E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukemia (CLL) |
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E.1.1.1 | Medical condition in easily understood language |
CLL is a type of a cancer in which the bone marrow (BM) makes too many lymphocytes (a type of white blood cell) |
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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 |
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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 |
- To evaluate the efficacy of venetoclax (Venclexa® or Venclyxto®) in combination with obinutuzumab (Gazyva® or Gazyvaro®) (VEN + G) compared with fludarabine, cyclophosphamide, and rituximab (FCR)/ bendamustine and rituximab (BR) on the basis of minimal residual disease (MRD) response rate |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of VEN + G compared with FCR/BR on the basis of progression-free survival, MRD response rate in PB and BM, objective response rate, complete response rate, duration of objective response, best response achieved, event-free survival, overall survival - To evaluate safety of VEN + G compared with FCR/BR on the basis of nature, frequency, and severity of adverse events, changes in vital signs, physical findings, clinical laboratory test results, premature withdrawals - To compare disease and treatment-related symptoms and to evaluate changes in physical functioning, role functioning, and global health status/quality of life following treatment with the combination of VEN + G compared with FCR/BR in patients with previously untreated CLL without del(17p) or TP53 mutation measured by M.D. Anderson Symptom Inventory (MDASI-CLL) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Ability to comply with the study protocol, in the investigator's judgment - Aged 18 years or older - Have previously untreated documented CLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria - CLL requiring treatment according to the iwCLL criteria - Cumulative illness rating scale score <=6 and creatinine clearance >=70 mL/min - Hematology values within the following limits, unless cytopenia is caused by the underlying disease (i.e., no evidence of additional BM dysfunction; e.g., myelodysplastic syndrome, hypoplastic BM): o Absolute neutrophil count >=1.0 × 10^9/L, unless there is BM involvement o Platelet count >=75 × 10^9/L and more than 7 days since last transfusion, or >=30 × 10^9/L if there is BM involvement - Adequate liver function as indicated by a total bilirubin, aspartate aminotransferase, and Alanine transaminase <=2 times the institutional upper limit of normal value, unless directly attributable to the patient’s CLL - Life expectancy >6 months - For women of childbearing potential: agreement to remain abstinent or use contraception and agreement to refrain from donating eggs, women must remain abstinent or use contraceptive methods with a failure rate of <=1% per year during the treatment period and for at least 30 days after the last dose of venetoclax or 18 months after the last dose of obinutuzumab for patients in Arm A and for at least 6 months after the last dose of bendamustine, fludarabine or cyclophosphamide or 12 months after the last dose of rituximab for patients in Arm B, whichever is later - For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm, with a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 90 days after the last dose of venetoclax or 18 months after the last dose of obinutuzumab for patients in Arm A, and for at least 6 months after the last dose of bendamustine, fludarabine, or cyclophosphamide or 12 months after the last dose of rituximab for patients in Arm B, whichever is later
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E.4 | Principal exclusion criteria |
- Transformation of CLL to aggressive non-Hodgkin’s lymphoma - Patients with small lymphocyclic lymphoma - Known central nervous system involvement - Patients with a history of confirmed progressive multifocal leukoencephalopathy - Detected del (17p) or TP53 mutation - An individual organ/system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system - Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia - History of prior malignancy - Patients with infections requiring IV treatment (Grade 3 or 4) within the last 8 weeks prior to enrollment - Evidence of other clinically significant uncontrolled condition(s) including but not limited to active or uncontrolled systemic infection - History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products - Hypersensitivity to fludarabine, bendamustine, cycolphosphamide, rituximab, obinutuzumab, or venetoclax or to any of the excipients - Pregnant women and nursing mothers - Vaccination with a live vaccine <=28 days prior to randomization - Prisoners or patients who are institutionalized by regulatory or court order or persons who are in dependence to the Sponsor or an investigator - History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment - Positive test results for chronic hepatitis B virus infection and for hepatitis C - Patients with known infection with HIV or Human T-Cell Leukemia Virus 1 - Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study - Received any of the following agents within 28 days prior to the first dose of study treatment: o Immunotherapy o Radiotherapy o Hormone therapy o Any therapies intended for the treatment of lymphoma/leukemia whether approved or experimental - Patients who have received the following agents: o Strong and moderate CYP3A inhibitors and inducers within 7 days prior to the initiation of study treatment o Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids within 7 days prior to the first dose of study drug administration o Consumed grapefruit, grapefruit products, Seville oranges , or star fruit within 3 days prior to the first dose of study drug and throughout venetoclax administration - Inability to swallow a large number of tablets
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E.5 End points |
E.5.1 | Primary end point(s) |
1. MRD response rate measured in PB at Month 15 in the first 140 patients recruited 2. Nature , frequency, and severity of adverse events and serious adverse events
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At Month 15 for each patient, Month 36 in the study 2. Up to 28 days after the last dose of study drug, or until initiation of another anti-cancer therapy
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E.5.2 | Secondary end point(s) |
1. Progression-free survival 2. MRD response rate, in PB at end of treatment response visit 3. MRD response rate in BM at end of treatment response visit 4. Objective response rate 5. Complete response rate 6. MRD response rate in PB in patients with a complete remission /complete remission with incomplete blood count recovery (CR/Cri) at Month 15 7. MRD response rate in BM in patients with a CR/CRi at end of treatment visit 8. Best response 9. Duration of objective response 10. Event-free survival 11. Overall survival 12. Changes in vital signs, physical findings, and clinical laboratory test results during and following study treatment 13. Premature withdrawals 14. Change in disease and treatment-related symptoms following treatment with the combination of VEN + G compared with FCR/BR in patients with previously untreated CLL without del (17p) or TP53 mutation as measured by MDASI-CLL 15. Change in physical functioning, role functioning and health-related quality of life following treatment with the combination of VEN + G compared with FCR/BR in patients with previously with previously untreated CLL without del(17p) or TP53 mutation as measured by EORTC QLQ-C30
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Every year after disease progression until end of study (up to 46 months) 2-3. At end of treatment response visit (up to 36 months) 4-6. At Month 15 for each patient, Month 36 in the study 7. At end of treatment response visit (up to 36 months) 8. At Month 15 for each patient, Month 36 in the study 9-11. Every year after disease progression until end of study (up to 46 months) 12. Up to 28 days after the last dose of study drug, or until initiation of another anti-cancer therapy 13. Up to 46 months 14-15. Arm A: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm B: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit |
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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 | 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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient reported Outcomes (PRO) |
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Australia |
France |
Italy |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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The end of study is defined as 2 years after the last patient is enrolled, allowing for completion of the maximum duration of planned therapy (in the absence of disease progression) as well as at least 1 year of follow-up for all patients. In addition, the Sponsor may decide to terminate the study at any time. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |