| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003908 |
| E.1.2 | Term | B-cell small lymphocytic lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008958 |
| E.1.2 | Term | Chronic lymphocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 assess whether MRD-driven finite AV treatment is NI to MRD-driven finite VO treatment with respect to PFS. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the effect of AV treatment compared with VO treatment on uMRD at sequential timepoints
- To assess the effect of AV treatment compared with VO treatment on OS
- To assess the effect of AV treatment compared with VO treatment on EFS
- To assess the effect of AV treatment compared with VO treatment on ORR
- To assess symptoms, functional status, global health status/QoL, and patient perceived benefitrisk
in participants treated with AV versus VO using the EORTC QLQ-C30, EORTC QLQCLL17, NCI PRO-CTCAE item for Bruising, and PGI-BR |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Participant must be ≥ 18 years at the time of screening.
- Documented TN CLL/SLL requiring treatment according to iwCLL guidelines 2018 (Hallek et al 2018) including a detectable clonal B-cell population at baseline for purposes of measuring for Minimal Residual Disease.
- Adequate BM function independent of growth factor or platelet transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL/SLL:
(a) Absolute neutrophil count ≥ 1.0 × 10^9/L.
(b) Platelet counts ≥ 30 × 10^9/L; in cases of thrombocytopenia clearly due to CLL/SLL (per the discretion of the investigator), platelet count should be ≥ 10 × 10^9/L.
- Estimated CrCL > 30 mL/min calculated according to Cockcroft-Gault (using actual body weight), or serum creatinine <2xULN.
- Adequate liver function, as indicated by a total bilirubin ≤ 1.5 × ULN and serum AST and ALT ≤ 3 × the upper limit of normal (ULN) value, unless directly attributable to the participant’s CLL/SLL or to Gilbert’s Syndrome (The ULN is based on institutional values).
- Eastern Cooperative Oncology Group Performance Status performance status 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing. |
|
| E.4 | Principal exclusion criteria |
- As judged by the investigator, any evidence of past or current diseases that, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize their safety or compliance with the protocol or would put the study at risk.
- Clinically significant cardiovascular disease, such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction, within 6 months of screening or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
- Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease).
- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
- History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study intervention.
- Child-Pugh B/C liver cirrhosis.
- History of prior or current malignancy (including but not limited to known CNS lymphoma/leukemia or known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome) that could affect compliance with the protocol or interpretation of results. Exceptions can be made for the following based on physician discretion:
(a) Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study.
(b) Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which the participant is disease-free for ≥ 3 years without further treatment.
- Any prior CLL/SLL-specific therapies, except prior rituximab if used for autoimmune
cytopenias and not as anti-CLL/SLL treatment.
- Corticosteroid use > 20 mg within 1 week before the first dose of study intervention,
except as indicated for other medical conditions, such as autoimmune cytopenias, inhaled
steroid for asthma, topical steroid use, or as premedication for administration of study
intervention or contrast.
- Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer. The use of
strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the
first dose of study drug is prohibited.
- Concurrent participation in another therapeutic clinical trial. Use of investigational agents that interfere with the study intervention(s) within 30 days or 5 half-lives (whichever is shorter) prior to registration for study screening.
- Prothrombin time (PT)/INR or activated partial thromboplastin time, in the absence of
lupus anticoagulant, > 2 × ULN.
- Currently pregnant (confirmed with positive pregnancy test) or breast feeding.
- Women of Childbearing Potential (WOCBP) unless the following criteria are met - a negative pregnancy test is required for all WOCBP within 21 days before start of study intervention, followed by immediate highly effective contraception; further pregnancy testing will be performed monthly. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from the date of randomization until date of objective progressive disease per iwCLL 2018 criteria as assessed by the investigator or death from any cause in the absence of progression. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis is event-based and will be conducted after enrollment is completed and approximately 112 investigator-assessed PFS events have occurred. |
|
| E.5.2 | Secondary end point(s) |
- Rate of peripheral blood uMRD
- Overall survival
- Event-free survival
- Overall response rate
- CR rate after completion of 12 cycles of venetoclax
- Change from baseline in EORTC QLQ-C30, EORTC QLQ-CLL17 scales
- Proportion of participants experiencing bruising
- Proportion of participants reporting each response option of the PGI-BR |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The initial analysis of the study will be conducted on the key secondary endpoint, uMRD rate after 6 and 12 cycles of venetoclax. The analysis will be conducted at approximately 33 and 39 months, respectively, after the first participant is randomized (assuming 24 months enrollment and 9- and 15-months treatment periods, respectively). |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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 | No |
| 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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