Ibrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia

NCT03755947 | Completed Phase 2

• 1 other identifier: HAL 306/2018
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

B-Cell Chronic Lymphocytic Leukemia; B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis)

Outcome Measures

Primary Outcomes (1)

• Best response obtained

  The best response obtained will be defined as CR with negative MRD by the iwCLL response criteria measured subsequent a cytoreduction treatment, induction and consolidation with the triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax in patients with chronic lymphocytic leukemia.

  Two months after finishing the triple sequencing therapy

Secondary Outcomes (4)

• Overall Survival

  Three years

• Relapse-Free Survival

  Three years

• Rate of AcuteToxicity

  Two years

• Rate of Late Toxicity

  Three years

Study Arms (1)

IGV

EXPERIMENTAL

Cytoreduction 3 cycles (I) Ibrutinib, \[Imbruvica, Janssen\] Induction 6 cycles (G) Obinutuzumab, \[Gazyva, Roche\] Consolidation 12 cycles (V) Venetoclax, \[Venclexta, Abbvie\].

Drug: Ibrutinib; Drug: Obinutuzumab; Drug: Venetoclax

Interventions

Ibrutinib DRUG

Ibrutinib Oral Capsule \[Imbruvica\] Tablets 120 mg. Oral. 420mg/day, day 1 to 28, every 28 days. 3 cycles.

Also known as: Imbruvica

IGV

Obinutuzumab DRUG

Obinutuzumab Injection. Intravenous Solution \[Gazyva\] Parenteral. 1000 mg, day 1 of every cycle, every 28 days. 6 cycles.

Also known as: Gazyva

IGV

Venetoclax DRUG

Venetoclax Oral Tablets \[Venclexta\] Tablets 100 mg. Oral. 400 mg/day. Day 1 to 28, every 28 days. 12 cycles.

Also known as: Venclexta

IGV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients diagnosed with B cell chronic lymphocytic leukemia according to 2017 WHO criteria by immunophenotype/immunohistochemistry with active disease according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and do not present TP53 mutation and/or del(17)p. (Cohort 1).
• Patients diagnosed with relapsed/refractory chronic lymphocytic leukemia that have previously received at least one line of treatment that does not include the drugs in the study scheme. (Cohort 2).
• Functional stage of 0 - 2 measured by the Eastern Cooperative Oncology Group (ECOG) scale.
• Creatinine depuration ≥ 30 ml/min measured in a 24-hour urine recollection or utilizing the CKD-EPI formula.
• Proper liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN in patients with Gilbert syndrome, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN.
• Capacity and willingness to provide a written informed consent.

You may not qualify if:

• T cell lymphocytic leukemia diagnosis.
• TP53 mutation and/or del(17)p presence.
• Non-controlled systematic active infection (viral, bacterial and/or fungic).
• Patients with known infection by human immunodeficiency virus (HIV).
• Active infection by hepatitis B (defined as the presence of detectable HBV's DNA, HBe antigen or HBs antigen). Patients with serological evidence of previous vaccination (HBsAg negative, anti-HBs positive antibodies, anti-HBc negative antibodies) are eligible. The patients that are HBsAg negative/ anti-Hbs positive antibodies but anti-HBc positive antibodies are eligible, if the HBV DNA is negative, and the HBV-DNA PCR is realized every 12 months after the last cycle of treatment.
• Active infection by hepatitis C, defined by the ribonucleic acid (RNA) of hepatitis C is detectable in plasma by polymerase chain reaction (PCR).
• Significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure or acute myocardial infarction within 2 months prior to screening, or any class 3 or 4 heart disease according to the functional classification of the NYHA.
• Diagnosis of previous malignancies for 2 years, with exception of patients with basal or squamous cell carcinoma or "in situ" carcinoma of cervix or breast.
• Requiring therapy with inhibitors or potent inducers of CYP3A4 and CYP3A5 inhibitors.
• Anticoagulant therapy with acenocoumarol or warfarin.
• History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to screening.
• History of allergic reaction or severe anaphylaxis to humanized or murine monoclonal antibodies.
• Pregnant or lactating women.

Sponsors & Collaborators

• Grupo Cooperativo de Hemopatías Malignas: lead

Study Sites (1)

Grupo Cooperativo de Hemopatías Malignas

Huixquilucan, State of Mexico, 52763, Mexico

Location

Related Publications (12)

• 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.

  PMID: 29540348 BACKGROUND

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

  PMID: 28705863 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.

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• 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.

  PMID: 24065239 BACKGROUND

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Disease

Interventions

ibrutinib; obinutuzumab; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study

Study Record Dates

• First Submitted: November 20, 2018
• First Posted: November 28, 2018
• Study Start: December 1, 2018
• Primary Completion: December 31, 2020
• Study Completion: February 1, 2021
• Last Updated: February 2, 2021

Record last verified: 2021-02

Locations

ME (1)