Sequential Regimen of Bendamustine-Debulking Followed by CAL-101 and GA101-Induction and -Maintenance in CLL (CLL2-BCG)

Study Overview
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Brief Summary
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The CLL2-BCG-trial is a prospective, open-label, multicenter phase-II-trial to evaluate the efficacy and safety of a sequential regimen of a debulking with bendamustine followed by an induction with GA101 (obinutuzumab) and CAL-101 (idelalisib) followed by CAL-101 and GA101-maintenance in CLL patients

Detailed Description
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In the CLL2-BCG-trial, a total of 62 patients of an allcomer CLL population (irrespective of physical fitness, previous therapies and prognostic factors) with an indication for treatment will be included. Patients will receive 2 cycles of debulking treatment with bendamustine unless contraindications (e.g. refractoriness) are present or a debulking is not indicated due to a low tumor burden. Afterwards, 6 cycles of induction treatment with GA101 (obinutuzumab, 3 doses in the first cycle and monthly in cycles 2-6) and CAL-101 (idelalisib, continuously starting in cycle 2) will be applied. The primary endpoint overall response rate will be assessed at final restaging (2 months after end of induction treatment). Patients benefitting from treatment receive further therapy with GA101 (3 monthly) and CAL-101 (continuously) in a maintenance phase for up to 24 months. Maintenance treatment will be stopped in case of achievement of a complete remission and confirmation of MRD (minimal residual disease) negativity in peripheral blood or if unacceptable toxicity or progression occurs.

Official Title
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Prospective, Open-label, Multicenter Phase-II Trial to Evaluate Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 (Obinutuzumab) and CAL-101 (Idelalisib) Followed by CAL-101 and GA101 Maintenance in CLL Patients

Conditions
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Chronic Lymphocytic Leucemia

Intervention / Treatment
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* Drug: Bendamustine
* Drug: GA101
* Drug: CAL-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: documented chronic lymphocytic leukemia (CLL) requiring treatment according to International Working Group on CLL (iwCLL) criteria adequate hematologic function: platelets ≥ 25.000/µl, neutrophils ≥ 1.000/µl and hemoglobin ≥8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration) adequate renal function: a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection adequate liver function: total bilirubin ≤1,5x, aspartate aminotransferase (AST) / alanin aminotransferase (ALT) ≤2.5x the institutional upper limit of normal (ULN) value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome negative serological testing for hepatitis B, negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2, ECOG 3 is only permitted if related to CLL life expectancy ≥ 6 months ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements Exclusion Criteria: transformation of CLL (i.e. Richter's transformation, prolymphocytic leukemia) known central nervous system (CNS) involvement confirmed progressive multifocal leukoencephalopathy (PML) malignancies other than CLL currently requiring systemic therapies uncontrolled infection requiring systemic treatment any comorbidity or organ system impairment rated with a cumulative illness rating scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening 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) ongoing inflammatory bowel disease ongoing drug induced pneumonitis use of investigational agents which would interfere with the study drug ≤28 days prior to registration known hypersensitivity to GA101 (obinutuzumab), CAL-101 (idelalisib) or any of the excipients pregnant women and nursing mothers 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 18 months after end of study treatment vaccination with a live vaccine ≤28 days prior to registration legal incapacity prisoners or subjects who are institutionalized by regulatory or court order persons who are in dependence to the sponsor or an investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine + GA101 + CAL-101<br>Bendamustine: 70 mg/m2 i.v. GA101: 1000 mg CAL-101: 150 mg p.o. | Drug: Bendamustine<br>* Debulking: Cycles 1 - 2, d1 & 2: 70 mg/m2 i.v.<br>Drug: GA101<br>* Induction: Cycle 1: d1: 100mg, d1(or2): 900mg, d8 & 15: 1000mg; Cycle 2-6: d1: 1000mg Maintenance: Cycle 1-8 (Duration 12 weeks): d1 1000 mg.<br>* Other names: Obinutuzumab;Drug: CAL-101<br>* Induction: Cycle 2-6: d1-28: 150 mg p.o. Maintenance: Cycles 1-8 (Duration 12 weeks): d1-84 150 mg p.o.<br>* Other names: Idelalisib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Proportion of patients responding according to international working Group on chronic lymphocytic leukemia criteria | 84 days after start of the last induction cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) and adverse events of special interest (AESI) | Type, frequency and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment | up to 40 months after first dose of study drug | 
| Rate of minimal residual disease (MRD) | Rate of MRD responses in peripheral blood measured by immunophenotyping | up to 40 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL