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