E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
First line patients with chronic lymphocytic leukemia (CLL) with need for treatment. |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Lymphocytic Leukemia (CLL) |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 first-line patients with CLL. |
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E.2.2 | Secondary objectives of the trial |
To compare the confirmed CR rate after 6 cycles of treatment between the 2 treatment arms for the previously enrolled second-line patient population, and for pooled first and second-line populations patients with CLL.
To further collect information on efficacy for the 2 treatment combinations 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 further collect information on safety for the 2 treatment combinations in terms of adverse events (AEs), serious adverse events (SAEs), laboratory tests (standard hematology, and clinical chemistry), weight, vital signs, and physical examination. |
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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+ CD19+, and CD23+.
4. Patients with active CLL (Binet B and C) who require therapy per criteria according to the National Cancer Institute (NCI) criteria 2008.
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. 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. |
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E.4 | Principal exclusion criteria |
1. From amendment No. 2, patients already treated for their CLL (second-line patients) will not be allowed to enter in the study.
2. Any other concomitant anti-cancer therapy (e.g., chemotherapy, monoclonal antibodies, signal transduction inhibitors or antineoplastic hormones). Corticosteroids are allowed if they are given for reasons other than CLL and the dose is ≤ 20 mg of prednisolone-equivalent /day.
3. Patients with transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter’s syndrome or B-cell prolymphocytic leukemia [PLL]).
4. Known or suspected central nervous system (CNS) involvement of CLL.
5. Any other malignancy within 5 years prior to enrolment except curatively treated carcinoma in situ of the cervix, squamous cell carcinoma of the skin, or basal cell skin cancer. Cervical carcinoma stage 1B or less, breast cancer in situ, or localized prostate cancer stage T1c or less may be considered, provided that the patient was treated with curative intent and was relapse-free for at least 2 years prior to enrolment.
6. Major surgery (excluding lymph node biopsy) within 28 days prior to first cycle of study treatment.
7. Chronic or ongoing active infectious disease requiring systemic treatment, e.g., osteomyelitis.
8. History of clinically significant cerebrovascular disease with residual sequelae: e.g., prolonged reversible ischemic neurologic deficit or stroke (hemorrhagic or ischemic).
9. Patients who have known human immuno-deficiency virus infection or active hepatitis B virus or hepatitis C virus infection.
10. 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.
11. Screening laboratory values: check all laboratory values for adequate renal and hepatic function a) Creatinine clearance (CrCl) <30ml/minutes, b) Total bilirubin > 1.5 times upper limit of normal (ULN), c) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5 times ULN, d) Alkaline phosphatase > 2.5 times ULN.
12. Inadequate hematological function: a) Absolute Neutrophil Count (ANC) < 1.0 × 10exp9/L, unless due to involvement of BM by CLL, b) Platelet count < 50 × 10exp9/L, unless due to involvement of BM by CLL, c) Hemoglobin < 9.0g/dL, unless due to involvement of BM by CLL.
13. Known or suspected hypersensitivity to components of investigational product (in particular, known hypersensitivity or anaphylactic reactions to murine
antibodies or proteins).
14. Life expectancy less than 6 months.
15. Patients known or suspected of not being able to comply with a study protocol.
16. Pregnant or breast feeding patients.
17. 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.
18. Patients unable to provide informed consent.
19. Patients with severe autoimmune cytopenia as assessed by the physician (Coombs positive patients without clinical signs of autoimmune hemolytic anemia are eligible for study entry).
20. Patients who have received any investigational treatment within 30 days before screening.
21. Medical condition requiring chronic use of oral corticosteroids in doses > 20 mg of prednisolone-equivalent/day. Inhaled or topical steroids are permitted. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint is confirmed CR rates (Yes/No) after 6 treatment cycles (definition of confirmed CR rates is provided in section 5.3.2 of the protocol) in the first-line patient population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. "Confirmed CR rate" after 6 cycles in the previously enrolled second-line patient population, and for pooled first and second-line populations.
2. Overall response rate, complete response, partial response, stable disease, progression-free survival, disease-free survival, time to next leukemia treatment, duration of response, overall survival, molecular response, minimal residual disease
3. Safety: AEs, laboratory parameters
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. event-driven, tumour assessment after cycles 3, 6 and 12, and 3-monthly thereafter for at least 1 year.
2. throughout study, laboratory parameters every 4 weeks.
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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 | 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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | 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 | 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 |
Canada |
Finland |
France |
Netherlands |
Portugal |
Spain |
Sweden |
Tunisia |
Turkey |
United Kingdom |
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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 end of the clinical part of the study is the date of last patient last visit (LPLV), expected about June 2013. The patients will be followed until the cut off date for data collection (about 3Q/June 2013, or month 36, whichever is first). |
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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 | 5 |
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 |