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| 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) and ABT-199 (venetoclax) followed by ABT-199 and GA101 maintenance in CLL patients |
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| Protocol IDs | EudraCT: 2014-000580-40 NCT02401503 |
| Status | in extended follow up In the event of a relapse, study patients already enrolled have the option of being re-treated with obinutuzumab and venetoclax |
| Contact | Medical Management: Dr. Paula Cramer Dr. Paula Cramer Marie Kronmüller Olga Korf Sabine Frohs |
| Contact for scientific queries | Dr. Paula Cramer Dr. Paula Cramer Dr. Anna Fink |
| Design | Prospective, multicenter, single-arm, open-label phase-II trial |
| Objective | To evaluate the efficacy and the safety of the therapeutic regimen |
| Primary Endpoint | Overall response rate (ORR) at final restaging (RE) including all patients achieving CR, CRi or PR |
| Secondary Endpoints | - Safety parameters: AEs, AESI and their relationship to study treatment - MRD levels measured in peripheral blood at · final restaging after end of induction treatment · every 3 - 6 months during the maintenance phase dependent on the state of remission achieved · every 6 months during follow up - MRD level in bone marrow - Best response rate (BRR) until 6 months after RE - ORR after debulking, maintenance therapy,in the two strata of previously untreated and relapsed/refractory patients, as well as in the fit and unfit patients for all response definitions, in biological defined risk groups - (Clinical) complete response rate (CR) - Progression-free survival (PFS) - Event-free survival (EFS) - Overall survival (OS) - Duration of response, treatment free survival and time to next treatment - Evaluation of relationship between various baseline markers and clinical outcome parameters - Efficacy and safety of re-treatment with venetoclax and obinutuzumab |
| Target Population | - According to amendment 4 only patients already included in the CLL2-BAG trial qualify for re-treatment with venetoclax and obinutuzumab.
Re-treatment is scheduled to start by the end of September 2020.
No new patients will be recruited. - B-CLL according to iwCLL criteria (2008), requiring treatment - Previously untreated or relapsed/refractory CLL - ECOG performance status 0 – 2 (ECOG 3 only permitted if related to CLL) - Age ≥ 18 years |
| Treatment | Debulking 2 debulking cycles 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 q 28d Please note: Patients re-treated with venetoclax and obinutuzumab (amendment 4) receive no debulking with bendamustine |
| Induction Obinutuzumab i.v. Cycle 1: d1 - 100 mg, d1 (or d2) - 900 mg, d8 + d15 - 1000 mg Cycle 2 - 6: 1000 mg, d1 + Venetoclax p.o. Cycle 2: Dose eskalation d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg Cycle 3 - 6: 400 mg daily q 28d During the phase of staging between induction and maintenance the intake of Venetoclax is continued. |
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| Maintenance Obinutuzumab i.v. Cycle 1 - 8: 1000 mg, d1 + Venetoclax p.o. Cycle 1 - 8: 400 mg daily q 84d Maintenance treatment will be continued until (whichever occurs first): - 3 months after confirmation of achievement of MRD negativity in patients with a (clinical) CR/CRi, - progression of CLL or start of a subsequent therapy - unacceptable toxicity - maintenance cycle 8 |
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| Patients recruited | 66 patients ( re-treatment: up to 20 patients) |
| Time schedule | Recruitment period: 06 May 2015 - 04 January 2016 Re-Screening: by the end of Q3/2020 End of study: Q3/2022 |
| Protocol Version | 12 March 2015 Protocol (Version 2.2) 21 October 2015 Amendment 1 (Version 3.0) 22 August 2016 Amendment 2 (Version 4.0) 07 June 2017 Amendment 3 (Version 5.0) 11 Nov 2019 Amendment 4 (Version 6.0) |
| Sponsor | University of Cologne |
| Principal Investigator | Dr. med. Paula Cramer, Department I of Internal Medicine, University Hospital of Cologne |
| Coordinating Physician | Dr. med. Anna Fink |
| Documents (publicly available) |
Synopsis incl. Amendment 6 (Version 8.0 | 27.06.2022) |
| Documents (password protected) |
Protocol and other documents see Download Center |
| Publications | Cramer P, Tausch E, von Tresckow J, Giza A, Robrecht S, Schneider C, Fürstenau M, Langerbeins P, Al-Sawaf O, Pelzer BW, Fink AM, Fischer K, Wendtner CM, Eichhorst B, Kneba M, Stilgenbauer S, Hallek M Durable Remissions Following Combined Targeted Therapy in Patients with CLL Harboring TP53 Deletions and/or Mutations Blood. 2021 Jun 4 blood.2020010484. doi: 10.1182/blood.2020010484. Online ahead of print. Cramer P, von Tresckow J, Bahlo J, Robrecht S, Langerbeins P, Al-Sawaf O, Engelke A, Fink AM, Fischer K, Tausch E, Seiler T, Fischer von Weikersthal L, Hebart H, Kreuzer KA, Böttcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, Hallek M Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial Lancet Oncol. 2018 Aug 13 pii: S1470-2045(18)30414-5. doi: 10.1016/S1470-2045(18)30414-5. [Epub ahead of print] |