| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated or Relapsed Chronic Lymphocytic Leukaemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic lymphocytic leukemia is a condition where too many abnormal white blood cells are produced which build up and reduce the number of normal blood cells that can be made. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 | 10008968 |
| E.1.2 | Term | Chronic lymphocytic leukaemia stage A(0) |
| 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 |
| The primary objective of this study is to evaluate the investigator assessed overall response rate (ORR), using the IWCLL updated NCI-WG guidelines [Hallek 2008], in two populations i.e., subjects with previously untreated CLL and subjects with relapsed CLL administered ofatumumab plus bendamustine. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate overall response rate with CT scan assessment, complete response rate with and without CT scan assessment, progression-free-survival, overall survival, time to response, duration of response, time to progression and time to next therapy in the two separate subject populations i.e., subjects with untreated CLL and subjects with relapsed CLL.
• To evaluate the safety and tolerability in the two separate subject populations i.e., subjects with untreated and subjects with relapsed CLL.
• To evaluate disease, prognostic and biological marker correlation with clinical response in the two separate subject populations i.e. subjects with untreated CLL and subjects with relapsed CLL.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. A diagnosis of CLL defined by:
a. A circulating B-lymphocyte count of ≥5,000/μL at study entry or at any time in the past.
b. Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20, CD23, CD79b, and surface Ig prior to first dose of study treatment.
2. Active disease and indication for treatment based on the IWCLL updated NCI-WG guidelines [Hallek 2008], defined by presence of at least any one of the following conditions:
• Evidence of progressive marrow failure as manifested by development or worsening of anaemia and/or thrombocytopenia.
• Massive (i.e. at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
• Massive nodes (i.e. at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
• Progressive lymphocytosis with an increase of more than 50% over a two-month period or a lymphocyte doubling time of less than 6 months.
In subjects with initial blood lymphocyte counts of less than 30x109/L, lymphocyte doubling time should not be used as a single parameter to define a treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
• A minimum of any one of the following disease-related symptoms must be present:
a. Unintentional weight loss ≥ 10% within the previous six months;
b. Fevers > 100.5°F (38.0°C) for ≥ 2 Weeks without evidence of infection;
Or
c. Night sweats for more than 1 month without evidence of infection.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
4. Age ≥ 18 years.
5. Signed written informed consent from either the subject, or their legally acceptable representative if the subject is incapable of giving their own consent, prior to performing any study-specific tests or procedures.
Subjects enrolled into the previously untreated subject cohort must also meet all of the following criteria:
6. No prior treatment for CLL (prior corticosteroid immunosuppression treatment for autoimmune hemolytic anaemia and idiopathic thrombocytopenic purpura (ITP) is permitted).
7. Considered inappropriate for fludarabine-based therapy for reasons that include, but are not limited to, advanced age or presence of co-morbidities.
Subjects enrolled into the relapsed subject cohort must also meet the following criteria:
8. Relapsed CLL: defined as a subject who has received at least one prior CLL therapy and previously achieved a complete or partial remission/response lasting at least 6 months [Hallek, 2008].
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months of the last anti-CLL therapy [Hallek, 2008].
2. Previous autologous or allogeneic stem cell transplantation.
3. Active autoimmune hemolytic anaemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) requiring corticosteroid therapy >25 mg prednisone (or equivalent) or chemotherapy.
4. Known transformation of CLL (e.g. Richter’s).
5. Known central nervous system involvement by CLL.
6. Screening laboratory values:
a. Platelets < 100 x 109/L (unless due to CLL involvement of the bone marrow).
b. Neutrophils < 1.5 x 109/L (unless due to CLL involvement of the bone marrow).
c. Serum creatinine > 1.5 times the upper limit of normal (ULN); subjects with a serum creatinine > 1.5 ULN will be eligible if the calculated creatinine clearance [Cockcroft, 1976] is ≥ 30 mL/min.
d. Total bilirubin > 1.5 times ULN (unless due to liver involvement by CLL or Gilbert’s disease).
e. Transaminases > 2.5 times ULN.
