| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic lymphocytic leukaemia / Small Lymphocytic Lymphoma |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10041152 |
| E.1.2 | Term | Small lymphocytic lymphoma, consistent with CLL (Working Formulation) |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
Complete Response (CR) rates for patients with high-risk CLL (Chronic Lymphocytic Leukaemia) remains an area where improved outcome is somewhat elusive. CLL210 is a study which hopes to improve the outcome of high-risk CLL patients by exploring whether the addition of a third drug called lenalidomide, and replacing alemtuzumab with another monoclonal antibody called ofatumumab to the regimen used in the CLL206 trial will improve patient outcome.
The addition of lenalidomide to ofatumumab and dexamethasone, together with additional drugs to reduce side effects, hopes to answer two specific questions. These primary outcomes are:
- INDUCTION QUESTION: CR\CRi and Tolerance rate after 6 months of induction therapy; tolerance is defined as absence of Grade 3+ infection and no treatment related death.
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| E.2.2 | Secondary objectives of the trial |
Another change from the CLL206 trial is the replacement of a steroid called HDMP with a different steroid called dexamethasone. Again the intention is to reduce toxicities experienced by patients receiving the treatment.
The secondary endpoints of the CLL210 trial are to assess:
- Overall, complete and partial response rates following induction therapy
- Minimal residual disease (MRD) negativity rate following induction therapy
- Overall survival (time from start of study treatment to death)
- Progression-free survival (time from initiation of study treatment to progression or death)
- Time to treatment failure (time from initiation of study treatment to treatment failure defined as progression, death or initiation of alternative treatment due to failure to achieve CR or PR)
- Duration of response (time from first achievement of CR or PR to first time of progression or death)
- Toxicity
- Quality of life
- Descriptive summary of Progression-free and overall survival among |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• CLL/SLL requiring treatment by IWCLL 2008 criteria. At least one of the following criteria should be met:
o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia.
o Massive (i.e. at least 6cm below the left costal margin) or progressive or symptomatic splenomegaly.
o Massive (i.e. at least 10cm in longest diameter) or progressive or symptomatic lymphadenopathy.
o Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months from a baseline value of at least 30x10^9/l and not due to causes other than CLL.
o Constitutional symptoms defined as at least 10% unintentional weight loss within the previous 6 months, significant fatigue preventing usual activities, or fever of at least 38°C for at least 2 weeks or night sweats for at least one month in the absence of infection.
• High risk CLL/SLL defined by at least one of the following criteria:
o TP53 deletion or mutation affecting at least 20% of CLL cells
o Resistant (SD/PD) to fludarabine-containing combination therapy
o Relapse within 12 months of responding to fludarabine-containing combination therapy
• No prior treatment with ofatumumab or lenalidomide
• CLL not known to be resistant to glucocorticoids
• No more than 3 previous treatment episodes for CLL
• WHO performance status 0-2
• Aged at least 18 years
• Written Informed Consent
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| E.4 | Principal exclusion criteria |
• Neutrophil count less than 0.5x10^9/l or platelet count less than 25x10^9/l
• Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia
• Total bilirubin >1.5 times upper normal limit (unless due to involvement of liver or a known history of Gilbert’s disease) or ALT >2.5 times upper normal limit (unless due to disease involvement of liver)
• Active infection
• Active gastritis or peptic ulcer disease
• Uncontrolled diabetes mellitus or hypertension
• History of recurrent thromboembolism
• Seropositivity for HIV, HCV or HBV (surface antigen)
• Renal impairment (eGFR less than 30ml/min)
• Hepatic impairment (serum bilirubin more than twice the upper limit of normal unless due to Gilbert’s syndrome or CLL)
• Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg od
• Presence or history of CNS disease (either CNS lymphoma or leukaemic meningitis)
• History of Richter transformation
• Concomitant malignancies except adequately treated localised non-melanoma skin cancers and other in-situ cancers, or invasive cancers that have been in remission for a period of time considered by the local investigator to pose a negligible risk of relapse during the period of the trial.
• Major surgery within 28 days prior to registration
• Any serious underlying medical or psychological conditions, which could impair the ability of the patient to participate in the trial or compromise ability to give informed consent
• Treatment within a clinical trial within 30 days prior to trial entry
• Adult patient under tutelage (not competent to sign informed consent)
• Pregnant or lactating women
• Patients unwilling or not able to adhere to the Lenalidomide Pregnancy Prevention Plan
• Women taking the oral contraceptive pill within 4 weeks of study registration owing to an increased risk of thromboembolism
• Women of childbearing potential, including women whose last menstrual period was less than 24 months prior to screening, unable or unwilling to use adequate contraception from study start to 28 days after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• INDUCTION THERAPY: (co-primary outcome):
- Tolerance rate for safety (<30% versus >50%) defined as the proportion of patients without Grade 3+ infection and treatment related death during induction therapy.
- CR rate for efficacy (<10% versus >20%, including patients with incomplete bone marrow recovery) after 6 months of induction therapy.
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| E.5.2 | Secondary end point(s) |
• Overall, complete and partial response rates following induction therapy
• Minimal residual disease (MRD) negativity rate following induction therapy
• Overall survival (time from start of study treatment to death)
• Progression-free survival (time from initiation of study treatment to progression or death)
• Time to treatment failure (time from initiation of study treatment to treatment failure defined as progression, death or initiation of alternative treatment due to failure to achieve CR or PR)
• Duration of response (time from first achievement of CR or PR to first time of progression or death)
• Toxicity
• Quality of life
• Descriptive summary of Progression-free and overall survival among transplant-eligible patients
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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 | 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 |
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| 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 | 27 |
| 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
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| The last visit of the last patient will define the end of the trial. This will be followed by the completion of a study report. |
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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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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