Clinical Trials /

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

NCT02320383

Description:

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

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CLLR3
  • NCT ID: NCT02320383

Conditions

  • Chronic Lymphocytic Leucemia

Interventions

DrugSynonymsArms
GA101 (Obinutuzumab)GazyvaroB + GA101
BendamustineRibomustin, LevactB + GA101

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
B + GA101ExperimentalInduction: 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
  • Bendamustine

Eligibility Criteria

        Inclusion Criteria:

          1. Diagnosis of CLL in need of treatment according to the iwCLL guidelines

          2. Relapsed or refractory disease after at least one, but no more than 3 prior regimens
             for CLL

          3. Medically fit patients without relevant comorbidity, defined as total CIRS score ≤6
             (single score < 4 for one organ category)

          4. ECOG performance status of 0 - 2

          5. 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):

               1. Absolute neutrophil count ≥1.5 x 109/L

               2. Platelets ≥50 x 109/L and more than 7 days since last transfusion

          6. Creatinine clearance >60 ml/min calculated according to the modified formula of
             Cockcroft and Gault or directly measured after 24 h urine collection

          7. 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

          8. 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

          9. 18 years of age or older

         10. Life expectancy >6 months

         11. Able and willing to provide written informed consent and to comply with the study
             protocol procedures

        Exclusion Criteria:

          1. Detected del(17p) or TP53 mutation

          2. Refractoriness to FCR / BR

          3. Transformation of CLL to aggressive NHL (Richter's transformation)

          4. Known central nervous system (CNS) involvement

          5. Evidence of significant uncontrolled concomitant disease

          6. Major surgery < 30 days before screening

          7. Decompensated hemolytic anemia 28 days before screening

          8. Hemolytic cystitis 28 days before screening

          9. Patients with a history of confirmed PML

         10. Prior treatment with GA101

         11. 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:

               1. Malignancies treated with curative intent and with no known active disease
                  present for ≥ 2 years before registration

               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease at screening

               3. Adequately treated cervical carcinoma in situ without evidence of disease at
                  screening

               4. Surgically adequately treated low grade, early stage localized prostate cancer
                  without evidence of disease at screening

         12. Use of investigational agents or concurrent anticancer treatment within the last 4
             weeks before registration

         13. Patients with active infection requiring systemic treatment

         14. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
             antibodies and/ or known hypersensitivity to any constituent of the product

         15. Hypersensitivity to fludarabine, cyclophosphamide, bendamustine, GA101 and/ or to any
             of the excipients for example mannitol

         16. An individual organ/ system impairment score of 4 as assessed by the CIRS definition
             limiting the ability to receive an intensive therapy for CLL

         17. Legal incapacity

         18. Women who are pregnant or lactating

         19. Fertile men or women of childbearing potential unless:

               1. surgically sterile or ≥2 years after the onset of menopause

               2. 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

         20. Vaccination with a live vaccine within a minimum of 28 days before screening

         21. Participation in any other clinical trial which would interfere with the study drug

         22. Prisoners or subjects who are institutionalized by regulatory or court order

         23. Persons who are in dependence to the sponsor or an investigator
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Time Frame:The response to the induction phase will be performed 84 days after first dose of last cycle of induction administered
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:MRD levels
Time Frame: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
Safety Issue:
Description:MRD levels (evaluation of minimal residual disease (MRD)) by flow cytometry during treatment and maintenance
Measure:Progression free survival (PFS)
Time Frame: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
Safety Issue:
Description: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.
Measure:Event-free survival (EFS)
Time Frame: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
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame: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
Safety Issue:
Description:
Measure:Duration of response in patients with CR/ CRi, clinical CR / clinical CRi or nPR/ PR
Time Frame: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
Safety Issue:
Description:
Measure:Time to next anti-leukemia treatment
Time Frame: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
Safety Issue:
Description:
Measure:Overall response rate in biological defined risk groups
Time Frame:The response to the induction phase will be performed 84 days after first dose of last cycle of induction administered
Safety Issue:
Description: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.
Measure:Complete response rate
Time Frame:The response to the induction phase will be performed 84 days after first dose of last cycle of induction administered
Safety Issue:
Description: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).
Measure:Safety parameters during induction and maintenance phase
Time Frame: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Munich Municipal Hospital

Trial Keywords

  • CLL

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