E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukaemia |
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E.1.1.1 | Medical condition in easily understood language |
Chronic lymphocytic leukemia is a cancer of the B-cells (a type of 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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068919 |
E.1.2 | Term | B-cell 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 |
The primary objective is to evaluate progression free survival (PFS) of ofatumumab maintenance treatment versus no further treatment after remission induction in subjects with relapsed Chronic Lymphocytic Leukaemia (CLL). |
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E.2.2 | Secondary objectives of the trial |
● To evaluate the improvement in response, improvement in response time to next CLL treatment and overall survival in subjects receiving ofatumumab maintenance compared to no further treatment
● To evaluate the PFS after next-line therapy and the time to progression after nextline therapy
● To evaluate the safety and tolerability in subjects with CLL receiving ofatumumab maintenance compared to no further treatment
● To evaluate the health-related quality of life in subjects with CLL receiving ofatumumab maintenance compared to no further treatment as assessed by changes in patient reported outcome (PRO) measures relative to baseline
● To evaluate prognostic marker correlation with clinical response in subjects with CLL receiving ofatumumab maintenance compared to no further treatment
● To evaluate ofatumumab pharmacokinetic parameters in subjects with CLL receiving maintenance ofatumumab every 2 months
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
Adults with documented diagnosis of CLL based on the modified IWCLL updated NCIWG guidelines
1. At least PR according to the revised 2008 NCI-WG CLL criteria within 3 months of the response assessment after the last dose of 2nd/3rd line treatment
2. The anti-leukemic treatment before study entry should have been for at least 3 months or 3 cycles
3. ECOG Performance Status of 0-2
4. Signed written informed consent prior to performing any study-specific procedures
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
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E.4 | Principal exclusion criteria |
1. Known primary or secondary fludarabine-refractory subjects, defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months
2. Prior maintenance therapy
3. Known transformation of CLL (e.g. Richter’s transformation), prolymphocytic leukemia (PLL), or CNS involvement of CLL
4. Active Autoimmune Hemolytic Anemia (AIHA) requiring treatment except if in the opinion of the investigator it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data
5. Previous autologous or allogeneic stem cell transplantation
6. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis B or C (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 HBV DNA test will be performed and if positive the subject will be excluded*.)
7. Other past or current malignancy (with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix or breast) unless the tumor was successfully treated with curative intent at least 2 years prior to trial entry except if in the opinion of the investigator it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data
8. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities except if in the opinion of the investigator it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data
9. History of significant cerebrovascular disease or event with symptoms or sequelae
10. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study
11. Other anti-leukemic use of medications including glucocorticoids
12. Known HIV positive
13. Screening laboratory values:
• Platelets<50 x 10^9/L
• Neutrophils<1.0 x 10^9/L
• Creatinine > 1.5 times upper normal limit (unless normal creatinine clearance)
• Total bilirubin > 1.5 times upper normal limit (unless due to liver involvement of CLL or Gilbert’s syndrome)
• Alanine Aminotransferase (ALT) > 2.5 times upper normal limit (unless due to liver involvement of CLL)
• Alkaline phosphatase > 2.5 times upper normal limit
14. Known or suspected hypersensitivity to ofatumumab that in the opinion of the investigator or medical monitor contraindicates study participation
15. Subjects who have received treatment with any non-marketed drug substance or experimental therapy within 5-terminal half-lives or 4 weeks whichever is longer prior to first dose of study medication or currently participating in any other interventional clinical study
Note: Participation in any other interventional clinical study after disease progression during post PD follow-up is permitted.
16. Lactating women, women with a positive pregnancy test at Visit 1 or women (of childbearing potential) as well as men with partners of childbearing potential, who are not willing to use adequate contraception from study start through one year following last ofatumumab dose. Adequate contraception is defined as abstinence, oral hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that subject. For females in the USA, the use of a double barrier method is also considered adequate (condom or occlusive cap plus spermicidal agent).
* If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring (see Section 6.3.4 of study protocol). Prophylactic antiviral therapy may be initiated at the discretion of the investigator. Consult with a physician experienced in the care and management of subjects with hepatitis B to manage/treat subjects who are anti-HBc positive. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is progression-free-survival which is defined as the time from randomization to the date of disease progression or death due to any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Calculated from entry into the study until the time of disease progression (or death due to any cause). To be evaluated at interim efficacy analysis (events =187 events) and at the time the full number of events are reached (280 events)
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E.5.2 | Secondary end point(s) |
Secondary Endpoints:
Clinical:
● Improvement in response
● Time to next treatment
● Overall survival
● Progression-free survival after next-line therapy
● Time to progression after next-line therapy
● Changes in patient reported outcome (PRO) measures
● Changes in patient reported outcome (PRO) scores
● Improvement of ECOG performance status
● B-symptoms/Constitutional symptoms/fatigue
● Incidences of and number of subjects with grade 3 and 4 infections
● Incidence, severity of adverse events, serious adverse events and other safety parameters
● Evaluation of myelosuppression (anemia, neutropenia, thrombocytopenia)
● Frequency of transfusions
● Incidence of Autoimmune Hemolytic Anemia (AIHA)
● Human Anti Human Antibodies (HAHA)
● IgG, IgA, IgM serum levels
Disease markers:
● Minimal Residual Disease (MRD)
● B-cell monitoring
● Prognostic markers correlating with clinical response:
● Cytogenetics by fluorescent in situ hybridization (FISH)
● IgVH mutational status
● β2 microglobulin
● Changes in complement levels
Pharmacokinetics:
● Plasma ofatumumab concentrations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Improvement in response--- assessed at each visit (every 2 months during study, every 3 months in follow-up)
•Time to next treatment—following progressive disease, assessed ~ every 3 months in survival follow-up (at minimum- yearly)
•Overall survival-assessed at each visit (e every 2 months during study, every 3 months in follow-up, ~ every 3 months in survival follow-up) until time of death
•PFS after next-line treatment- assessed after next CLL treatment at every survival follow-up visit (~ every 3 months)
•Changes in PRO measures –assessed at baseline, study visits and follow-up
•Changes in PRO scores- assessed at baseline, study visits and follow-up
•Improvement of ECOG performance- assessed at baseline, study visits and follow-up |
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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 | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 81 |
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 |
Argentina |
Australia |
Brazil |
Canada |
India |
Israel |
Korea, Republic of |
Russian Federation |
Turkey |
Ukraine |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |