E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment |
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E.1.1.1 | Medical condition in easily understood language |
Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment |
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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 | 20.0 |
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) |
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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 |
The primary objective of the study is to evaluate the efficacy of a regimen of two debulking cycles of bendamustine chemotherapy followed by a sequential combination therapy of ofatumumab and ibrutinib for induction and maintenance treatment in CLL patients. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the safety of a regimen of two cycles of bendamustine followed by a sequential combination therapy of ofatumumab and ibrutinib for induction and maintenance treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Documented CLL requiring treatment (irrespective if first- or relapse treatment) according to iwCLL criteria1
In case of previously treated patients, these must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BIO trial:
- chemotherapy within ≥ 28 days
- antibody treatment within ≥ 14 days
- kinase inhibitors, Bcl-2-antagonists or immunomodulatory agents within ≥ 3 days
- corticosteroids may be applied until the start of the BIO-regimen, these have to be reduced to an equivalent of ≤ 20 mg prednisolone during treatment
2. Adequate hematologic function as indicated by a platelet count ≥ 25 x 109/L, a neutrophil count ≥ 1 ,0 x 1 09/L and a hemoglobin value ≥ 8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
3. Adequate renal function as indicated by a creatinine clearance ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hrs urine collection
4. Adequate liver function as indicated by a total bilirubin ≤ 2x, AST/ALT ≤ 2.5x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome
5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every two months until 6 months after last dosage of ofatumumab), negative testing for hepatitis-C RNA and negative HIV antibody test within 6 weeks prior to registration
6. Age ≥ 18 years
7. ECOG 0 to 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
8. Life expectancy ≥ 6 months
9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements |
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E.4 | Principal exclusion criteria |
1. Transformation of CLL (i.e. Richter’s transformation, prolymphocytic leukemia)
2. Known central nervous system (CNS) involvement
3. Patients with confirmed PML
4. Malignancies other than CLL currently requiring systemic therapy
5. Uncontrolled infection requiring systemic Treatment
6. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other lifethreatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion - could compromise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
7. Use of investigational agents which might interfere with the study drug within 3 days prior to registration
8. Known hypersensitivity to ofatumumab, ibrutinib or any of the excipients
Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
9. Requirement of treatment with strong CYP3A4-inhibitors/-inducers or anticoagulant with phenoprocoumon (marcumar), warfarin, or other vitamin k antagonists
10. History of stroke or intracranial hemorrhage within 6 months prior to registration
11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment, on day one of every debulking and induction cycle (monthly) and on day one of every maintenance cycle (every three months))
12. Fertile men or women of childbearing potential unless:
- surgically sterile or ≥ 2 years after the onset of menopause, or
- willing to use two methods of reliable contraception including one highly effective (Pearl
Index < 1) and one additional effective (barrier) method during study treatment and for 12 months after end of study treatment.
13. Vaccination with a live vaccine ≤ 28 days prior to registration
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regulatory or court order
16. Persons who are in dependence to the sponsor or an investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At final restaging (RE) 12 weeks after the start of the last cycle of induction therapy (end of induction treatment response = EOIT) including all patients achieving:
- a (clinical) complete response ((clinical) CR),
- a (clinical) CR with incomplete recovery of the bone marrow ((clinical) CRi),
- a partial response (PR) or PR with lymphocytosis. |
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E.5.2 | Secondary end point(s) |
Safety parameters: Type, frequency, and severity of
- adverse events (AE) and
- adverse events of special interest (AESI) and their relationship to study treatment
MRD levels (MRD negativity is defined as < 1 CLL-cell in 10,000 leukocytes analyzed [0.01%], i.e. < 10-4) measured in peripheral blood at
- final restaging after end of induction Treatment (12 weeks after last cycle of induction treatment) in all patients responding to study treatment and
- every 12 weeks (= 3 months) during the maintenance phase if the patient achieved a (clinical) CR or CRi or
- every 24 weeks (= 6 months) during the maintenance phase in patients with a PR or PR with lymphocytosis
MRD level in bone marrow optionally in patients with (clinical) CR or CRi 3 months after achievement of MRD negativity in peripheral blood
Best response rate (BRR) until 6 months after RE
ORR after debulking
ORR after end of maintenance treatment
ORR in the two strata of previously untreated and relapsed / refractory patients, as well as in the fit and unfit patients for all mentioned response definitions
ORR in biological defined risk groups
(Clinical) CR / CRi rate
Progression-free survival (PFS)
Event-free survival (EFS)
Overall survival (OS)
Duration of response in patients with:
- (clinical) complete response (CR),
- (clinical) CR with incomplete recovery of the bone marrow (CRi),
- partial response (PR) and
- PR with lymphocytosis
Treatment free survival and time to next CLL treatment
Evaluation of relationship between various baseline markers and clinical outcome parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ongoing evaluation during the trial |
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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 | 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.8.3 |
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 | 20 |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |