B-cell MalignanciesPhase 1NCT02457598
Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination With Other Targeted Anti-cancer Therapies in Adults With B-cell Malignancies
A Phase 1 study testing Tirabrutinib, Idelalisib and Entospletinib in people with B-cell Malignancies, run by Gilead Sciences at 15 sites in 3 countries.
Trial summary
The primary objectives of this study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of tirabrutinib (ONO/GS-4059) in combination with other targeted anti-cancer therapies and to evaluate the long-term safety of tirabrutinib as a monotherapy and in… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- B-cell Malignancies
- What is being tested?
- Tirabrutinib, Idelalisib and Entospletinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 203 participants
- Where
- 15 sitesin 3 countries
- Study dates
- 16 Jun 2015to 25 Sep 2024
- Phase
- Phase 1
- 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
- Diagnosis of follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL) (meeting International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria 2008), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), or non-germinal center B-cell lymphoma (GCB) diffuse large B-cell lymphoma (DLBCL) as documented by medical records on World Health Organization (WHO) criteria
- Prior treatment for FL, MZL, SLL, MCL, WM with ≥ 2 or for CLL or non-GCB DLBCL ≥ 1 chemotherapy-based or immunotherapy-based regimen, and not transplant eligible and have had either progressive disease (PD) or no response to previous treatment
- For diseases other than Waldenstrom's macroglobulinemia (WM), presence of radiographically measurable presence of ≥ 1 lesion that measures ≥ 2.0 cm in the longest dimension (LD) and ≥ 1.0 cm in the longest perpendicular dimension (LPD)
- Eastern Cooperative Oncology Group (ECOG) ≤ 2
- Platelets ≥ 50 x 10^9/L; Hb ≥ 8.0 g/dL; absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
- Without transfusion and growth factors within 7 days
Show all 14Show fewer
- Aspartate transaminase/alanine transaminase (AST/ALT) ≤ 2.5 x upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 x ULN
- Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min
- Not pregnant
- Willingness and ability to comply with protocol-specified Pneumocystis jirovecii pneumonia (PJP) prophylaxis
- Long-term Safety Monitoring group only (Group VI):
- Currently enrolled in Study GS-US-401-1787 or previously enrolled in Study GS-US-401-1757 or Study GS-US-401-1787 and currently receiving continued treatment via named patient use
- Continuing to benefit from the current treatment regimen in the opinion of the investigator/treating physician
Who cannot join
- Hepatitis B surface antigen (HBsAG) positive or hepatitis B core antibody positive
- Hepatitis C virus (HCV) antibody positive
- History of long QT syndrome or whose corrected QT(QTc) interval measured (Fridericia method) at screening is prolonged (>450 ms)
- Long-term Safety Monitoring group only (Group VI):
- Evidence of clinical or radiological disease progression
- Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Trial locations and contacts
15 sites in 3 countries.
15 sites in 3 countries
United Kingdom7 sites
Cambridge University Hospitals NHS Foundation Trust
Cambridge, CB20QQ
Cardiff and Vale Health Board, Clinical Research Facility
Cardiff, CF14 4XW
Leeds Teaching Hosptials NHS Trust, Dept of Haematology
Leeds, LS9 7TF
University Hospitals of Leicester NHS Trust
Leicester, LE1 5WW
The Christie NHS Foundation Trust
Manchester, M20 4BX
Plymouth Hospitals NHS Trust
Plymouth, PL68DH
University Hospital Southampton NHS Foundation Trust
Southampton, SO16 6YD
France5 sites
CHRU de Lille, Hopital Claude Huriez
Lille, 59037
Hopital Saint Eloi
Montpellier, 34295
Chu Haut Leveque
Pessac, 33604
Centre Hospitalier de Lyon Sud
Pierre-Bénite, 69310
Institut Universitaire du Cancer-Oncopole I.U.C.T-O
Toulouse, 3110
United States3 sites
Indiana University Health Goshen Center for Cancer Care
Goshen, Indiana, 46506
Oregon Health and Science University
Portland, Oregon, 97239
Georgetown University Medical Center
Washington D.C., District of Columbia, 20007
About this study
Official title: A Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib (ONO/GS-4059) in Combination With Other Targeted Anti-cancer Therapies in Subjects With B-cell Malignancies
The primary objectives of this study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of tirabrutinib (ONO/GS-4059) in combination with other targeted anti-cancer therapies and to evaluate the long-term safety of tirabrutinib as a monotherapy and in combination with other targeted anti-cancer therapies in adults with relapsed or refractory B-cell lymphoproliferative malignancies.
This study consists of three parts: Dose Escalation, Dose Expansion, and Long-term Safety Monitoring. During the Dose Escalation phase, participants will be sequentially enrolled in a standard 3 + 3 dose escalation study design, to receive oral tirabrutinib combined with idelalisib entospletinib +/- obinutuzumab. The Dose Expansion Phase will enroll additional participants with a single B-cell lymphoproliferative malignancy disease type to further evaluate efficacy, safety, tolerability, PK, and pharmacodynamics. The Long-term Safety Monitoring phase will evaluate the long-term safety of tirabrutinib both as a monotherapy and in combination with other anti-cancer therapies. As of Amendment 9, all participants currently on the study who have no clinical evidence of disease progression will transition into long-term safety monitoring. Participants from the ongoing Study GS-US-401-1787 and participants who came off Study GS-US-401-1757 and Study GS-US-401-1787 but continued to receive treatment via named patient use (or individual expanded use) will be enrolled into the long-term safety monitoring group (Group VI). Participants enrolled in Group VI will continue the same treatment regimen in Study GS-US-401-1787 or named patient use (or individual expanded use). As of Protocol Amendment 8, the maximum treatment duration for any participant is an additional 6 years from the date of this amendment (ie. until November 2025). As of Amendment 9, entospletinib will be provided until 31 December 2020 to participants who are currently receiving entospletinib. Participants treated with entospletinib as part of a combination regimen with tirabrutinib will stop receiving entospletinib by 31 December 2020 but may continue to be treated with tirabrutinib monotherapy. Idelalisib will be provided as 50 mg tablets until 31 December 2020 and 100 mg tablets until study completion. Participants assigned to the 50 mg tablet will be given the option, at the investigator's discretion, to switch to 100 mg once daily idelalisib dose.
- Conditions
- B-cell Malignancies
- Being tested
- Tirabrutinib, Idelalisib, Entospletinib, Obinutuzumab
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TirabrutinibDrug
Also called ONO/GS-4059
Capsules or tablets administered orally
IdelalisibDrug
Also called Zydelig®, GS-1101, CAL-101
Tablets administered orally twice daily
EntospletinibDrug
Also called GS-9973
Tablets administered orally
ObinutuzumabDrug
Administered intravenously
| Study group | Role | What they receive |
|---|---|---|
| Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID) | Experimental | Participants will receive tirabrutinib 20 mg tablet once daily (QD) for up to 209 weeks and idelalisib 50 mg tablet twice daily (BID) orally for up to 120 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib |
| Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID) | Experimental | Participants will receive tirabrutinib 40 mg tablet QD for up to 251 weeks and idelalisib 50 mg tablet BID orally, for up to 245 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib |
| Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID) | Experimental | Participants will receive tirabrutinib 80 mg tablet QD for up to 212 weeks and idelalisib 50 mg tablet BID orally, for up to 26 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib |
| Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD) | Experimental | Participants will receive tirabrutinib 80 mg tablet QD for up to 227 weeks and idelalisib 100 mg tablet QD orally, for up to 227 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib |
| Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD) | Experimental | Participants will receive tirabrutinib 160 mg tablet QD for up to 151 weeks and idelalisib 100 mg tablet QD orally, for up to 151 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib |
| Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID) | Experimental | Participants will receive tirabrutinib 20 mg tablet BID for up to 207 weeks and idelalisib 50 mg tablet BID orally, for up to 207 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib |
| Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD) | Experimental | Participants will receive tirabrutinib 40 mg tablet QD for up to 250 weeks and entospletinib 200 mg tablet QD orally, for up to 250 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib |
| Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD) | Experimental | Participants will receive tirabrutinib 80 mg tablet QD for up to 234 weeks and entospletinib 200 mg tablet QD orally, for up to 220 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib |
| Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD) | Experimental | Participants will receive tirabrutinib 150 mg tablet QD for up to 103 weeks and entospletinib 200 mg tablet QD orally, for up to 88 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib |
| Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD) | Experimental | Participants will receive tirabrutinib 40 mg tablet QD for up to 119 weeks and entospletinib 400 mg tablet QD orally, for up to 119 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib |
| Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD) | Experimental | Participants will receive tirabrutinib 80 mg tablet QD for up to 232 weeks and entospletinib 400 mg tablet QD orally, for up to 229 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib |
| Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD) | Experimental | Participants will receive tirabrutinib 160 mg tablet QD for up to 44 weeks and entospletinib 400 mg tablet QD orally, for up to 44 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib |
| Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg) | Experimental | Participants will receive tirabrutinib 80 mg tablet QD for up to 199 weeks; Idelalisib 100 mg tablet QD orally for up to 199 weeks, and single dose of obinutuzumab 1000 mg intravenously (IV) for up to 22 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Idelalisib; Drug: Obinutuzumab |
| Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg) | Experimental | Participants will receive tirabrutinib 80 mg tablet QD for up to 196 weeks; entospletinib 400 mg tablet QD orally for up to 196 weeks and single dose of obinutuzumab 1000 mg IV for up to 22 weeks. Both drugs will be administered for 28-day cycles. Receives: Drug: Tirabrutinib; Drug: Entospletinib; Drug: Obinutuzumab |
| Group V Single Agent Tirabrutinib | Experimental | Participants will receive tirabrutinib 80 mg tablet QD orally, for each 28-day cycle up to 194 weeks. Receives: Drug: Tirabrutinib |
| Group VI Single Agent Tirabrutinib: CLL | Experimental | Participants with CLL who received tirabrutinib in this or a previous tirabrutinib study will continue to receive tirabrutinib at the original dose (between the range of 40 - 400 mg), tablet QD, for each 28-day cycle up to 441 weeks. Participants will be monitored for the long-term safety of tirabrutinib in this group. Receives: Drug: Tirabrutinib |
| Group VI Single Agent Tirabrutinib: NHL | Experimental | Participants with NHL who received tirabrutinib in this or a previous tirabrutinib study will continue to receive tirabrutinib at the original dose (between the range of 60 - 480 mg), tablet QD, for each 28-day cycle up to 441 weeks. Participants will be monitored for the long-term safety of tirabrutinib in this group. Receives: Drug: Tirabrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With Dose Limiting Toxicities (DLTs)
A DLT was defined as a ≥ Grade 3 AE that was assessed as related to study drug that occurred during the 28-day DLT assessment period with protocol-defined allowed exceptions. Any treatment-emergent adverse event (TEAE) that was, in the opinion of the Clinical Trial Steering Committee, of potential clinical significance such that further dosing exposed participants to unacceptable risk, was considered a DLT.
