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Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Primary Purpose

Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Tirabrutinib

Idelalisib

Obinutuzumab

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

Documentation of relapsed or refractory CLL
Requiring treatment per modified International Workshop on CLL (IWCLL) 2008 criteria; individuals without radiographically measurable disease (defined as ≥ 1 lesion > 1.5 centimetre (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 grams per decilitre (g/dL) unless lower values are directly attributable to documented bone marrow burden of CLL
Creatinine clearance (CrCl) ≥ 50 milliliter 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, hepatitis C virus (HCV) infection, and cytomegalovirus (CMV) 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 including mandatory prophylaxis for Pneumocystis jirovecii pneumonia (PJP)

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 individuals with prior treatment with agents in these classes should be reviewed by the sponsor or the German CLL Study Group (GCLLSG) study 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
Treatment or prophylaxis for CMV within the past 28 days
History of stroke or intracranial hemorrhage within 12 months of randomization; patients requiring therapeutic anticoagulation for any indication should be discussed with the GCLLSG cooperating physician and/or medical monitor prior to screening.
Use of a strong CYP3A4 or a strong P-glycoprotein (P-gp) inducer within 2 weeks of first dose of study treatment or anticipated chronic use while on study
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.

Sites / Locations

Ambulante Krebszentrum Schaubstraße
Hämatologische-onkologische Gem.-Praxis Dres. Brudler-Heinrich-Bangerter, Augsburg
Internistische Gemeinschaftspraxis Dres. Schliesser-Käbisch-Weber, Gießen
Uniklinik Koln
Uniklinik Leipzig
Luebecker Onkologische Schwerpunktpraxis
Universitasmtedizin Mannheim
Stauferklinikum Schwäbisch Gmünd
KH Maria Hilf-Franziskushaus, Mönchengladbach
Krankenhaus München-Schwabing
Klinikum Rechts der Isar der Technischen Universität München
Studienzentrum Onkologie Ravensburg
Facharztzentrum Regensburg
Universitätsklinikum Ulm

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Tirabrutinib + Idelalisib

Tirabrutinib + Idelalisib + Obinutuzumab

Arm Description

Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily for up to 104 weeks.

Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily 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, and then every 4 weeks through Week 21.

Outcomes

Primary Outcome Measures

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

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

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.

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.

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.

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

Treatment-emergent AEs are defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug Any AEs 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.

Full Information

NCT ID

NCT02968563

First Posted

November 16, 2016

Last Updated

December 24, 2021

Sponsor

Gilead Sciences

Collaborators

German CLL Study Group

1. Study Identification

Unique Protocol Identification Number

NCT02968563

Brief Title

Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Official Title

A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (GS-4059) and Idelalisib With and Without Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

December 2021

Overall Recruitment Status

Completed

Study Start Date

December 13, 2016 (Actual)

Primary Completion Date

June 17, 2019 (Actual)

Study Completion Date

January 14, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gilead Sciences

Collaborators

German CLL Study Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The primary objective of this study is to determine the preliminary efficacy of the combination of tirabrutinib and idelalisib with obinutuzumab in adults with relapsed or refractory chronic lymphocytic leukemia (CLL). The study has a 6 participant per arm safety run-in to evaluate safety prior to the enrollment of subsequent participants. The treatment period is adaptive, with a duration of active treatment 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

35 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Tirabrutinib + Idelalisib

Arm Type

Experimental

Arm Description

Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily for up to 104 weeks.

Arm Title

Tirabrutinib + Idelalisib + Obinutuzumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Tirabrutinib

Other Intervention Name(s)

GS-4059

Intervention Description

Tablets administered orally

Intervention Type

Drug

Intervention Name(s)

Idelalisib

Other Intervention Name(s)

Zydelig®, GS-1101, CAL-101

Intervention Description

Tablets administered orally

Intervention Type

Drug

Intervention Name(s)

Obinutuzumab

Other Intervention Name(s)

Gazyvaro®, Gazyva®, GA101

Intervention Description

Administered intravenously

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Week 25

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Week 25

Title

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

Description

Time Frame

Week 25

Title

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

Description

Time Frame

Week 25

Title

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

Description

Time Frame

First dose date up to the last dose date (maximum: 105 weeks) plus 30 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: Documentation of relapsed or refractory CLL Requiring treatment per modified International Workshop on CLL (IWCLL) 2008 criteria; individuals without radiographically measurable disease (defined as ≥ 1 lesion > 1.5 centimetre (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 grams per decilitre (g/dL) unless lower values are directly attributable to documented bone marrow burden of CLL Creatinine clearance (CrCl) ≥ 50 milliliter 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, hepatitis C virus (HCV) infection, and cytomegalovirus (CMV) 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 including mandatory prophylaxis for Pneumocystis jirovecii pneumonia (PJP) 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 individuals with prior treatment with agents in these classes should be reviewed by the sponsor or the German CLL Study Group (GCLLSG) study 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 Treatment or prophylaxis for CMV within the past 28 days History of stroke or intracranial hemorrhage within 12 months of randomization; patients requiring therapeutic anticoagulation for any indication should be discussed with the GCLLSG cooperating physician and/or medical monitor prior to screening. Use of a strong CYP3A4 or a strong P-glycoprotein (P-gp) inducer within 2 weeks of first dose of study treatment or anticipated chronic use while on study 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gilead Study Director

Organizational Affiliation

Gilead Sciences

Official's Role

Study Director

Facility Information:

Facility Name

Ambulante Krebszentrum Schaubstraße

City

Frankfurt

State/Province

Brandenburg

ZIP/Postal Code

60596

Country

Germany

Facility Name

Hämatologische-onkologische Gem.-Praxis Dres. Brudler-Heinrich-Bangerter, Augsburg

City

Augsburg

ZIP/Postal Code

86150

Country

Germany

Facility Name

Internistische Gemeinschaftspraxis Dres. Schliesser-Käbisch-Weber, Gießen

City

Gießen

ZIP/Postal Code

35392

Country

Germany

Facility Name

Uniklinik Koln

City

Köln

ZIP/Postal Code

50937

Country

Germany

Facility Name

Uniklinik Leipzig

City

Leipzig

ZIP/Postal Code

04103

Country

Germany

Facility Name

Luebecker Onkologische Schwerpunktpraxis

City

Luebeck

ZIP/Postal Code

23562

Country

Germany

Facility Name

Universitasmtedizin Mannheim

City

Mannheim

ZIP/Postal Code

68167

Country

Germany

Facility Name

Stauferklinikum Schwäbisch Gmünd

City

Mutlangen

ZIP/Postal Code

73557

Country

Germany

Facility Name

KH Maria Hilf-Franziskushaus, Mönchengladbach

City

Mönchengladbach

ZIP/Postal Code

41063

Country

Germany

Facility Name

Krankenhaus München-Schwabing

City

München

ZIP/Postal Code

80804

Country

Germany

Facility Name

Klinikum Rechts der Isar der Technischen Universität München

City

München

ZIP/Postal Code

81675

Country

Germany

Facility Name

Studienzentrum Onkologie Ravensburg

City

Ravensburg

ZIP/Postal Code

88212

Country

Germany

Facility Name

Facharztzentrum Regensburg

City

Regensburg

ZIP/Postal Code

93053

Country

Germany

Facility Name

Universitätsklinikum Ulm

City

Ulm

ZIP/Postal Code

89081

Country

Germany

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://www.dcllsg.de/studie/cllrUmbrella1/

Description

Click here for more information about this study: CLLRUmbrella1 (German CLL Study Group)

Learn more about this trial

Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

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