E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukaemia |
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MedDRA Classification |
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 of combination ofatumumab-fludarabine-cyclophosphamide therapy vs. fludarabine-cyclophosphamide therapy for the treatment of relapsed CLL. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate clinical benefit, changes in patient reported outcome (PRO) measures, safety, tolerability and pharmacokinetics of subjects treated with ofatumumab in combination with fludarabine and cyclophosphamide. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A sub-study will be conducted at selected sites in order to determine whether ofatumumab has an effect on the corrected QT interval (QTc) interval or on fludarabine or cyclophosphamide pharmacokinetics.
Details are included in Appendix 6 of the protocol (OMB110913, dated 2008-08-22), Section 11.6.
All patients enrolled at participating sites are encouraged to enroll in the QTc and drug-drug interaction sub-study in order to avoid patient selection bias. A total of 50 subjects (25 per treatment arm) will participate in the sub-study.
Objectives:
- To evaluate the potential effect of ofatumumab on QTc interval
- To evaluate the potential effect of ofatumumab on fludarabine or cyclophosphamide pharmacokinetics |
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E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20, CD23, CD79b, and surface Ig prior to Visit 2
2. Active disease and indication for treatment based on modified IWCLL updated NCI-WG guidelines [Hallek, 2008] defined by presenting at least one of the following conditions:
• Evidence of progressive marrow failure as manifested by development of, or worsening of anemia, and/or thrombocytopenia
• Massive (i.e., greater than 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
• Massive nodes (i.e., greater than 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of more than 50% over a 2 month period or lymphocyte doubling time of less than 6 months
• A minimum of any one of the following disease-related symptoms must be present:
a. Unintentional weight loss more than or equal to 10% within the previous 6 months
b. Fevers of greater than 100.5○F (38.0ºC) for 2 or more weeks without other evidence of infection
c. Night sweats for more than 1 month without evidence of infection
3. Relapsed CLL: defined as a subject who has received at least one prior CLL therapy and previously achieved a complete or partial remission/response, but after a period of 6 or more months, demonstrate evidence of disease progression [Hallek 2008].
4. ECOG Performance Status of 0-2
5. Life expectancy of at least 6 months
6. Age ≥ 18 years
7. 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. Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months of last anti-leukemic therapy [Hallek, 2008]
2. Subjects with platelet count less than 50,000/microliter and ANC less than or equal to 1000/microliter
3. Previous autologous or allogeneic stem cell transplantation
4. Active Autoimmune Hemolytic Anemia (AIHA) requiring corticosteroid therapy greater than 100mg equivalent to hydrocortisone, or chemotherapy
5. Known transformation of CLL (e.g. Richter’s Transformation/syndrome)
6. Known CNS involvement of CLL
7. 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 C
8. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible
9. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities
10. History of significant cerebrovascular disease or event with significant symptoms or sequelae
11. Glucocorticoid unless given in doses ≤ 100mg/day hydrocortisone (or equivalent dose of other glucocorticoid) for less than 7 days for exacerbations other than CLL (e.g. asthma)
12. Known HIV positive
13. Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive and HBsAb negative, a HB DNA test will be performed and if positive the subject will be excluded. Note: If HBcAb positive and HBsAb positive, which is indicative of a past infection, the subject can be included.
14. Screening laboratory values:
• 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)
• Alanine Aminotransferase (ALT) > 3.0 times upper normal limit (unless due to liver involvement of CLL)
15. Previous treatment or known or suspected hypersensitivity to ofatumumab
16. Treatment with any known non-marketed drug substance or experimental therapy within 5-terminal half-lives or 4 weeks prior to Visit 1, whichever is longer or currently participating in any other interventional clinical study
17. Subjects known or suspected of not being able to comply with a study protocol
18. 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 treatment dose. Adequate contraception is defined as abstinence, oral hormonal birth control, hormonal birth control injections, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that subject. The double barrier method can be used in regions where considered acceptable and adequate (condom or occlusive cap plus spermicidal agent).
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E.5 End points |
E.5.1 | Primary end point(s) |
• Progression free survival (PFS), defined as the interval between randomization until disease progression or death |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 77 |
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 | Information not present in EudraCT |
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 |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |