CLLR3: Bendamustine + GA101 (BG) in Relapsed or Refractory CLL Followed by GA101 Maintenance for Responding Patients

Study Overview
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Brief Summary
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A Prospective, Multicenter, Randomized Phase-Ii Trial Comparing Efficacy And Safety Of Fludarabine + Cyclophosphamide + Ga101 (Fcg) And Bendamustine + Ga101 (Bg) In Patients With Relapsed Or Refractory Cll Followed By Maintenance Therapy With Ga101 For Responding Patients

Detailed Description
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The type II anti-CD20 antibody GA101 has demonstrated a high efficacy as single agent (ORR 62%) and was well tolerated in previously treated patients with CLL. Additionally, there is evidence that immunochemotherapy consisting of fludarabine, cyclophosphamide and rituximab (FCR) is active in patients with refractory and relapsed CLL. Besides FCR, the combination of bendamustine with rituximab (BR) has shown to be active in both relapsed and previously untreated patients with CLL. In preclinical studies GA101, a glycoengineered, humanized type II anti-CD20 antibody, has shown superior activity compared with type I antibodies. Therefore, a combination therapy with FC + GA101 (FCG) or B + GA101 (BG) might further improve the therapeutic outcome in relapsed or refractory CLL. The CLLR3 trial was designed to investigate and to compare the efficacy and safety of induction with both immunochemotherapies followed additionally by a maintenance therapy with GA101 for responding patients.

Official Title
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A Prospective, Multicenter, Phase-II Trial Evaluating Efficacy and Safety of Bendamustine + GA101 (BG) in Patients With Relapsed CLL Followed by Maintenance Therapy With GA101 for Responding Patients

Conditions
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Chronic Lymphocytic Leucemia

Intervention / Treatment
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* Biological: GA101 (Obinutuzumab)
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CLL in need of treatment according to the iwCLL guidelines Relapsed or refractory disease after at least one, but no more than 3 prior regimens for CLL Medically fit patients without relevant comorbidity, defined as total CIRS score ≤6 (single score < 4 for one organ category) ECOG performance status of 0 - 2 Hematology values within the following limits unless cytopenia is caused by the underlying disease, i.e. no evidence of additional bone marrow dysfunction (e.g. myelodysplastic syndrome (MDS), hypoplastic bone marrow due to toxicity of prior therapy): Absolute neutrophil count ≥1.5 x 109/L Platelets ≥50 x 109/L and more than 7 days since last transfusion Creatinine clearance >60 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection Adequate liver function as indicated by a total bilirubin, AST, and ALT ≤2 the institutional ULN value, unless directly attributable to the patient's CLL Negative serological Hepatitis B test (i.e. HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative); negative testing of Hepatitis C RNA; negative HIV test within 6 weeks prior to registration 18 years of age or older Life expectancy >6 months Able and willing to provide written informed consent and to comply with the study protocol procedures Exclusion Criteria: Detected del(17p) or TP53 mutation Refractoriness to FCR / BR Transformation of CLL to aggressive NHL (Richter's transformation) Known central nervous system (CNS) involvement Evidence of significant uncontrolled concomitant disease Major surgery < 30 days before screening Decompensated hemolytic anemia 28 days before screening Hemolytic cystitis 28 days before screening Patients with a history of confirmed PML Prior treatment with GA101 History of prior malignancy, except for conditions as listed below (a-d) and if patients have recovered from the acute side effects incurred as a result of previous therapy: Malignancies treated with curative intent and with no known active disease present for ≥ 2 years before registration Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease at screening Adequately treated cervical carcinoma in situ without evidence of disease at screening Surgically adequately treated low grade, early stage localized prostate cancer without evidence of disease at screening Use of investigational agents or concurrent anticancer treatment within the last 4 weeks before registration Patients with active infection requiring systemic treatment History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies and/ or known hypersensitivity to any constituent of the product Hypersensitivity to fludarabine, cyclophosphamide, bendamustine, GA101 and/ or to any of the excipients for example mannitol An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive an intensive therapy for CLL Legal incapacity Women who are pregnant or lactating Fertile men or women of childbearing potential unless: surgically sterile or ≥2 years after the onset of menopause willing to use a highly effective contraceptive method (Pearl Index <1) such as those listed at section 4.2.2 Exclusion criteria during study treatment and for 12 months after end of study treatment Vaccination with a live vaccine within a minimum of 28 days before screening Participation in any other clinical trial which would interfere with the study drug 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: B + GA101<br>Induction: Bendamustine + GA101; a maximum of 6 cycles of BG will be administered; each cycle with a duration of 28 days Maintenance: GA101 i.v. 1000 mg (flat dose): every 84 days starting on final restaging continued until progression or to a maximum of 2 years | Biological: GA101 (Obinutuzumab)<br>* Induction Cycle 1: d1 - 100 mg, (d1 or) d2 - 900 mg, d8+15 - 1000 mg i.v., q28d Cycle 2 - 6: d1 - 1000 mg i.v., q28d Maintenance GA101 iv 1000 mg (flat dose): every 84 days<br>* Other names: Gazyvaro;Drug: Bendamustine<br>* Induction Cycle 1: d3+4 (or d2+3) - 70 mg/m² i.v., q28d Cycle 2 - 6: d2+3 - 70 mg/m i.v., q28d<br>* Other names: Levact;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of two regimens of immunochemotherapy, i.e. Response rates of Fludarabine, Cyclophosphamide plus GA101 (FCG) and Bendamustine plus GA101 (BG), in patients with relapsed or refractory CLL. | Efficacy of FCG and/ or BG is confirmed if the ORR is at least 80% (response rate of an active regimen) respectively and is assessed to be not effective if the ORR is 60% or less (ORR of an uninteresting regimen). | The response to the induction phase will be performed 84 days after first dose of last cycle of induction administered | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD levels | MRD levels (evaluation of minimal residual disease (MRD)) by flow cytometry during treatment and maintenance | MRD levels will be assessed at 84 days after first dose of last cycle of induction and during maintenance every 3 months up to 2 years for responding patients | 
| Progression free survival (PFS) | From the date of randomization to the date of first disease progression (as defined by the iwCLL response criteria) or death by any cause, whichever occurs first. | The time to disease progression will be measured from the date of randomization to the date of first disease progression, assessed up to 54 months | 
| Event-free survival (EFS) |  | From the date of randomization to the date of first disease progression, start of next CLL treatment or death by any cause, whichever occurs first, assessed up to 54 months | 
| Overall survival (OS) |  | Overall survival (OS) will be calculated from the date of randomization to the date of death due to any cause, assessed up to 54 months | 
| Duration of response in patients with CR/ CRi, clinical CR / clinical CRi or nPR/ PR |  | This will be measured from the date of first documentation of response to the date of first disease progression, or death by any cause, whichever occurs first, assessed up to 54 months | 
| Time to next anti-leukemia treatment |  | From time of randomization to the date of initiation of next treatment for CLL or death by any cause, whichever occurs first, assessed up to 54 months | 
| Overall response rate in biological defined risk groups | Is defined by the proportion of patients having achieved a CR/ CRi, clinical CR/ CRi or nPR/ PR as best response based on the respective population. | The response to the induction phase will be performed 84 days after first dose of last cycle of induction administered | 
| Complete response rate | Is defined by the proportion of patients having achieved a CR/ CRi as best response based on the respective population (= number of patients with best response CR/ CRi divided by the number of the respective population). | The response to the induction phase will be performed 84 days after first dose of last cycle of induction administered | 
| Safety parameters during induction and maintenance phase | During induction and maintenance phase until End of Study. Safety parameters: type, frequency, and severity of adverse events (AEs) and relationship of AEs to study treatment. Furthermore the safety profile including second malignancies of patients treated with FCG/ BG induction treatment and patients with and without maintenance will be evaluated and compared descriptively. | SAE: until end of study, AE: From day 1 of the first cycle until 28 days after the end of the treatment, assessed up to 54 months | 

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