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Chronic Lymphocytic LeukemiaPhase 2NCT02983617

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

A Phase 2 study testing Tirabrutinib, Entospletinib and Obinutuzumab in people with Chronic Lymphocytic Leukemia, run by Gilead Sciences at 15 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia
What is being tested?
Tirabrutinib, Entospletinib and Obinutuzumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
15 sitesGermany
Study dates
6 Apr 2017to 1 Oct 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

Germany15 sites

  • Studienzentrum Aschaffenburg

    Aschaffenburg, 63739

  • Evangelisches Diakoniekrankenhaus Bremen Hämatologie

    Bremen, 28239

  • Uniklinik Köln Klinik I für Innere Medizin

    Cologne, 50937

  • St.-Johannes-Hospital

    Dortmund, D-44137

  • University Medical Center Freiburg

    Freiburg im Breisgau, 79106

  • Onkologische Schwerpunktpraxis Lerchenfeld

    Hamburg, 22081

  • Universitätsklinikum Heidelberg, Abteilung Innere Medizin V

    Heidelberg, 69120

  • Marienhospital Herne, Dept. of Internal Medicine

    Herne, 44625

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

    Kiel, 24105

  • Mannheimer Onkologie Praxis

    Manheim, 68161

  • Gemeinschaftspraxis für Hämatologie und Onkologie

    Münster, 48149

  • Kreiskliniken Reutlingen GmbH Klinikum am Steinenberg

    Reutlingen, 72764

  • Praxis für Hämatologie und Onkologie

    Saarbrücken, 66113

  • Robert-Bosch-Krakenhaus

    Stuttgart, 70376

  • Universitätsklinik Ulm - Klinik für Innere Medizin III

    Ulm, 89081

Other trials in Germany

About this study

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

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).

Being tested
Tirabrutinib, Entospletinib, Obinutuzumab
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TirabrutinibDrug

    Also called GS-4059, ONO-4059

    Administered orally once daily

  • EntospletinibDrug

    Also called GS-9973

    Administered orally once daily

  • ObinutuzumabDrug

    Also called Gazyvaro®, Gazyva®, GA101

    Administered intravenously

Study groups in NCT02983617
Study groupRoleWhat they receive
Tirabrutinib + EntospletinibExperimentalParticipants 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.
Receives: Drug: Tirabrutinib; Drug: Entospletinib
Tirabrutinib + Entospletinib + ObinutuzumabExperimentalParticipants 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.
Receives: Drug: Tirabrutinib; Drug: Entospletinib; Drug: Obinutuzumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Week 25

Secondary outcomes (4)

  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

    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.

    Measured: Week 25

  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

    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.

    Measured: Week 25

  3. Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at 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.

    Measured: Week 25

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

    A treatment emergent AE is defined as an AE that occurs or worsens in severity on or after the date of the first dose of study drug but no later than 30 days after the permanent discontinuation of study drug or an AE leading to discontinuation of study drug. A SAE is defined as an event that, at any dose, resulted in any of the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or a medically important event or reaction.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Dec 2016 (estimated)
  2. Study start6 Apr 2017
  3. Primary completion20 Feb 2019
  4. Study completion1 Oct 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
36 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02983617
Sponsor's protocol ID
GS-US-401-2076
Other IDs
2016-002768-15, CLLRUmbrella2, 2016
Status last verified
Dec 2021
First submitted
2 Dec 2016
Last updated
21 Dec 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tirabrutinib, Entospletinib and Obinutuzumab in people with Chronic Lymphocytic Leukemia, run by Gilead Sciences at 15 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Week 25). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02983617, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Dec 2021.

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