E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukemia |
|
E.1.1.1 | Medical condition in easily understood language |
Chronic Lymphocytic Leukemia |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009310 |
E.1.2 | Term | CLL |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- Evaluate efficacy of ibrutinib + venetoclax (VI) in terms of proportion of patients fulfilling the criteria for progression free survival (PFS) at 12 months after stopping therapy (27 months after starting treatment) for patients randomized to stop treatment (arm B of the study), reinitiated treatment due to MRD positivity not considered progression |
|
E.2.2 | Secondary objectives of the trial |
- Evaluation of the efficacy in terms of minimal residual disease (MRD) at 12 months after stopping treatment (month 27) - Evaluation of efficacy in terms of PFS (IWCLL criteria) - Time to and number of patients reinitiating treatment - Time to treatment failure after reinitiated treatment - Time to next CLL treatment, - MRD after cycle 12 (PB) and 15 (PB and BM) and at later time points in PB, - Overall Survival (OS), - Complete response (CR)/ Partial Response (PR)/ Stable disease (SD) after cycle 3, 9, 12, 15, and at month 27 and month 51 (3 years after stopping treatment) - Duration of response – To evaluate safety with regards to type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment. – To evaluate patient related outcomes, measured in terms of health-related quality of life (QoL) by EORTC QLQ-C30 and QLQ-CLL16 questionnaires.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy. • Age at least 18 years. • Adequate bone marrow function defined as: - Absolute neutrophil count (ANC) >0.75 x 10^9/L - Platelet count >30,000 /µL 30 x 10^9/L. - Hemoglobin >8.0 g/dL (5 mmol/L) Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy • Creatinine clearance (CrCL) ≥ 30ml/min . • Adequate liver function as indicated - AST or ALT≤ 3.0 x ULN - Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) -Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). • Negative serological testing for hepatitis B, negative testing for hepatitis C RNA within 42 days prior to registration. • WHO/ECOG performance status 0-3 stage 3 only if attributable to CLL. • Negative pregnancy test at study entry (for women of childbearing potential). • Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control during the period of therapy and for 90 days after the last dose of study drug. • Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements. • Written informed consent.
|
|
E.4 | Principal exclusion criteria |
• Any prior therapy with ibrutinib and/or venetoclax. • Transformation of CLL (Richter’s transformation). • Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML). • Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment. • Known allergy to xanthine oxidase inhibitors and/or rasburicase. • Known bleeding disorders (e.g., von Willebrand’s disease or hemophilia). • Uncontrolled or active infection. •Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. • History of stroke or intracranial hemorrhage within 6 months prior to randomization. • Major surgery within 28 days prior to registration. • Use of investigational agents which might interfere with the study drug within 28 days prior to registration. • Vaccination with live vaccines within 28 days prior to registration • Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon’s, or replacement/stress corticosteroids. • Pregnant women and nursing mothers. • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Proportion of patients fulfilling the criteria for progression free survival (PFS) at 12 months after stopping therapy (27 months after starting treatment) for patients randomized to stop treatment. In this trial, reinitiated treatment due to MRD positivity will not be considered as progression, and symptomatic CLL according to IWCLL criteria within 12 months after randomization followed by reinitiation treatment resulting in a response (at least SD) before or at 12 months after randomization will neither be considered as progression. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated when data of all patients randomized to stop treatment, until 12 months after randomization (27 months after start treatment) are available. |
|
E.5.2 | Secondary end point(s) |
• Minimal residual disease (MRD) at 12 months after stopping treatment (month 27) for patients randomized to stop of treatment. • PFS of all study groups. • Time to and number of patients reinitiating treatment • Time to treatment failure after reinitiated treatment • Time to next CLL treatment • MRD after cycle 12 (PB) and 15 (PB and BM) and at later time points in PB • Overall survival (OS) • Complete response (CR)/ Partial Response (PR)/ Stable disease (SD) after cycle 3, 9, 12, 15 and month 27 and month 51 (3 years after stopping treatment) • Duration of response • Safety parameters: Type, frequency, and severity of - adverse events (AEs) and - adverse events of special interest (AESI) and their relationship to study treatment • Health-related quality of life (QoL) by EORTC QLQ-C30 and QLQ-CLL16 questionnaires • Exploratory endpoints: • Evaluation of relationship between various baseline markers and clinical outcome parameters • Various markers at time of progression • Correlation between MRD in BM and PB • Correlation between MRD in BM and PFS/OS • Correlation between MRD in PB and PFS/OS
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints will be evaluated when relevant data of all patients are available |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 10 |
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 | 10 |