| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) |
|
| 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 | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| 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 assess progression-free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC). |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives are to evaluate the following:
- rate of minimal residual disease (MRD)-negative remissions
- overall response rate (ORR), including complete response (CR) rate, and response duration as assessed by an IRC
- overall survival (OS)
- time to next treatment
- trough levels of ibrutinib and venetoclax when given in combination
- safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult subjects who are:
a. ≥65 years old or,
b. 18 to 64 years old and have at least 1 of the following:
- Cumulative Illness Rating Scale (CIRS) score >6
- Creatinine clearance (CrCl) estimated <70 mL/min using the Cockcroft-Gault equation.
2. Diagnosis of CLL or SLL that meets iwCLL criteria.
3. Active CLL/SLL requiring treatment per the iwCLL criteria:
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia or both;
b. Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly;
c. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy;
d. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time of less than six months;
e. Constitutional symptoms, defined as 1 or more of the following:
- Unintentional weight loss ≥10% within the previous 6 months prior to the start of screening;
- Significant fatigue (inability to work or perform usual activities);
- Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without evidence of infection;
- Night sweats for more than 1 month without evidence of infection.
4. Measurable nodal disease (by computed tomography [CT]) is defined as at least one lymph node >1.5 cm in longest diameter.
5. ECOG Performance Status Grade ≤2.
6. Adequate organ function defined as follows:
a. Absolute neutrophil count (ANC) ≥750 cells/µL independent of growth factor support;
b. Platelets ≥50,000 cells/µL independent of transfusion support for at least 7 days prior to randomization;
c. Hemoglobin >8.0 g/dL independent of transfusion support for at least 7 days prior to randomization;
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x upper limit of normal (ULN);
e. Total bilirubin ≤1.5 x ULN (unless due to Gilbert’s syndrome);
f. Estimated CrCl ≥30 mL/min (Cockcroft-Gault equation). |
|
| E.4 | Principal exclusion criteria |
1. Prior anti-leukemic therapy for CLL or SLL.
2. Presence of del17p or known TP53 mutation detected at a threshold of >10% variable allele frequency (VAF).
3. Major surgery within 4 weeks of first dose of study treatment.
4. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
5. Central nervous system (CNS) involvement or suspected Richter’s syndrome.
6. An individual organ/system impairment score of 4 as assessed by CIRS, except for the eyes, ears, nose, throat, and larynx system, limiting the ability to receive treatment in this study.
7. Uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia (Coombs positivity in the absence of hemolysis is not an exclusion).
8. Chronic use of corticosteroids more than 20 mg/day of prednisone or its equivalent within 7 days of initiation of study treatment.
9. History of prior malignancy, except:
a. Malignancy treated with curative intent and with no known active disease present for ≥24 months before randomization;
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
c. Adequately treated cervical carcinoma in situ without evidence of disease;
d. Malignancy, which is considered cured with minimal risk of recurrence.
10. Received live, attenuated vaccine within 4 weeks of randomization.
11. History of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic condition that in the opinion of the investigator would adversely affect a subject’s participation in the study.
12. Currently active, clinically significant Child-Pugh Class B or C hepatic impairment according to the Child Pugh classification (see Attachment 4 Child-Pugh classification)
13. Uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
14. Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From the date of randomization to date of disease progression or death, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
1 - Proportion of subjects who reach MRD negative disease status (ie, <1 CLL cell per 10,000 leukocytes or <0.01%) in the bone marrow.
2 - Overall response rate, defined as the proportion of subjects who achieve a response ie, CR, CRi, nPR, and PR.
3 - CR rate, defined as the proportion of subjects who achieve CR.
4 - Response duration in days from the date of initial documentation of a response to the date of first documented evidence of PD or death.
5 - Overall survival.
6 - Time to next treatment.
7 - Time to worsening in functional status and fatigue.
8 - Safety.
9 - Hematologic improvement (hemoglobin and platelets).
10 - Descriptive statistics of ibrutinib and venetoclax trough levels in plasma. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - Evaluated at week 36 and week 84
2 & 3 - Evaluations will be performed every 12 weeks after randomization through Week 60, then every 16 weeks through Week 156, then every 24 weeks thereafter until disease progression or death
4 - From the date of initial documentation of a response to the date of first documented evidence of PD or death
5 - From the date of randomization to the date of death from any cause
6 - From date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment
7 - Throughout trial
8 - Throughout trial
9 - Improvement lasting for 56 days without transfusions or growth factors
10 - Cycle 2, 3, 5 and 6 |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Israel |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
|
| 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
|
| The study is considered completed approximately 5 years after the last subject is randomized into the study or after 50% of the subjects have died, whichever comes first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
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