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, active Hepatitis C, and known Human Immunodeficiency Virus (HIV) disease. All HIV-positive subjects are excluded from this study, regardless of whether they have an Acquired Immunodeficiency Syndrome (AIDS) defining disease and/or are on antiviral therapy.
8. 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 tumour was successfully treated with curative intent at least 2 years prior to trial entry.*
9. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to first study treatment, 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 use, unless given in doses ≤ 25mg/Day prednisone (or equivalent) for <7 Days for exacerbations other than CLL (e.g. asthma).*
12. Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg but Hepatitis B core antibody (HBcAb) positive, a Hepatitis B Virus (HBV) DNA test will be performed and if positive the subject will be excluded.
If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring at Cycles 2, 3, 4, 5 and 6 depending on the number of Cycles administered and during the follow-up phase at the 3 Month and 6 Month post drug visits. Prophylactic antiviral therapy may be initiated at the discretion of the investigator. Please see Table 5 for further details.
13. Known or suspected hypersensitivity to ofatumumab or bendamustine that in the opinion of the investigator is a contraindication to their participation in the present study.
14. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 Weeks prior to first study treatment dose, whichever is longer, or participation in any other interventional clinical study.
15. Known or suspected inability to comply with the study protocol.
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 sterilisation 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).
*Subjects can participate in the study 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall response rate (ORR) as determined by Investigator evaluation, is the percentage of subjects achieving an objective response (i.e., partial response or better), using the IWCLL updated NCI-WG guidelines [Hallek 2008]. Response assessment is planned at the following time-points:
• After 3 Cycles of ofatumumab plus bendamustine treatment.
• After 6 Cycles of ofatumumab plus bendamustine treatment.
• After the last dose, if not after 6 cycles, of ofatumumab plus bendamustine treatment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 3 Cycles of ofatumumab plus bendamustine treatment. Last Subject = approx. Nov-2012
After 6 Cycles of ofatumumab plus bendamustine treatment. Last Subject = approx. Feb-2013
After the last dose, if not after 6 cycles, of ofatumumab plus bendamustine treatment. Last Subject = approx. Feb-2013
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| E.5.2 | Secondary end point(s) |
• Overall Response Rate (ORR) with CT-scan assessment as determined by Investigator evaluation, is the percentage of subjects achieving an objective response (i.e., partial response or better), using the IWCLL updated NCI-WG guidelines [Hallek 2008]. Response assessment is planned at the following time-points:
- After 3 Cycles of ofatumumab plus
bendamustine treatment.
- After 6 Cycles of ofatumumab plus
bendamustine treatment.
- After the last dose, if not after 6
cycles, of ofatumumab plus bendamustine
treatment.
• Complete responses rate (CRR) as determined by Investigator evaluation, using the IWCLL updated NCI-WG guidelines [Hallek 2008], with and without CT scan assessment.
• Progression free survival (PFS).
• Overall survival (OS).
• Time to response and duration of response.
• Time to progression and time to next therapy.
• Incidence and severity of adverse events.
• Incidence and severity of serious adverse events.
• Incidence and severity of infusion reactions.
• Frequency of transfusions.
• Incidence of autoimmune hemolytic anaemia (AIHA).
• Development of Human Anti Human Antibodies (HAHA).
• Incidences of Grade 3 and 4 infections and myelosuppression (anaemia, neutropenia, thrombocytopenia).
• Changes in B-cell levels.
• Change in IgG, IgA, IgM quantities.
• Improvement of ECOG (Eastern Cooperative Oncology Group) performance status.
• Improvement in constitutional symptoms.
• Improvement in fatigue.
• Minimal Residual Disease (MRD), for subjects achieving a CR, as determined by flow cytometry.
• Cytogenetics by fluorescent in situ hybridization (FISH).
• β2 microglobulin.
• IgVH mutational status, VH3-21 usage.
• ZAP70.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As above and at the completion of the study (Jun-2016) |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Belgium |
| Czech Republic |
| Germany |
| Greece |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| United States |
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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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| LSLV will be the end of 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
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