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

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ClinicalTrials.gov Identifier: NCT02320383
Recruitment Status : Active, not recruiting
First Posted : December 19, 2014
Last Update Posted : August 13, 2018
Sponsor:
Collaborator:
German CLL Study Group
Information provided by (Responsible Party):
Munich Municipal Hospital

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leucemia Biological: GA101 (Obinutuzumab) Drug: Bendamustine Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 2014
Actual Primary Completion Date : December 2017
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: B + GA101

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)

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

Other Name: Gazyvaro

Drug: Bendamustine

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

Other Names:
  • Ribomustin
  • Levact




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. 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 ]
    MRD levels (evaluation of minimal residual disease (MRD)) by flow cytometry during treatment and maintenance

  2. 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 ]
    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.

  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
    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.

  8. 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 ]
    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).

  9. 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 ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02320383


Locations
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Germany
German CLL Study Group
Cologne, Germany, 50923
Sponsors and Collaborators
Munich Municipal Hospital
German CLL Study Group
Investigators
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Principal Investigator: Clemens-Martin Wendtner, Prof. Dr. Klinikum München GmbH

Additional Information:
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Responsible Party: Munich Municipal Hospital
ClinicalTrials.gov Identifier: NCT02320383     History of Changes
Other Study ID Numbers: CLLR3
First Posted: December 19, 2014    Key Record Dates
Last Update Posted: August 13, 2018
Last Verified: August 2018
Keywords provided by Munich Municipal Hospital:
CLL
Additional relevant MeSH terms:
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Bendamustine Hydrochloride
Obinutuzumab
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological