Title | A prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by GA101 (obinutuzumab), acalabrutinib (ACP-196) and ABT-199 (venetoclax) in patients with relapsed/refractory CLL |
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Protocol IDs | EudraCT: 2017-003133-28 NCT03787264 |
Participating Countries | Germany |
Status | in follow up |
Contact | Medical Management: Dr. Paula Cramer Dr. Paula Cramer Berit Falkowski Berit Falkowski Laura Miesen Olga Korf Tanja Annolleck |
Contact for scientific queries | Dr. Paula Cramer Dr. Paula Cramer Dr. Moritz Fürstenau |
Design | Prospective, multicenter, single-arm, open-label, phase-II trial |
Primary Endpoint | Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry at final restaging (RE) |
Secondary Endpoints | – Overall response rate (ORR) at RE, including all patients achieving: · a complete response (CR), · CR with incomplete recovery of the bone marrow (CRi), or · a partial response (PR). – CR / CRi rate at RE – Differentiation of patients with a PR according to iwCLL crite-ria into patients achieving: · an unconfirmed (clinical) CR/CRi lacking a CT/MRI scan and/or a bone marrow biopsy · a PR due to residual lymphadenopathy and/or hepatosplenomegaly, or · a PR due to residual bone marrow infiltration – Safety parameters: adverse events (AE), serious adverse events (SAE) and adverse events of particular interest (AEPI) – MRD in PB measured by 4-color flow cytometry to guide the duration of maintenance therapy at: · RE 12 weeks after the start of the last cycle of induc-tion therapy in all patients responding to study treat-ment and · every 12 weeks (= approx. 3 months) during the maintenance phase.every 24 weeks (= approx. 6 months) during the follow-up – and MRD in PB measured by 4-color flow cytometry for the assessment of the kinetics of response to the different treatment phases at: · screening/baseline · staging after debulking (if applicable) · before start with acalabrutinib (cycle 2, d1) · before start with venetoclax (cycle 3, d1) · interim staging (after 3 induction cycles) · initial response assessment (after 6 induction cycles) – MRD in bone marrow measured by 4-color flow cytometry op-tionally in patients with (clin.) CR/CRi (or PR almost fulfilling CR criteria, e.g. with residual splenomegaly) 12 weeks after achievement of MRD negativity in PB – Best response rate (BRR) until 6 months after RE – ORR after debulking and after end of maintenance treatment – Progression-free survival (PFS) – Event-free survival (EFS) – Overall survival (OS) – Duration of response in patients with a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), a partial remission (PR) (including patients with a PR due to residual lymphadenopathy and/or hepatosplenomegaly or due to residual bone marrow infiltration as well as patients with an unconfirmed (clinical) CR/CRi lacking a CT/MRI scan and/or a bone marrow biopsy) – Treatment-free survival (TFS) and time to next CLL treatment (TTNT) |
Target Population | Relapsed/refractory CLL in need of treatment according to iwCLL criteria - Creatinine clearance ≥30ml/minL - ECOG performance status 0 – 2 (ECOG 3 only permitted if related to CLL) - Age ≥ 18 years |
Treatment | Debulking 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated Bendamustin i.v. Cycle 1 - 2: 70 mg/m², d1+2 |
Induction 6 cycles, q 28d Obinutuzumab (GA101) i.v. Cycle 1: d1 - 100 mg, d1 (or d2) - 900 mg, d8 + d15 - 1000 mg Cycle 2 - 6: 1000 mg, d1 + Acalabrutinib (ACP-196) p.o. Cycle 1: -- Cycles 2 - 6: d1-28: 2 x 100mg + Venetoclax (ABT-199) p.o. Cycles 1 + 2: -- Cycle 3: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg Cycle 4 - 6: d1-28: 400 mg |
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Maintenance max. 8 cycles, q 84d Obinutuzumab i.v. Cycle 1 - 8: 1000 mg, d1 + Acalabrutinib (ACP-196) p.o. Cycle 1 - 8: d1-84: 2 x 100mg + Venetoclax p.o. Cycle 1 - 8: d1-84: 400 mg Maintenance treatment will be continued until (whichever occurs first): - 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity - maintenance cycle 8 - progression of CLL or start of a subsequent therapy - unacceptable toxicity |
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Patients recruited | 46 patients |
Time schedule | Recruitment period: 14 Jan 2019 - 25 Jun 2020 End of trial Q3/2023 |
Protocol Version | 06 Nov 2018 Protocol (Version 1.2) 26 Nov 2019 Amendment 1 (Version 2.0) Amendment 2 ( (no new protocol version) |
Sponsor | University of Cologne |
Principal Investigator | Dr. med. Paula Cramer, Department I of Internal Medicine, Cologne University Hospital |
Documents (publicly available) |
Synopsis (Version 2.0 | 26 Nov 2019) |
Documents (password protected) |
Protocol and other documents see Download Center |