Ibrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia

Summary

Background: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the occidental countries. Until now, it is considered a chronic disease without a cure. The development of new molecular therapies have showed that the cure may be an option. This protocol propose a triple sequential therapy with three direct therapies for the leukemic cell: an inhibitor of Bruton´s tyrosine kinase (ibrutinib), a second generation monoclonal antibody versus CD20 (obinutuzumab) and a BCL-2 inhibitor (venetoclax) as treatment of first or second line in CLL. Objective: Negativize the minimal residual disease and by this way obtain longer survivals (overall survival and relapse free survival). Design: This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study coordinated by the "Grupo Cooperativo de Hemopatías Malignas" situated on Hospital Angeles Lomas in Huixquilucan, México. The study, is a phase II clinical study that will employ three target therapy drugs in sequencing phases. It will start with a BTK inhibitor as induction, later an anti-CD20 will be used for consolidation and it will end with a BH3 analog as maintenance for one year. The primary outcome is the negativization of minimal residual disease.

Timeline

Start

2018-12-01

Primary completion

2020-12-31

Completion

2021-02-01

Publications

• Background Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O'Brien S, Robak T, Seymour JF, Kipps TJ. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018 Jun 21;131(25):2745-2760. doi: 10.1182/blood-2017-09-806398. Epub 2018 Mar 14.
• Background Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016 Mar;91(3):330-40. doi: 10.1002/ajh.24282.
• Background Garcia Marco JA, Giraldo Castellano P, Lopez Jimenez J, Rios Herranz E, Sastre Moral JL, Terol Castera MJ, Bosch Albareda F; en representacion del Grupo Espanol de Leucemia Linfatica Cronica (GELLC); Sociedad Espan ola de Hematologi a y Hemoterapia. [National guidelines for the management of patients with chronic lymphocytic leukemia. Sociedad Espan ola de Hematologi a y Hemoterapia and Grupo Espan ol de Leucemia Linfoci tica Cro nica]. Med Clin (Barc). 2013 Aug 17;141(4):175.e1-8. doi: 10.1016/j.medcli.2013.04.041. Epub 2013 Jul 3. Spanish.
• Background Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. doi: 10.1182/blood-2014-07-586610. Epub 2014 Aug 20.
• Background Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. doi: 10.1016/S1470-2045(14)71182-9. Epub 2014 Dec 31.
• Background Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. doi: 10.1056/NEJMoa1400376. Epub 2014 May 31.
• Background Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. doi: 10.3324/haematol.2018.192328. Epub 2018 Jun 7.
• Background Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6.
• Background 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, Bottcher 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 Sep;19(9):1215-1228. doi: 10.1016/S1470-2045(18)30414-5. Epub 2018 Aug 13.
• Background Fischer K, Al-Sawaf O, Fink A-M, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702-2705. Blood. 2017 Jul 13;130(2):232. doi: 10.1182/blood-2017-05-787366. No abstract available.
• Background Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. doi: 10.1056/NEJMoa1713976.
• Background Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013 Nov 28;122(23):3723-34. doi: 10.1182/blood-2013-05-498287. Epub 2013 Sep 24.

Drugs

Indications