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Safety and Efficacy of the Combination of Tirabrutinib and Entospletinib With and Without Obinutuzumab in Adults With Chronic Lymphocytic Leukemia (CLL)

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ClinicalTrials.gov Identifier: NCT02983617
Recruitment Status : Completed
First Posted : December 6, 2016
Results First Posted : February 28, 2020
Last Update Posted : November 13, 2020
Sponsor:
Collaborators:
German CLL Study Group
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:

The primary objective of this study is to determine the preliminary efficacy of the combination of tirabrutinib (formerly GS-4059) and entospletinib with obinutuzumab in adults with relapsed or refractory chronic lymphocytic leukemia (CLL).

The secondary objective is evaluation of safety and tolerability of the combination of tirabrutinib and entospletinib with and without obinutuzumab. The treatment period is up to two years and a total follow-up on study for up to 30 days post end of treatment, or up to Week 25 should a participant discontinue treatment prior to Week 25 for reasons other than disease progression. The study has a 6 participant per arm safety run-in to evaluate safety prior to the enrollment of subsequent participants.


Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Tirabrutinib Drug: Entospletinib Drug: Obinutuzumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (GS-4059) and Entospletinib With and Without Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia
Actual Study Start Date : April 6, 2017
Actual Primary Completion Date : February 20, 2019
Actual Study Completion Date : October 1, 2020


Arm Intervention/treatment
Experimental: Tirabrutinib + Entospletinib
Participants will receive tirabrutinib and entospletinib for up to 104 weeks.
Drug: Tirabrutinib
80 mg (1 x 80 mg or 4 x 20 mg or 2 x 40 mg) tablets administered orally once daily
Other Name: GS-4059

Drug: Entospletinib
400 mg (2 x 200 mg) tablets administered orally once daily
Other Name: GS-9973

Experimental: Tirabrutinib + Entospletinib + Obinutuzumab
Participants will receive obinutuzumab over 21 weeks and the combination of tirabrutinib and entospletinib for up to 104 weeks.
Drug: Tirabrutinib
80 mg (1 x 80 mg or 4 x 20 mg or 2 x 40 mg) tablets administered orally once daily
Other Name: GS-4059

Drug: Entospletinib
400 mg (2 x 200 mg) tablets administered orally once daily
Other Name: GS-9973

Drug: Obinutuzumab
Obinutuzumab 100 mg on Day 1, 900 mg on Day 1 or 2, and 1000 mg subsequently for up to 8 doses administered intravenously over 21 weeks
Other Names:
  • Gazyvaro®
  • Gazyva®
  • GA101




Primary Outcome Measures :
  1. Rate of Complete Response/Complete Remission (CR), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at Week 25 [ Time Frame: Week 25 ]
    Rate of CR per modified IWCLL 2008 criteria at Week 25 was defined as the percentage of participants who achieved CR/complete remission with incomplete recovery of the bone marrow (CRi) at Week 25. CR: meeting following criteria and no disease related symptoms: no lymphadenopathy > 1.5 cm/hepatomegaly/splenomegaly; lymphocytes < 4000/μL; bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules; platelets > 100,000/µL; hemoglobin > 11 g/dL; and neutrophils > 1500/µL. CRi: CR criteria (no lymphadenopathy > 1.5 cm/hepatomegaly/splenomegaly; lymphocytes < 4000/μL; bone marrow [hypocellular] with 30% lymphocytes and no B-lymphoid nodules), persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity.


Secondary Outcome Measures :
  1. Rate of CR With Bone Marrow Minimal Residual Disease (CR/BM MRD) Negativity, as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25 [ Time Frame: Week 25 ]
    Rate of CR/BM MRD at Week 25 was defined as percentage of participants who achieved CR/CRi per modified IWCLL 2008 criteria and also achieved BM MRD negativity at Week 25. CR: meeting following criteria and no disease related symptoms: no lymphadenopathy > 1.5 cm/hepatomegaly/splenomegaly; lymphocytes < 4000/μL; bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules; platelets > 100,000/µL; hemoglobin > 11 g/dL; and neutrophils > 1500/µL. CRi: CR criteria (no lymphadenopathy > 1.5 cm/hepatomegaly/splenomegaly; lymphocytes < 4000/μL; bone marrow [hypocellular] with 30% lymphocytes and no B-lymphoid nodules), persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. MRD response was assessed with four-color-flow cytometry (FACS) and MRD negativity was defined as one CLL cell per 10,000 leukocytes [0.01%], ie,<10^-4 and participants were defined as MRD negative if their disease burden was below this threshold.

  2. Rate of CR With Peripheral Minimal Residual Disease (CR/PB MRD) Negativity, as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25 [ Time Frame: Week 25 ]
    Rate of CR/PB MRD at Week 25 was defined as the percentage of participants who achieved CR/CRi per modified IWCLL 2008 criteria and also achieved PB MRD negativity at Week 25. CR: meeting following criteria and no disease related symptoms: no lymphadenopathy > 1.5 cm/hepatomegaly/splenomegaly; lymphocytes < 4000/μL; bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules; platelets > 100,000/µL; hemoglobin > 11 g/dL; and neutrophils > 1500/µL. CRi: CR criteria (no lymphadenopathy > 1.5 cm/hepatomegaly/splenomegaly; lymphocytes < 4000/μL; bone marrow [hypocellular] with 30% lymphocytes and no B-lymphoid nodules), persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. MRD response was assessed with FACS and MRD negativity was defined as one CLL cell per 10,000 leukocytes [0.01%], ie,<10^-4 and participants were defined as MRD negative if their disease burden was below this threshold.

  3. Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25 [ Time Frame: Week 25 ]
    ORR was assessed based on modified IWCLL 2008 criteria and was defined as percentage of participants achieving a CR, CRi, partial remission (PR; including nodular partial response [nPR]), and PR with lymphocytosis (PR-L). CR and CRi: meeting all the criteria that have been defined in Outcome measures 1, 2 and 3. PR: ≥ 2 of these: ≥ 50% decrease in lymphocytes, lymphadenopathy, size of liver, size of spleen, and 50% decrease in bone marrow infiltrates; and ≥ 1 of these: neutrophils > 1500/μL or ≥ 50% increase from Baseline, platelets ≥ 100,000/µL or ≥ 50% increase from Baseline, hemoglobin >11 g/dL or ≥ 50% increase from Baseline. PR-L: meeting PR criteria; however, a lymphocytosis related to treatment may be present. nPR: All criteria for a CR/CRi were fulfilled, but the bone marrow showed lymphoid nodules.

  4. Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) [ Time Frame: First dose date up to the last dose date plus 30 days (maximum: 105 weeks) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Documentation of relapsed or refractory CLL
  • Requiring treatment per modified International Workshop on CLL (IWCLL) 2008 criteria; adults without radiographically measureable disease (defined as ≥ 1 lesion > 1.5 cm in diameter as assessed by computed tomography (CT) or magnetic resonance imaging (MRI)) must have bone marrow evaluation at screening
  • Adequate hematologic function: platelet count ≥ 50 × 10^9/L, neutrophil count ≥ 1 × 10^9/L, hemoglobin ≥ 8 g/dL unless lower values are directly attributable to documented bone marrow burden of CLL
  • Creatinine clearance (CrCl) ≥ 50 mL/min
  • Total bilirubin ≤ 1.5× institutional upper limit of normal (ULN) unless attributed to Gilbert's syndrome and aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5×ULN
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
  • Absence of active human immunodeficiency virus (HIV), hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection
  • Satisfies the following criteria:

    • For females of childbearing potential, willingness to abstain from sexual intercourse or use a protocol-specified method of contraception as described in the study protocol
    • Males of reproductive potential who engage in sexual intercourse must agree to use protocol-specified method(s) of contraception as described in the study protocol
  • Able to comply with study procedures and restrictions

Key Exclusion Criteria:

  • Known transformation of CLL (ie, Richter's transformation, prolymphocytic leukemia)
  • Known central nervous system (CNS) involvement
  • Progression on treatment with any inhibitor of Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (BCL-2), or obinutuzumab. The treatment and disease response history of participants with prior treatment with agents in these classes should be reviewed by the sponsor or the German CLL Study Group office prior to enrollment to clarify sensitivity to these treatments
  • Any treatment for CLL other than corticosteroids for symptomatic management within 28 days of the start of study treatment
  • Participation on a concurrent therapeutic clinical trial unless all treatment is complete with only ongoing surveillance
  • Diagnosis of or concern for progressive multifocal leukoencephalopathy
  • History of myelodysplastic syndrome or another malignancy other than CLL, except for the following: any malignancy that has been in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to start of study therapy
  • Active infection requiring systemic therapy
  • Pregnant or nursing women (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment and monthly during therapy)
  • Active autoimmune disease or the need for higher than prednisone 10 mg daily unless for management of CLL symptoms
  • History of stroke or intracranial hemorrhage within 12 months of randomization; participants requiring therapeutic anticoagulation for any indication should be discussed with the German CLL Study Group (GCLLSG) cooperating physician and/or medical monitor prior to screening
  • Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, moderate CYP2C9 inducers, or strong P-gp inducers while on study; use within 2 weeks of first dose of study treatment should be avoided
  • Requirement for proton pump inhibitor (PPI) therapy
  • Demonstration of corrected QT (QTc) interval > 450 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval

Note: Other protocol defined Inclusion/Exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02983617


Locations
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Germany
Studienzentrum Aschaffenburg
Aschaffenburg, Germany, 63739
Evangelisches Diakoniekrankenhaus Bremen Hämatologie
Bremen, Germany, 28239
St.-Johannes-Hospital
Dortmund, Germany, D-44137
University Medical Center Freiburg
Freiburg, Germany, 79106
Onkologische Schwerpunktpraxis Lerchenfeld
Hamburg, Germany, 22081
Universitätsklinikum Heidelberg, Abteilung Innere Medizin V
Heidelberg, Germany, 69120
Marienhospital Herne, Dept. of Internal Medicine
Herne, Germany, 44625
Universitätsklinikum Schleswig-Holstein Klinik für Innere Medizin II - Hämatologie und Onkologie
Kiel, Germany, 24105
Uniklinik Köln Klinik I für Innere Medizin
Köln, Germany, 50937
Mannheimer Onkologie Praxis
Manheim, Germany, 68161
Gemeinschaftspraxis für Hämatologie und Onkologie
Münster, Germany, 48149
Kreiskliniken Reutlingen GmbH Klinikum am Steinenberg
Reutlingen, Germany, 72764
Praxis für Hämatologie und Onkologie
Saarbrücken, Germany, 66113
Robert-Bosch-Krakenhaus
Stuttgart, Germany, 70376
Universitätsklinik Ulm - Klinik für Innere Medizin III
Ulm, Germany, 89081
Sponsors and Collaborators
Gilead Sciences
German CLL Study Group
Ono Pharmaceutical Co. Ltd
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol  [PDF] January 15, 2019
Statistical Analysis Plan  [PDF] January 30, 2020

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02983617    
Other Study ID Numbers: GS-US-401-2076
2016-002768-15 ( EudraCT Number )
CLLRUmbrella2 ( Other Identifier: German CLL Study Group )
First Posted: December 6, 2016    Key Record Dates
Results First Posted: February 28, 2020
Last Update Posted: November 13, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Obinutuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents