E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic lymphocytic leukemia |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008977 |
E.1.2 | Term | Chronic lymphocytic leukemia recurrent |
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 safety and tolerability of obinutuzumab alone or in combination with chemotherapy |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory, CLL, as measured by:
- Minimal residual disease (MRD)-negativity 3 months after the last dose (i.e. at final response assessment visit)
- Overall response rate (ORR) at time of final response assessment visit
- Progression-free survival (PFS)
- Time to Response (TTR)
- Event-free survival (EFS)
- Best overall response (BOR)
- Overall survival (OS)
- Time to new anti-leukemia therapy (TTNT)
- Duration of response (DoR) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Documented CLL either previously untreated or relapsed and/or refractory
• Age ≥ 18 years
• ECOG performance status 0–2
• Adequate haematological function |
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E.4 | Principal exclusion criteria |
• Patients who have received more than 3 previous CLL treatment lines
• Documented transformation of CLL to aggressive lymphoma (Richter’s transformation)
• Patients who are refractory to immunochemotherapy
• Calculated CrCl < 30 mL/min, or AST or ALT > 2.5 × ULN, or Total bilirubin ≥ 3 × ULN
• One or more individual organ/system impairment score of 4 as assessed by the CIRS definition
• Patients with a history of progressive multifocal leukoencephalopathy (PML)
• Regular treatment (i.e. more than 5 consecutive days) with corticosteroids during the 4 weeks prior to the start of Cycle 1, Day 1, unless administered for indications other than CLL at a dose equivalent to ≤ 30 mg/day prednisone
• Regular treatment with immunosuppressive medications following previous organ transplantation
• Vaccination with live vaccines within 28 days prior to start of treatment
• Positive test results for chronic hepatitis B, hepatitis C infections (HCV antibody are eligible only if PCR is negative for HCV RNA), positive test results (serology) for HIV, positive test results for HTLV 1 (un endemic areas)
• Women that are pregnant or lactating
• Fertile men or women of childbearing potential unless: (1) surgically sterile or (for women) ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method, during study and for 12 months (females) or 6 months (males) after end of treatment |
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E.5 End points |
E.5.1 | Primary end point(s) |
• To evaluate the safety and tolerability of obinutuzumab alone or in combination with chemotherapy
• Incidence, type, and severity of all adverse events (AEs), based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE, v4.0)
• Serious adverse events (SAEs)
• AEs of special interest (AESIs; AEs associated with any obinutuzumab infusion [defined as any serious treatment-related AEs occurring during or within 24 hours of an obinutuzumab infusion], serious infections, serious neutropenia, and tumor lysis syndrome)
• Dose delays/discontinuations
• Abnormalities identified through physical examinations, vital signs, and laboratory assessments |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessed at each visit: screening, days 1, 2, 8, 15, 29, 57, 85, 113, 141 during treatment, 169 then 225 and every 3 months until the end of study. |
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E.5.2 | Secondary end point(s) |
• To evaluate the efficacy of obinutuzumab alone or in combination with chemotherapy, as measured by:
- Minimal residual disease (MRD)-negativity by flow cytometry 3 months after last dose (i.e. at final response assessment visit).
- Overall response rate (ORR) at time of final response assessment visit
- Progression-free survival (PFS)
- Time to Response (TTR)
- Event-free survival (EFS)
- Best overall response (BOR)
- Overall survival (OS)
- Time to new anti-leukemia therapy (TTNT)
- Duration of response (DoR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessed at: screening, day 85 during treatment, 169 then 225 and every 3 months until the end of study. |
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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 | 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 | Yes |
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) | 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 142 |
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 |
Albania |
Argentina |
Belgium |
Bosnia and Herzegovina |
Brazil |
Canada |
China |
Denmark |
Egypt |
Estonia |
Finland |
France |
Germany |
Greece |
Ireland |
Israel |
Italy |
Korea, Republic of |
Latvia |
Lithuania |
Macedonia, the former Yugoslav Republic of |
Mexico |
Poland |
Romania |
Russian Federation |
Serbia |
Slovakia |
Slovenia |
Spain |
Switzerland |
Thailand |
Uruguay |
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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
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The study will end 30 months after the last patient has been enrolled, or earlier, if one of the following is documented for all treated patients: withdrawal from the study; loss to follow-up; death; or the study is prematurely terminated by the sponsor, whichever occurs first. The final analysis of OS and PFS will be conducted, and updated safety parameters will be summarized at this stage. |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |