|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Chronic Lymphocytic Leukaemia (CLL).
|Medical condition in easily understood language
|Chronic Lymphocytic Leukaemia (CLL).
|Diseases [C] - Blood and lymphatic diseases [C15]
|E.1.2 Medical condition or disease under investigation
|Neoplasms benign, malignant and unspecified (incl cysts and polyps)
|System Organ Class
|10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The principal research question this trial aims to answer is does obinutuzumab given within 3-12 months following a good response to prior treatment for chronic lymphocytic leukaemia (CLL) improve the length of time that patients are progression free when compared to having no consolidation treatment.
The phase II primary objective is to determine the rate of achieving MRD negativity and to assess the safety of obinutuzumab in a consolidation setting.
The phase III primary objective is to compare consolidation therapy with obinutuzumab against no consolidation therapy with respect to progression-free survival in participants who responded to previous therapy with a complete or good partial remission with low levels of MRD.
|Secondary objectives of the trial
|To assess and compare between trial arms:
• Proportion of participants with undetectable minimal residual disease (MRD) (as defined by the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria)
• Overall survival
• Treatment-free survival
• Response and rate of response to therapy (as defined by IWCLL criteria)
• Progression-free survival and overall survival for participants who are or become MRD negative
• Duration of MRD negativity for participants who become MRD negative
• Safety and toxicity
• Health related quality of life
|Trial contains a sub-study
|Principal inclusion criteria
|• At least 18 years old
• Previous confirmation of B-CLL with a characteristic immunophenotype (for example, CD5+, CD19+, CD23+ lymphoproliferative disorder) on peripheral blood flow cytometry
• Maximum of three prior therapies received for CLL treatment and between 3 and 24 months post therapy at registration.
• Response to most recent chemotherapy treatment for CLL with PR, CRi or CR
• World Health Organisation (WHO) performance status (PS) of 0 or 1
• Able to provide written informed consent
• Peripheral B-Cell count <5x10^9 L
• For randomisation, the first MRD positive peripheral blood sample (disease level found in peripheral blood is greater than 0.01%) must be between 3 and 12 months since completing most recent therapy for CLL
• Absence of clinically or radiologically evident lymphadenopathy (largest lymph node 1.5 cm or less in minimum diameter)
• Creatinine and bilirubin <2 times upper limit of normal unless secondary to direct infiltration of the liver by CLL or haemolysis
|Principal exclusion criteria
|• Disease progression after response to latest therapy
• Active infection
• Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies
• Previous treatment with obinutuzumab
• CNS involvement with CLL
• Mantle cell lymphoma
• Moderate or severe cardiac disease that would preclude treatment with obinutuzumab
• Other severe, concurrent diseases or mental disorders that could interfere with ability to participate
• Known HIV positivity
• Active secondary malignancy excluding basal cell carcinoma
• Active haemolysis
• Patients previously treated with allogeneic Stem Cell Transplant
• Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment has finished
• Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment has finished, unless they are surgically sterile
• Persisting severe pancytopenia (neutrophils <0.5 x 10^9/L or platelets <50 x 10^9/L) or trans fusion dependent anaemia
• Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
• Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result.
|E.5 End points
|Primary end point(s)
|Phase II - Proportion of participants with undetectable minimal residual disease at 6 months post randomisation.
Phase III - Progression free survival: time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression free.
|Timepoint(s) of evaluation of this end point
|Analysis on the phase II primary endpoint, proportion of participants with undetectable minimal residual disease, will be carried out after 9 and 23 participants have received at least 4 weeks of obinutuzumab treatment and followed up for the MRD response at 6 months post randomisation.
A formal interim analysis on progression-free survival will be carried out when half the required number of events have been observed (60 events). Final analysis will be carried out when at least 120 participants have progressed and there is sufficient follow up of participants, anticipated to be 3 years after the close of recruitment.
|Secondary end point(s)
|Proportion of participants with undetectable MRD assessed at 6 months post randomisation in the obinutuzumab arm will be summarised with 95% confidence intervals reported.
Overall survival (OS): Cox proportional hazards model will be fitted to analyse time from randomisation until death, adjusting for the minimisation factors. Overall survival curves will be reported by trial arm using Kaplan-Meier methods, and hazard ratios and corresponding 95% confidence intervals will be calculated.
Treatment-free survival (TFS): Cox proportional hazards model will be fitted to analyse time from randomisation until next treatment or death, adjusting for the minimisation factors. Treatment-free survival curves will be reported by trial arm using Kaplan-Meier methods, and hazard ratios and corresponding 95% confidence intervals will be calculated.
Response will be assessed at 6 months post randomisation in the obinutuzumab arm, as defined by IWCLL criteria. Response categories and changes in response from previous therapy will be summarised. The proportion of participants achieving a Complete Response (CR+CRi) and an Overall Response (at least a PR) will be summarised with corresponding 95% confidence intervals.
Progression-free survival and overall survival from date of first documentation of MRD eradication: the analyses to compare PFS and OS for participants who are MRD negative at registration with those who become MRD negative after obinutuzumab consolidation will be the same as those for the randomised treatment groups, with the exception that survival will be calculated from the end date of prior treatment for CLL.
Duration of MRD negativity for participants who are or become MRD negative: Cox regression analysis will be used to analyse time to MRD relapse for participants who are MRD negative from most recent prior therapy and those who become MRD negative following obinutuzumab consolidation, adjusting for the minimisation factors. MRD relapse survival curves will be reported by trial arm using the Kaplan-Meier methods, and hazard ratios and corresponding 95% confidence intervals will be calculated.
Safety and toxicity will be assessed by summaries of the AE, AR, SAE, SAR, and SUSAR rates by treatment received and overall, based on the safety population. The suspected relationship to the protocol treatment will be presented along with other causality, outcome and event duration. ARs will be presented by NCI-CTCAE toxicity grade (V4.03). Individual SUSAR/SAR/SAE line listings will be reported by treatment received and MedDRA System Organ class (where applicable). Treatment related mortality rates will be presented by treatment received.
Quality of life will be summarised using adjusted for baseline mean scores and 95% CIs for all domains of the EORTC QLQ-C30 and CLL specific module, EORTC QLQ-CLL16 for each trial arm, at each assessment time-point and overall. Missing data patterns will be examined carefully, and if missing data patterns suggest data are not missing at random, analyses will also be carried out using multi-level repeated measures and pattern-mixture models, and data summarised using the Standardised Area Under the Curve.
|Timepoint(s) of evaluation of this end point
|Secondary endpoints will be analysed when at least 120 participants have progressed and there is sufficient follow up of participants, anticipated to be 3 years after the close of recruitment, but survival analyses will also be updated at a later as more data becomes available.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|No treatment (as standard)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The date of collection of the last participant's last data item.
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days