| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First line or second line (maximum of 1 line of previous treatment) patients with chronic lymphocytic leukemia (CLL) with need for treatment. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
|
| 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 |
| To compare the confirmed complete response (CR) rate after 6 cycles of treatment between the two treatment arms for the pooled first-line and second-line patients with CLL. |
|
| E.2.2 | Secondary objectives of the trial |
To further confirm the effectiveness of addition of Rituximab to Bendamustine or Chlorambucil with respect to tumor response categories (overall response rate [ORR], CR, CR with incomplete marrow recovery (CRi), partial response [PR], nodular partial response [nPR], stable disease [SD] or progressive disease [PD]), progression-free survival (PFS), disease-free survival (DFS), event-free survival (EFS), time to next leukemia treatment (TNLT), duration of response, overall survival (OS), molecular response, and minimal residual disease (MRD).
To assess safety in terms of adverse events (AEs), serious adverse events (SAEs), laboratory tests (standard hematology, immunoglobulins and clinical chemistry), weight, vital signs and physical examination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent.
2. 18 years of age or older.
3. Tumor cell phenotype consistent with CLL: CD5 + CD20 + CD23 +.
4. Active CLL with progressive Binet stage B or C and requiring therapy according to National Cancer Institute (NCI) criteria 2008 [Appendix 5 of the protocol] (Please
note; only one of the criteria listed needs to be met).
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
6. Ineligible for treatment with fludarabine. Reasons can be:
a) Concurrent medical conditions, such as history of opportunistic infections, repeated grade 3 or 4 infections of other types,
b) Patients with severe impairment of bone marrow (BM) function (thrombocytopenia, anemia, and/or granulocytopenia), other than for reasons of underlying disease (CLL),
c) Immunodeficiency,
d) Elderly persons (≥ 75 years) since there are limited data
for the use of fludarabine in this population,
e) Previous history of autoimmune processes or positive Coombs test status,
f) Autoimmune phenomena (e.g., autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans’
syndrome),
g) Judgment of the treating physician.
7. Only pretreatment with Rituximab and/or Chlorambucil is allowed for second-line patients.
8. A negative serum pregnancy test within 1 week before the first cycle of treatment must be available for women who are ≤ 2 years after the onset of menopause and not sterilized surgically. |
|
| E.4 | Principal exclusion criteria |
1. Patients who have received prior treatment with Rituximab or Chlorambucil who have relapsed in less than 12 months since the first dose of first-line therapy (second-line patients only).
2. Previous autologous stem cell transplantation or planned autologous stem cell transplantation during the study.
3. Previous allogeneic stem cell transplantation or planned allogeneic stem cell transplantation during the study.
4. Radioimmunotherapy within the last 6 months before starting treatment.
5. Any other concurrent anti-cancer therapy (e.g., alkylating agents, anti-metabolites, purine analogues, monoclonal antibodies) or glucocorticoid unless given in doses equivalent to ≤ 20 mg of prednisolone/day. Inhaled or topical steroids are permitted.
6. Patients previously treated with Ofatumumab.
7. Patients with transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter’s syndrome or B-cell prolymphocytic leukemia [PLL]).
8. Known or suspected central nervous system (CNS) involvement of CLL.
9. Past or current malignancy within the last 2 years before screening, except for: a) Cervical carcinoma Stage 1B or less, b) Non-invasive basal cell and squamous cell skin carcinoma, c) Malignant melanoma with CR of a duration of > 10 years, d) Other cancer diagnoses with a CR of a duration of > 5 years.
10. Major surgery (excluding lymph node biopsy) within 28 days prior to first cycle of study treatment.
11. Chronic or ongoing active infectious disease requiring systemic treatment, e.g., osteomyelitis.
12. History of significant cerebrovascular disease, e.g., Prolonged Reversible Ischemic Neurologic Deficit or stroke (hemorrhagic or ischemic).
13. Patients who have known human immuno-deficiency virus infection or active hepatitis B virus or hepatitis C virus infection.
14. Serious underlying medical conditions, which could impair the ability of the patient to participate in the study (e.g., uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease, uncontrolled hypertension or pre-existing cardiac condition, severe chronic obstructive pulmonary disease with hypoxemia, or major organ malfunction [liver, kidney]). The investigator’s judgment should be exercised.
15. Screening laboratory values: check all laboratory values a) Creatinine > 1.5 times upper normal limit [ULN], b) Total bilirubin > 1.5 times ULN (unless due to liver
involvement of CLL), c) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5 times ULN (unless due to liver involvement of CLL), d) Alkaline phosphatase > 2.5 times ULN (unless due to liver involvement of CLL).
16. Inadequate hematological function: a) Absolute Neutrophil Count (ANC) < 1.0 × 109/L, unless due to involvement of BM by CLL, b) Platelet count < 50 × 109/L, unless due to involvement of BM by CLL, c) Hemoglobin < 9.0g/dL, unless due to involvement of BM by CLL.
17. Known or suspected hypersensitivity to components of investigational product (in particular, known hypersensitivity or anaphylactic reactions to murine
antibodies or proteins).
18. Life expectancy less than 6 months.
19. Patients known or suspected of not being able to comply with a study protocol.
20. Pregnant or breast feeding patients.
21. Male and female patients with reproductive potential not willing to use effective method of contraception (oral contraceptives, intrauterine device or barrier method of
contraception in conjunction with spermicidal jelly or surgically sterile) during study and 1 year after last dose of study medication.
22. Patients unable to provide informed consent.
23. Patients with significant autoimmune cytopenia as assessed by the physician (Coombs positive patients without clinical signs of autoimmune hemolytic anemia are eligible for study entry).
24. Patients who have received any investigational treatment within 30 days before screening.
25. Medical condition requiring chronic use of oral corticosteroids. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is confirmed CR rates (Yes/No) after 6 treatment cycles |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| pronostic markers and confirmation of diagnosis assessment |
|
| 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 |
| comparison between two combination regimens |
|
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 |
|
| 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
|
see protocol section 3.1.3 page 29:
The end of the clinical part of the study is the date of last patient last visit (LPLV), expected about June 2013. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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