| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukaemia (CLL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Leukaemia is a cancer of the white blood cells. CLL is the most common type of Leukaemia. People with CLL make too many white blood cells called lymphocytes. |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008958 |
| E.1.2 | Term | Chronic lymphocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| This trial is intended to assess the efficacy of two doses of Ofatumumab (standard dose or high dose) in combination with chemotherapy (Fludarabine and Cyclophosphamide or Bendamustine) in relapsed B-CLL patients. The efficacy will be assessed by the complete response rates (CR or CR(i) by IWCLL criteria) in each treatment group. |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
The proportion of patients achieving undetectable minimal residual disease (MRD)(i.e. <0.01% CLL cells in the peripheral blood) following treatment.
-Overall response rates as defined by IWCLL criteria.
-Progression-free survival (i.e. time from randomisation to first evidence of disease progression or death).
-Overall survival (i.e. time from randomisation to date of death)
-Time to MRD relapse in MRD negative patients
-Dynamics of MRD relapse and its association with disease progression and survival
-Safety and toxicity (based on numbers of adverse events reported).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients fulfilling all of the following criteria are eligible for the study:
-At least 18 years old
-Chronic lymphocytic leukaemia requiring therapy
-Previous treatment with at least one chemotherapeutic regime
-Be capable of giving written informed consent
-World Health Organisation (WHO) performance status (PS) of 0, 1, or 2
-Life expectancy of at least 12 weeks
-Considered fit enough to receive fludarabine-based or bendamustine-based combinations
|
|
| E.4 | Principal exclusion criteria |
Patients with any of the following characteristics are ineligible for the trial:
-Applies only to participants to receive FC: Fludarabine refractory - defined as no response to or relapse within 6 months of fludarabine alone or in combination with cyclophosphamide (FC).
-Applies only to participants to receive FC: Relapse within 12 months of FC with rituximab (FCR).
-Applies only to participants to receive B: Bendamustine refractory (defined as no response to or relapse within 6 months of bendamustine alone or in any combinations other than with rituximab).
-Applies only to participants to receive B: Relapse within 12 months of bendamustine in combination with rituximab.
-Deletion of chromosome 17p on FISH
-Previous treatment with ofatumumab either alone or in combination with chemotherapy.
-Patients who previously experienced toxicity attributable to fludarabine or bendamustine such as autoimmune haemolytic anaemia, neurological toxicity or allergy should not be exposed to the same drug (if considered appropriate patients experiencing toxicity to fludarabine can be treated with bendamustine and vice versa).
-Active infection.
-Other severe, concurrent (particularly cardiac or pulmonary) diseases or mental disorders that could interfere with their ability to participate in the study.
-Patients with a creatinine clearance of less than 30ml/min should not be given fludarabine.
-Patients with a creatinine clearance of less than 10ml/min should not be given fludarabine or bendamustine.
-Pregnant, lactating or women of child bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.
-Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment has finished, unless they are surgically sterile. (Men who will be treated with bendamustine should seek advice about sperm conservation prior to treatment because of possible irreversible infertility)
Participants meeting any of the following criteria must not be enrolled in an ofatumumab study:
-Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
-Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
-Other past or current malignancy. Subjects who have been free of malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
-Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 3 months prior to start of therapy.
-Chronic or current 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.
-History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae
-Known HIV positive
-Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
-Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
-Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded. For subjects who are HBsAg negative, HBcAb positive and HB DNA negative a hepatitis B specialist should be consulted before ofatumumab treatment is initiated, and monitoring for HBV reactivation and preventative management should be undertaken during and for 6-12 months after the completion of ofatumumab treatment. If such a patient is being entered into the study please contact the Chief Investigator or one of the Co-Investigators to inform them of the management plan for the patient’s hepatitis during therapy.
-Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result
Screening laboratory values:
*platelets <50 x 109/L (unless due to involvement by CLL)
*neutrophils <1.0 x 109/L (unless due to in |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients achieving a Complete Response (CR or CR(i)) as defined by IWCLL criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 3 months after the end of therapy. |
|
| E.5.2 | Secondary end point(s) |
-Proportion of patients with undetectable minimal residual disease (MRD)
-Overall response rate defined as complete or partial remission by IWCLL Criteria
-Progression-free survival at 2 years
-Overall survival at 2 years
-Time to MRD relapse in MRD negative patients
-MRD growth rate following MRD becoming detectable
-Safety and toxicity
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Minimal residual disease (MRD): Baseline, After 3 cycles of therapy, 3 months after completion of therapy and 12, 18, 24 months post randomisation.
-Overall response rate: Baseline, After 3 cycles of therapy, 3 months after completion of therapy and 12, 18, 24 months post randomisation.
-Progression free survival: 24 months post randomisation.
-Overall survival: 24 months post randomisation
-Time to MRD relapse: 24 months post randomisation
_MRD growth rate: growth over a 1 year period from first detection
-Safety and toxicity: Reported based on adverse events, as graded by CTCAE V3.0, and determined by routine clinical assessments at each centre.
Patients will be followed up for disease progression and survival annually until death, as part of a long term follow up database. |
|
| 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) | No |
| 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
| 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 | 18 |
| 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 | No |
| 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
|
| The end of the trial is defined as the date of the collection of the last patient’s last data item. Long term follow up will continue via the CLL lon-term follow up database. |
|
| 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 | 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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