion Criteria

History of prior malignancy except: Malignancy treated with curative intent and no known active disease present for >= 2 years prior to initiation of therapy on current study, Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease, Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease, Asymptomatic prostate cancer managed with 'watch and wait' strategy, Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test in absence of hemolysis or history of immune-mediated cytopenias are not exclusions), Known positive test result for SARS-CoV-2 unless follow-up test was negative or investigator deems the infection is fully resolved, Known positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing) and a positive test result for HCV ribonucleic acid (RNA). Participants with positive serology are eligible in case of negative HCV RNA test results, Known positive test result for chronic hepatitis B virus (HBV) infection (defined by hepatitis B virus surface antigen [HBsAg] positivity), Participants with occult or prior HBV infection (defined as negative HBsAg and positive total hepatitis B core antibody) may be included if HBV deoxyribonucleic acid (DNA) was undetectable, provided that they are willing to undergo ongoing DNA testing, Antiviral prophylaxis may be administered as per institutional guidelines, Participants who have protective titers of HBsAb after vaccination or prior but cured hepatitis B are eligible, Known seropositive for or history of active viral infection with human immunodeficiency virus (HIV), 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), QTcF > 480 milliseconds based on Fridericia's formula, History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place, Known severe chronic obstructive pulmonary disease (COPD), Known hepatic cirrhosis or severe pre-existing hepatic impairment, Major surgery (requiring general anesthesia) within 14 days before the first dose of study drug or a scheduled surgery during study period, Patients with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere significantly with drug absorption, Females only: Pregnant or breastfeeding, Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures, Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

I have not had major surgery in the last 30 days.

I take more than 20 mg/day of prednisone or its equivalent.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-In

Evaluation of the safety and tolerability of tafasitamab and zanubrutinib

4 weeks

Weekly visits for safety assessments

Treatment

Patients receive tafasitamab IV and zanubrutinib PO, with blood samples, CT scans, and bone marrow biopsies conducted throughout the trial

24 months

Monthly visits for treatment and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Bi-annual visits for follow-up assessments

Treatment Details

Interventions

• Tafasitamab
• Zanubrutinib

Trial Overview The trial is testing the combination of tafasitamab, a monoclonal antibody, and zanubrutinib, a kinase inhibitor protein blocker, in treating newly diagnosed patients. It aims to see if this combo is more effective than individual treatments for stopping cancer cell growth.

Participant Groups

Group I: Treatment (tafasitamab and zanubrutinib) Experimental Treatment 5 Interventions

Patients receive tafasitamab IV and zanubrutinib PO on study. Patients also undergo collection of blood samples on study and undergo CT scan and bone marrow biopsy throughout the trial.

Tafasitamab is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Monjuvi for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, in adult patients who are not eligible for autologous stem cell transplant

Approved in European Union as Minjuvi for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adult patients who are not eligible for autologous stem cell transplant

Approved in Canada as Monjuvi for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adult patients who are not eligible for autologous stem cell transplant

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 3 study involving 590 patients with untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), zanubrutinib significantly improved progression-free survival compared to bendamustine-rituximab, with a hazard ratio of 0.42, indicating a strong efficacy advantage.

Zanubrutinib demonstrated an acceptable safety profile, with fewer severe adverse events like neutropenia compared to bendamustine-rituximab, suggesting it could be a promising new treatment option for patients with CLL and SLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Tam, CS., Brown, JR., Kahl, BS., et al.[2023]

In the phase 3 SEQUOIA trial involving adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), zanubrutinib significantly improved progression-free survival compared to the standard treatment of bendamustine plus rituximab (BR).

Patients treated with zanubrutinib reported better health-related quality-of-life outcomes at 12 and 24 weeks, including improvements in global health status, physical functioning, and reduced symptoms of diarrhea, fatigue, and nausea/vomiting compared to those receiving BR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Ghia, P., Barnes, G., Yang, K., et al.[2023]

Zanubrutinib (zanu) has been shown to significantly improve progression-free survival compared to bendamustine-rituximab in treatment-naive patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as a first-line treatment option.

In a direct comparison with ibrutinib, zanu demonstrated a better safety profile and enhanced clinical efficacy, leading to its approval by the FDA and EMA as a preferred treatment for CLL/SLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. Molica, S., Tam, C., Allsup, D., et al.[2023]

In a phase 3 trial involving 652 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), zanubrutinib demonstrated superior progression-free survival compared to ibrutinib, with a hazard ratio of 0.65, indicating a significant reduction in the risk of disease progression or death.

Zanubrutinib also had a better safety profile than ibrutinib, resulting in fewer adverse events that led to treatment discontinuation, particularly fewer cardiac events, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown, JR., Eichhorst, B., Hillmen, P., et al.[2023]

Zanubrutinib, a selective BTK inhibitor, was well-tolerated in a phase 1 study with 144 patients, showing no dose-limiting toxicities and achieving over 95% BTK occupancy in blood cells at all tested doses.

In patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), zanubrutinib demonstrated a remarkable overall response rate of 96.2% and a 100% estimated progression-free survival at 12 months, indicating strong efficacy with low major toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Tam, CS., Trotman, J., Opat, S., et al.[2021]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, was found to be generally well tolerated when combined with obinutuzumab in a phase 1 study involving 81 patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

The combination therapy showed high efficacy, achieving a 100% overall response rate in treatment-naïve CLL patients and a 92% response rate in relapsed/refractory CLL patients, with a 72% response rate in relapsed/refractory FL patients over a median follow-up of 20 to 29 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Tam, CS., Quach, H., Nicol, A., et al.[2021]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, showed a high overall response rate of 94.5% in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma carrying the del(17p) mutation, indicating its efficacy in a challenging patient population.

The treatment was well tolerated, with an estimated 18-month progression-free survival rate of 88.6% and an overall survival rate of 95.1%, although some patients experienced adverse events, including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. Tam, CS., Robak, T., Ghia, P., et al.[2021]

Zanubrutinib demonstrated a high overall response rate of 95.4% in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, with treatment-naïve patients showing even better outcomes (100% response) compared to those with relapsed/refractory disease (91.0%).

The long-term follow-up indicated that earlier treatment with zanubrutinib leads to significantly longer progression-free and overall survival, while maintaining a favorable safety profile, with serious adverse events primarily being infections and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. Xu, W., Yang, S., Tam, CS., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. [2022]