| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CD20+ CLL, Binet stage C or Binet stages A-B |
|
| 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 | 10008956 |
| E.1.2 | Term | Chronic lymphatic leukaemia |
|
| 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 evaluate the activity of the CLB and R combination in terms of overall tumor response (OR) at the end of the induction phase. |
|
| E.2.2 | Secondary objectives of the trial |
- Complete response rate (CR), complete response rate with incomplete bone marrow recovery (CRi) and partial response rate (PR) at the end of the induction phase
- overall tumor response, CR, CRi and PR at the end of the rituximab maintenance phase versus observation
- immunophenotypic CR, defined as absence of minimal residual disease (MRD) evaluated in CR by 4-color flow cytometry in PB and BM B cells
- molecular CR, defined as absence of MRD evaluated in CR by quantitative PCR in PB and BM B-cells
- event-free survival (EFS)
- progression-free survival (PFS)
- duration of response
- disease-free survival (DFS) in CR
- time to new CLL treatment or death (TTNT)
- overall survival (OS)
- response rate, duration of response, survival times and TTNT in biological subgroups defined on the basis of
o Serum parameters (serum levels)
o Genetic characteristics
o Immunophenotypic expression
o Molecular genetics
et al... |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Established diagnosis of CD20+ CLL by IWCLL criteria (6) (Appendix 15) updating the NCI 1996 guidelines (49)
- Criteria of disease requiring treatment (IWCLL criteria (6)):
– Binet stage C (Appendix 16)
– Binet stages A-B (Appendix 16) plus at least one of the following signs or symptoms:
(1) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
(2) Massive (i.e., >6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
(3) Massive nodes (i.e., >10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
(4) Progressive lymphocytosis with a >50% increase over a 2-months period, or a lymphocyte doubling time (LDT) of less than 6 months. LDT can be obtained by linear regression extrapolation of the absolute lymphocyte counts (ALC) obtained at intervals of two weeks over an observation period of 2-3 months; patients with initial blood lymphocyte counts of less than 30.000/μl may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
(5) Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy.
(6) A minimum of any one of the following disease-related symptoms must be present:
(a) Unintentional weight loss ≥10% within the previous 6 months.
(b) Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities).
(c) Fevers of greater than 100.5 F or 38.0 C for 2 or more weeks without other evidence of infection.
(d) Night sweats for more than 1 month without evidence of infection.
– No previous treatment of CLL by chemotherapy, radiotherapy or immunotherapy.
– Patients with age >65 years or with age between 60 and 65 years if not suitable for fludarabine-based regimens according to the investigator’s judgment.
– IgG levels ≥4 g/L.
– Life expectancy >6 months.
– ECOG performance status 0-1 or worse if caused by CLL.
– Willingness to use contraception for men for the entire duration of the treatment and for 12 months thereafter.
– Patient's written informed consent. |
|
| E.4 | Principal exclusion criteria |
– Patients with a history of other malignancies within 2 years prior to study entry, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin carcinoma, low grade, early stage localized prostate cancer treated surgically with curative intent, good prognosis DCIS of the breast treated with lumpectomy alone with curative intent.
– Patients with co-morbid conditions who would require long term use (>1 month) of systemic corticosteroids during study treatment (e.g. chronic obstructive pulmonary disease [COPD]). Steroid use ≤1 month is permissible.
– Patients with active bacterial, viral, or fungal infection requiring systemic therapy.
– Creatinine ≥2 ULN.
– Creatinine clearance <50 ml/min.
– Alkaline phosphatase and transaminases ≥2 ULN.
– Total bilirubin ≥2 ULN.
– HIV, HBV* and HCV positivity with viral load.
– Patients with a history of severe cardiac disease, e.g. NYHA functional class III or IV, heart failure, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, or unstable angina.
– Seizure disorders requiring anticonvulsant therapy and cerebral dysfunction which makes it impossible to perform therapy.
– Severe chronic obstructive pulmonary disease with hypoxemia.
– Uncontrolled diabetes mellitus.
– Uncontrolled hypertension.
– Clinically significant auto-immunocytopenia, Coombs-positive hemolytic anemia not responsive to steroids as judged by treating physician.
– Major surgery or significant traumatic injury within 4 weeks of study start.
– Transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter's syndrome, or prolymphocytic leukemia).
– Known hypersensitivity or anaphylactic reaction to monoclonal antibodies, proteins or chlorambucil.
– Any coexisting medical, psychological or social condition that would preclude participation in the required study procedures or compromise ability to give informed consent or may affect the interpretation of the results or render the patient at high risk from treatment complications.
– Treatment with any other investigational agent, or participating in another clinical trial within 30 days prior to entering this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall tumor response (responder/non-responder) at the end of the induction phase.
The primary analysis of primary endpoint will be performed on the ITT population. In order to assess the robustness of the primary analysis, the primary analysis will be repeated for the per-protocol population. |
|
| 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 | No |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
| |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 0 |
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