| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003946 |
| E.1.2 | Term | B-Lymphocytic, CLL (Kiel Classification) |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10041152 |
| E.1.2 | Term | Small lymphocytic lymphoma, consistent with CLL (Working Formulation) |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare efficacy between treatment groups in Cohort 1, as measured by progression-free survival determined by independent central review |
|
| E.2.2 | Secondary objectives of the trial |
Compare efficacy between Arms A and B, measured by:
- Overall response rate (ORR) and Duration of Response (DOR), Overall survival (OS), Progression-free survival (PFS), Patient-reported outcomes
Compare efficacy between Arms A and B in pooled Cohort 1/1a patients from Chinese sites, measured by:
- PFS, ORR, DOR
To evaluate efficacy in Cohort 2 (patients with del17p) for Arm C, measured by:
- ORR, PFS, DOR
To evaluate efficacy in Cohort 3 for Arm D, measured by:
- ORR, PFS, DOR, Assess undetectable minimal residual disease at 10^-4 sensitivity at various timepoints
Compare safety between the treatment groups in Cohort 1
Compare safety between the treatment groups in pooled Cohort 1/1a patients from Chinese sites
Summarize safety in Cohort 2 (Arm C), Cohort 3 (Arm D)
Evaluate zanubrutinib pharmacokinetics in Arms A and C
Evaluate pharmacokinetics of zanubrutinib and venetoclax (Arm D) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOKINETIC SUB-STUDY FOR PATIENTS IN COHORT 3 (ARM D)
This optional pharmacokinetic (PK) sub-study is designed to assess potential drug-drug interactions (DDI) between zanubrutinib and venetoclax. |
|
| E.3 | Principal inclusion criteria |
1.Patients must be unsuitable for treatment with FCR defined as: ≥ 65 years of age at the time of informed consent, OR 18 - 64 years of age and have one or more of the following factors:
a. Cumulative Illness Rating Scale (CIRS) score > 6. A CIRS is not required, it may be used to meet this inclusion requirement.
b. Creatinine clearance < 70 mL/min
c. History of previous serious infection or multiple infections in the past 2 years
NOTE: For Arm D only:
-Patients without del17p: must meet one of the above criteria for unsuitability for FCR.
-Patients with del17p/TP53 variant: central laboratory confirmation of del17p-positive CLL/SLL will fulfill the requirement for unsuitability for FCR. For patients with a central FISH test result other than del17p-positive CLL/SLL, a local laboratory test result documenting pathogenic TP53 variant may meet this requirement (refer to Appendix 18 of PA5).
2. Confirmed diagnosis of CD20-positive CLL or SLL that meets the CLL criteria (Hallek et al, 2008)
3. Measurable disease by CT/MRI. Measurable disease is defined as ≥ 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters.
4. CLL/SLL requiring treatment
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
6. Life expectancy ≥ 6 months
7. Adequate bone marrow function
8. Patient must have adequate organ function
9. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib, ≥ 30 days after the last dose of venetoclax,3 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
10. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or 3 months after the last dose of bendamustine whichever is longer.
11. Ability to provide written informed consent and can understand and comply with the requirements of the study
12. Must have FISH results from the study-specified central laboratory confirming the presence or absence of del17p.a. For Arm D only: Patients must have a central laboratory FISH test for del17p performed. A patient with a result other than “with del17p” may be eligible for enrollment into the del17p-positive subset only if the patient has a pathogenic TP53 variant previously documented per local laboratory test meeting the criteria specified in Appendix 18. Approval for enrollment by the
medical monitor is required. |
|
| E.4 | Principal exclusion criteria |
1. Previous systemic treatment for CLL/SLL
2. Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids must be fully tapered off/stopped at least 5 days before day of first study drug.
3. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation
4. Clinically significant cardiovascular disease
5. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.
6. History of severe bleeding disorder
7. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
8. Severe or debilitating pulmonary disease
9. Unable to swallow capsules 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
10. Active fungal, bacterial and/or viral infection requiring systemic therapy
11. Known central nervous system involvement by leukemia or lymphoma
12. 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
13. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection
14. Major surgery within 4 weeks of the first dose of study drug
15. Pregnant or lactating women
16. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
17. Ongoing alcohol or drug addiction
18. Hypersensitivity to zanubrutinib, bendamustine, rituximab or venetoclax (as applicable) or any of the other ingredients of the applicable study drugs
19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
20. Concurrent participation in another therapeutic clinical study.
21. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
22. Arm D only: requires ongoing treatment with warfarin or warfarin derivatives. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS in Cohort 1 (patients without del17p) determined by independent central review using the iwCLL guidelines with modification for treatment-related lymphocytosis in patients with CLL and the Revised Criteria for Response for Malignant Lymphoma in patients with SLL, and defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 interim analysis of progression-free survival by independent central review in Cohort 1, performed when approximately 86 events (73% of the target number of events at final analysis) from the Arms A and B are observed. It is estimated that it will take approximately 33 months to observe 86 events. The final analysis of progression-free survival will take place after 118 events are observed in Cohort 1, which is estimated as approximately 41 months from study start.
|
|
| E.5.2 | Secondary end point(s) |
• ORR in Cohort 1 defined as the proportion of patients who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by independent central review and by investigator assessment
• OS in Cohort 1 defined as the time from randomization to the date of death due to any reason
• Duration of response in Cohort 1 determined by independent central review and by investigator assessment using the iwCLL criteria with modification for treatment-related lymphocytosis (in patients with CLL) and the Lugano Classification for NHL (in patients with SLL), and defined as the time from the date that criteria for response (i.e. PRL or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first
• PFS in Cohort 1 determined by investigator assessment
• PROs in Cohort 1 measured by the European Quality of Life 5 Dimensions 5 Levels Health Questionnaire (EQ-5D-5L) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
• PFS in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment
• ORR in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment
• Duration of response in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment
• ORR in Cohort 2 (patients with del17p), Arm C, determined by independent central review and investigator review
• PFS in Cohort 2 (Arm C), determined by independent central review and investigator review
• Duration of response in Cohort 2 (Arm C), determined by independent central review and investigator review
• ORR in Cohort 3, Arm D, determined by investigator review
• PFS in Cohort 3 (Arm D), determined by investigator review
• Duration of response in Cohort 3 (Arm D), determined by investigator review
• Cohort 3 (Arm D) only: undetectable MRD4 rate
• Safety parameters, including AEs, SAEs, clinical laboratory tests, physical examination, and vital signs
• Pharmacokinetic parameters of zanubrutinib such as apparent clearance of the drug from plasma (CL/F) and AUC from time 0 to 12 hours postdose (AUC0-12) for Arms A, C, and D |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At time of interim analysis if the PFS comparison between the 2 arms in cohort 1 crosses the stopping boundary. Or at the time of final PFS analysis. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 111 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Taiwan |
| Australia |
| China |
| Russian Federation |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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