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