E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with poor risk CLL and Richter`s transformation requiring an allogeneic stem cell transplantation |
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E.1.1.1 | Medical condition in easily understood language |
Patients with poor risk CLL and Richter`s transformation requiring an allogeneic stem cell transplantation |
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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 | 20.0 |
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) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058728 |
E.1.2 | Term | Richter's syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective of the study is to evaluate the feasibility, efficacy and safety of an Obinutuzumab containing conditioning regimen for CLL patients and patients with Richter`s transformation requiring an allogeneic stem cell transplantation. |
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E.2.2 | Secondary objectives of the trial |
• Rate of patients free from disease progression at 12 months post-transplant • MRD negativity rate at different time points (days +60, +90, +180, +270 and months 12, 18 and 24 post transplant) • Overall response rate following treatment at 6 months post-transplant • Progression-free survival • Event-free survival • Overall survival • Chimerism at day 100 post-transplant • Non relapse mortality and relapse related mortality • Engraftment post-transplant defined as > 0.50 x 109/L Neutrophils and Platelets > 20 x 109/L without transfusion requirement at 30 days post-transplant • Incidences of grade III/IV adverse drug reactions • Incidence and severity of acute GvHD at 100 and 365 days post transplant • Incidence and severity of chronic GvHD within the first year post transplant • Correlation between MRD and PFS • Evaluation of relationship between various baseline markers and clinical outcome parameters |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have documented CLL according to iwCLL criteria 2. a) CLL requiring transplant according to the consensus statement 2014:1 • Non-response or early relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy plus high risk CLL TP53 deletion/mutation (del 17p-) and/or del 11 plus response to kinase inhibitors or other small molecules or • Non-response or early relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy and refractory to or non-tolerating kinase inhibitors or other small molecules or b) Transformation of CLL to aggressive NHL (Richter’s transformation) The CLL patients should have at least one therapy with the newer targeted agents such as BCL-2 inhibitors or BCR targeting agents. Both poor risk CLL patients and patients with Richter`s transformation should achieve the best possible response defined as disease sensitivity measured as CR, PR or SD prior to transplant with an available salvage therapy 3. Availability of a suitable fully matched (10/10) sibling or unrelated donor 4. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1. 5. Hematology values within the following limits unless cytopenia is caused by the underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g. myelodysplastic syndrome 2, hypoplastic bone marrow): • Absolute neutrophil count ≥ 1.0 x 109/L • Platelets ≥ 50 x 109/L and more than 7 days since last transfusion 6. Adequate liver function as indicated by a total bilirubin AST, and ALT ≤1.5 the institutional ULN value, unless directly attributable to the patient’s CLL 7. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 1 year after last dosage of obinutuzumab), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration 8. 18 years of age or older but not older then 70 years 9. Able and willing to provide written informed consent and to comply with the study protocol procedures 10. Patient agrees to inform other physicians about study participation |
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E.4 | Principal exclusion criteria |
11. Previous allogeneic stem cell transplant 12. Known central nervous system (CNS) involvement 13. Patients with a history of confirmed PML 14. Clinically significant cardiac disease including unstable angina, acute myocardial infarction withinsix months prior to randomization, congestive heart failure (left ventricular ejection fraction < 50%). 15. Organ dysfunction DLCO < 50%, TLC < 70%, FEV1 < 70% and or receiving supplementary oxygen, Inadequate renal function: Creatinine clearance < 50ml/min 16. Patients with active fungal infections with radiological progression despite treatment with Ambisome or active Triazole for more than a month 17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products 18. Hypersensitivity to Obinutuzumab or to any of the excipients such as for example Mannitol 19. Participation in another experimental drug trial (including chemotherapy, antibody treatment, kinase inhibitors, BCL2-antagonists or immunmodulatory agents) with start of the conditioning regimen/first Obinutuzumab application. 20. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment) 21. Fertile men or women of childbearing potential unless: • Surgically sterile or ≥ 2 years after the onset of menopause • Willing to use a highly effective contraceptive method (Pearl Index < 1) such as oral hormonal contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and for 12 months after end of study treatment. 22. Vaccination with a live vaccine a minimum of 28 days prior to randomization 23. Prisoners or patients who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
For this study there will be no formal primary endpoint which is connected to sample size calculation and confirmatory testing. According to the main study objective, the following key efficacy endpoint will be considered: • Rate of patients free from disease progression (PD-free rate) at 12 months post-transplant Moreover the following additional endpoints will be evaluated: Other efficacy endpoints • CLL patients: MRD negativity rate at different time points (days 60, 90, 180, 270 and months 12, 18 and 24 post-transplant) • Overall response rate (ORR) following treatment at 6 months post-transplant • Progression-free survival (PFS) • Event-free survival (EFS) • Overall survival (OS) Safety endpoints • Non relapse mortality (NRM) and relapse related mortality • Engraftment post-transplant defined as > 0,50 x 109/L Neutrophils and Platelets > 20 x 109/L without transfusion requirement at 30 days post-transplant • Chimerism at day 100 post-transplant • Incidences of grade III/IV adverse drug reactions • Incidence and severity of acute GvHD at 100 and 365 days post transplant • Incidence and severity of chronic GvHD within the first year post transplant Health-related quality of life by EORTC QLQ-C30 questionnaire Explorative endpoints • Correlation between MRD and PFS • Evaluation of relationship between various baseline markers and clinical outcome parameters |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis of key efficacy end point: Q1 2020 Final study report: Q1 2022
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | No |
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 | 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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40 patients shall be enrolled in the study. With an accrual rate of 1-2 patients per month the accrual duration will last 24 months (2 years). The additional time required from the time of last patient enrolled until the key efficacy endpoint is reached is approximately 12 months (1 year) followed by an additional observation time point at 24 months post transplantation for MRD and response resulting in total study duration of approximately 48 months (4 years). |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |