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

NCT02983617 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: GS-US-401-20762016-002768-15CLLRUmbrella2
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 15

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).

Conditions

Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Rate of Complete Remission/Complete Remission With Incomplete Recovery of the Bone Marrow (CR/CRi), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at 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.

  Week 25

Secondary Outcomes (4)

• 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

  Week 25

• 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

  Week 25

• Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25

  Week 25

• Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)

  First dose date up to the last dose date (maximum: 105.9 weeks) plus 30 days

Study Arms (2)

Tirabrutinib + Entospletinib

EXPERIMENTAL

Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks.

Drug: Tirabrutinib; Drug: Entospletinib

Tirabrutinib + Entospletinib + Obinutuzumab

EXPERIMENTAL

Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks + obinutuzumab 100 mg on Day 1, 900 mg on Day 1 or 2, and 1000 mg subsequently for up to 8 doses on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21.

Drug: Tirabrutinib; Drug: Entospletinib; Drug: Obinutuzumab

Interventions

Tirabrutinib DRUG

Administered orally once daily

Also known as: GS-4059, ONO-4059

Tirabrutinib + Entospletinib; Tirabrutinib + Entospletinib + Obinutuzumab

Entospletinib DRUG

Administered orally once daily

Also known as: GS-9973

Tirabrutinib + Entospletinib; Tirabrutinib + Entospletinib + Obinutuzumab

Obinutuzumab DRUG

Administered intravenously

Also known as: Gazyvaro®, Gazyva®, GA101

Tirabrutinib + Entospletinib + Obinutuzumab

Eligibility Criteria

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

You may qualify if:

• 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 centimetres (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/liter (L), neutrophil count ≥ 1 × 10\^9/L, hemoglobin ≥ 8 grams per deciliter (g/dL) unless lower values are directly attributable to documented bone marrow burden of CLL
• Creatinine clearance (CrCl) ≥ 50 milliliters per minute (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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead
• German CLL Study Group: collaborator

Study Sites (15)

Studienzentrum Aschaffenburg

Aschaffenburg, 63739, Germany

Location

Evangelisches Diakoniekrankenhaus Bremen Hämatologie

Bremen, 28239, Germany

Location

Uniklinik Köln Klinik I für Innere Medizin

Cologne, 50937, Germany

Location

St.-Johannes-Hospital

Dortmund, D-44137, Germany

Location

University Medical Center Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Onkologische Schwerpunktpraxis Lerchenfeld

Hamburg, 22081, Germany

Location

Universitätsklinikum Heidelberg, Abteilung Innere Medizin V

Heidelberg, 69120, Germany

Location

Marienhospital Herne, Dept. of Internal Medicine

Herne, 44625, Germany

Location

Universitätsklinikum Schleswig-Holstein Klinik für Innere Medizin II - Hämatologie und Onkologie

Kiel, 24105, Germany

Location

Mannheimer Onkologie Praxis

Manheim, 68161, Germany

Location

Gemeinschaftspraxis für Hämatologie und Onkologie

Münster, 48149, Germany

Location

Kreiskliniken Reutlingen GmbH Klinikum am Steinenberg

Reutlingen, 72764, Germany

Location

Praxis für Hämatologie und Onkologie

Saarbrücken, 66113, Germany

Location

Robert-Bosch-Krakenhaus

Stuttgart, 70376, Germany

Location

Universitätsklinik Ulm - Klinik für Innere Medizin III

Ulm, 89081, Germany

Location

Related Publications (1)

• Kutsch, N et al. A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Entospletinib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL), Blood (2019) 134 (Supplement_1): 4297.

  RESULT

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

tirabrutinib; 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; obinutuzumab

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

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2016
• First Posted: December 6, 2016
• Study Start: April 6, 2017
• Primary Completion: February 20, 2019
• Study Completion: October 1, 2020
• Last Updated: December 21, 2021
• Results First Posted: February 28, 2020

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (15)