Sequential Regimen of Bendamustin [B] Followed by GA101 and Ibrutinib [I] in CLL Patients

A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 and Ibrutinib (BIG) Followed by GA101 and Ibrutinib Maintenance in CLL Patients (CLL2-BIG Protocol)

A prospective, open-label, multicenter Phase-II trial to evaluate the efficacy and safety of a sequential regimen of Bendamustine followed by GA101 and Ibrutinib followed by Ibrutinib and GA101 maintenance in CLL patients.

In the CLL2-BIG trial an allcomer CLL population with indication for treatment will be included.

Patient will receive 2 cycles of debulking treatment with bendamustin unless contraindications are existing or debulking is not indicated.

Afterwards 6 cycles of induction therapy with GA101 and ibrutinib will be applied, each with a duration of 28 days. Primary endpoint overall Response rate will be assessed at final restaging.

Patients benefitting from BIG treatment will enter the maintenance phase of the trial. Maintenance treatment will be continued if no unacceptable toxicity occurs until three months after negativity of minimal residual disease [MRD] is achieved in peripheral blood in patients with (clinical) complete response (CR) or (clinical) incomplete complete response [CRi] (confirmed by 2 consecutive testings of MRD within 3 months), progression of CLL, start of a subsequent therapy or up to 8 cycles of maintenance (each cycle with a duration of 84 calendar days = 3 months), whichever occurs first.

Inclusion Criteria:

1. documented CLL requiring treatment (irrespective if first- or relapse treatment) according to the criteria of the international Workshop of CLL [iwCLL]

   In case of previously treated patients, these must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BIG trial:

   • chemotherapy within ≥ 28 days
   • antibody treatment within ≥ 14 days
   • kinase inhibitors, B-cell-lymphoma 2 [BCL2] -antagonists or immunomodulatory agents within ≥ 3 days
   • corticosteroids may be applied until the start of the BIG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolon during treatment

2. Creatinine clearance ≥ 30 ml/min

3. Adequate hematologic function

4. Adequate liver function

5. Negative serological testing for hepatitis B, hepatitis-C RNA and negative HIV test within 6 weeks prior to registration

6. Age at least 18 years

7. Eastern Cooperative Oncology Group [ECOG] status 0 - 2; ECOG 3 is only permitted if related to CLL

8. Life expectancy ≥ 6 months

9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

1. Transformation of CLL
2. Known central nervous system (CNS) involvement
3. Patients with a history of confirmed progressive multifocal leukoencephalopathy [PML]
4. Malignancies other than CLL currently requiring systemic therapies
5. Uncontrolled infection requiring systemic treatment
6. Use of investigational agents which would interfere with the study drug within 28 days prior to registration
7. Any comorbidity or organ system impairment rated with a cumulative illness rating scale [CIRS] score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
8. Known hypersensitivity to GA101, ibrutinib or any of the excipients
9. Requirement of treatment with strong cytochrome P450 3A4 [CYP3A4] -inhibitors/-inducers or anticoagulant with warfarin or phenprocoumon (marcumar)
10. History of stroke or intracranial hemorrhage within 6 months prior to registration
11. Pregnant women and nursing mothers
12. Fertile men or women of childbearing potential unless:surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment.
13. Vaccination with a live vaccine a minimum of 28 days prior to registration
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regulatory or court order
16. Persons who are in dependence to the sponsor or an investigator