Tafasitamab + Zanubrutinib for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: CYP3A4 inducers
Disqualifiers: Hepatitis B, HIV, Cardiovascular disease, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.
12345Is 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.
12367How 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.
12368Eligibility 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.
+17 more
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.
+4 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (tafasitamab and zanubrutinib)Experimental Treatment5 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Miami Sylvester Comprehensive Cancer CenterMiami, FL
City of Hope at Irvine LennarIrvine, CA
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. [2023]Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.
Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. [2023]Zanubrutinib is a highly selective, next-generation Bruton's tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients' health-related quality-of-life (HRQoL).
Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. [2023]Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine-rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.
Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2023]In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.
Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. [2021]Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.
Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.
Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. [2022]Zanubrutinib is a highly selective irreversible inhibitor of Bruton tyrosine kinase which has shown significant activity in lymphoid malignancies in early phase studies. We report here the long-term follow-up outcomes of zanubrutinib in various lines of therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).