Leukemia
Conditions
Interventions
Patients will be randomized in a 1:1 manner to one of the following treatment
arms:
• Arm A: Zanubrutinib 160 mg orally twice daily
• Arm B: Ibrutinib 420 mg orally once daily
Randomization will be
Sponsors
BeiGene, Ltd.
Eligibility
Inclusion criteria
Inclusion criteria: 1. Age 18 years or older 2. Confirmed diagnosis of CLL or SLL that meets the IWCLL criteria (Hallek et al 2008) 3. CLL/SLL requiring treatment as defined by at least 1 of the following criteria: a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia b. Massive (>= 6 cm below left costal margin), progressive, or symptomatic splenomegaly c. Massive nodes (>= 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte-doubling time of = 10% within the previous 6 months ii. Significant fatigue (ie, inability to work or perform usual activities) iii. Fevers > 100.5ºF or 38ºC for >= 2 weeks without other evidence of infection iv. Night sweats for > 1 month without evidence of infection 4. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current NCCN or ESMO guidelines or of an investigational regimen on a clinical trial 5. Measurable disease by CT/magnetic resonance imaging (MRI). Measurable disease is defined as >= 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters or an extranodal lesion must measure > 10 mm in longest perpendicular diameter (LPD). 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 7. Life expectancy >= 6 months 8. Adequate bone marrow function as defined by: a. Absolute neutrophil count (ANC) >= 1000/mm3 (growth factor use is allowed), except for patients with bone marrow involvement in which case ANC must be >= 750/mm3 - the screening hematology values confirming patient meets the ANC requirement must be dated at least 14 days following the most recent administration of pegfilgrastim and at least 7 days following the most recent administration of other myeliod growth factions (eg, G-CSF, GM-CSF) b. Platelet >= 75,000/mm3 (may be post-transfusion), except for patients with bone marrow involvement by CLL in which case the platelet count must be >= 30,000/mm3 c. Hemoglobin >= 7.5 g/dL (may be post-transfusion) 9. Patient must have adequate organ function defined as: a. Creatinine clearance >= 30 mL/min (as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease [MDRD] equation, or as measured by nuclear medicine scan or 24-hour urine collection) b. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase <= 2.5 × upper limi
Exclusion criteria
Exclusion criteria: 1. Known prolymphocytic leukemia or history of, or currently suspected, Richter*s transformation (biopsy based on clinical suspicion may be needed to rule out transformation) 2. Clinically significant cardiovascular disease including the following: a) Myocardial infarction within 6 months before screening b) Unstable angina within 3 months before screening c) New York Heart Association class III or IV congestive heart failure (Appendix 4) d) History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes) e) QTcF > 480 milliseconds based on Fridericia*s formula f) History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place g) Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening 3. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, or carcinoma in situ of the cervix or breast 4. 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 5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug 6. Severe or debilitating pulmonary disease 7. Unable to swallow study drug or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 8. Active fungal, bacterial, and/or viral infection requiring systemic therapy 9. Known central nervous system involvement by leukemia or lymphoma 10. Underlying medical conditions that, in the investigator*s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs 11. Known infection with HIV or 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 (< 20 IU), and if they are willing to undergo monitoring for HBV reactivation b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable 12. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C 13. Major surgery within 4 weeks of the first dose of study drug 14. Prior treatment with a BTK inhibitor 15. Last dose of prior therapy for CLL/SLL <= 14 days before randomization, with the following additional exclusion requirements: a.Treatment with monoclonal antibody-based therapy within 28 days of first dose of study drug b. Treatment with chimeric antigen receptor T-cell therapy within 180 days of first dose of study drug c. Treatment with Chinese herbal medicine with anticancer intent within 28 days of first dose of study drug d. Chemotherapy or radiation treatment within 21 days of first dose of study drug or hematopoietic s
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary efficacy analysis of ORR (PR or higher, defined as CR/CR with incomplete bone marrow recovery + PR + nodular PR)) will be conducted as assessed by the investigator, using the *modified* 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines, with modification for treatment related lymphocytosis for patients with CLL and per Lugano Classification for non-Hodgkin lymphoma for patients with SLL. While the primary efficacy endpoint is per investigator assessment, ORR per independent central review will also be analyzed to support the primary analysis. In the United States, ORR assessed by independent central review will be the basis for regulatory decisions. The primary hypothesis testing for ORR is for non-inferiority. The non inferiority of zanubrutinib to ibrutinib will be tested for the Intent-to-Treat Analysis Set under the pre-specified margin of 0.8558 (response ratio of zanubrutinib to ibrutinib). The primary objective of the study is met if the non inferiority is demonstrated. | — |
Secondary
| Measure | Time frame |
|---|---|
| Key secondary efficacy endpoint If the primary objective of demonstrating non-inferiority of zanubrutinib to ibrutinib in ORR is met, the key secondary efficacy endpoint of progression-free survival (PFS) by investigator assessment will be tested for non-inferiority under hierarchical testing to control study-wide type I error. There will be a single analysis of PFS when approximately 205 PFS events have occured, and PFS will be summarized descriptively at the time ORR is significant. While the key secondary efficacy endpoint is per investigator assessment, PFS per independent central review will also be analyzed to support the key secondary endpoint analysis. In the United States, PFS assessed by independent central review will be used to support regulatory decisions. PFS will be compared between the 2 arms using a stratified log-rank test based on the 4 randomization stratification factors. The non-inferiority margin for the test is 1.3319 in hazard ratio (HR; zanubrutinib/ibrutinib). If the p-value from the stratified log-rank test for non-inferiority is significant, the non-inferiority of zanubrutinib to ibrutinib in PFS is demonstrated, and further testing of superiority will be performed. The HR (zanubrutinib/ibrutinib) and its 95% CI will be estimated from a stratified Cox regression model. The distribution of PFS, including median and other quartiles, and PFS rate at selected timepoints will be estimated using the Kaplan-Meier method for each arm. | — |
Countries
Netherlands
Outcome results
None listed