Measured: Up to 28 days
Objective Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) at Week 12 in Participants With Non-Chronic Lymphocytic Leukemia (CLL) Type NHL
ORR for Waldenstrom Macroglobulinemia(WM):CR+VGPR+PR+MPR. CR: Absence of serum monoclonal IgM protein; normal serum IgM level: complete resolution of extramedullary disease, morphologically normal bone marrow/aspirate and trephine biopsy. Very good partial response (VGPR):Detectable monoclonal IgM; ≥90% reduction in serum IgM; Complete resolution of extramedullary disease; No new signs/symptoms. PR: Monoclonal immunoglobulin M (IgM) protein is detectable ≥50% but <90% reduction in serum IgM level from baseline; reduction of extramedullary disease; no new signs or symptoms of active disease. Minor response (MPR):Detectable monoclonal IgM; ≥25% but <50% reduction in serum IgM; No progression of extramedullary disease; No new signs/symptoms. Clopper-Pearson method was used in analysis. Data is reported by disease type: WM; Follicular Lymphoma (FL);Mantle Cell Lymphoma (MCL);Small Lymphocytic Lymphoma (SLL);Marginal Zone Lymphoma (MZL);Diffuse Large B-Cell Lymphoma (DLBCL) as applicable.
Measured: Week 12
ORR: Percentage of Participants With CR or PR in Participants With CLL at Week 24
ORR was defined as the percentage of participants who achieved a complete response (CR) or partial response (PR). CR and PR are defined in outcome measure#2. Clopper-Pearson method was used in outcome measure analysis. Percentages were rounded off.
Measured: Week 24
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. TEAEs were defined as an AE that onset in the period from the first dose of study treatment to 30 days after the last dose of study treatment. Percentages were rounded off.
Measured: First dose up to last dose date (up to 441 weeks) plus 30 days
Secondary outcomes (13)
ORR: Percentage of Participants With Complete Response (CR) or Partial Response (PR) in the Dose Escalation and Expansion Phase
ORR for WM is CR + VGPR + PR + MPR. CR, PR, VGPR and MPR are defined in outcome measure#2. Clopper-Pearson method was used in outcome measure analysis. Percentages were rounded off. Data is reported by disease type: CLL ; FL; MCL; MZL; SLL; WM; DLBCL.
Measured: Up to 281 weeks
Progression Free Survival (PFS) During the Dose Escalation Phase and Dose Expansion Phase
PFS was defined as the interval from the start of the study therapy to the earlier of the first documentation of definite disease progression (PD) or death from any cause. PD: ≥ 25% increase in serum IgM level from lowest nadir (requires confirmation) and/or progression in clinical features attributable to the disease. Kaplan-Meier (KM) estimate were used in outcome measure analysis. Data is reported by disease type: CLL; FL; MCL; MZL; other NHL; DLBCL.
Measured: Up to 281 weeks
Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase
DOR was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definite disease progression or death from any cause. CR and PR are defined in outcome measure# 2. PD is defined in outcome measure #6. KM estimates were used in outcome measure analysis. Data is reported by disease type: CLL; FL; MCL; MZL; SLL; WM; DLBCL
Measured: Up to 281 weeks
Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase
TTR was defined as the interval from start of treatment to the first documentation of CR or PR. CR and PR are defined in outcome measure# 2. Data is reported by disease type: CLL; FL; MCL; MZL; SLL; WM; DLBCL.
Measured: Up to 281 weeks
Percentage of Participants Who Achieved Minimal Residual Negative Disease (< 1 Leukemia Cell/10,000 Leukocytes) During the Dose Escalation Phase and Dose Expansion Phase in Participants With CLL
Achieving Minimal Residual Disease was defined as < 1 leukemia cell/10,000 leukocytes (10-4) in participants who have also achieved a CR. CR is defined in outcome measure #2.
Measured: Up to 281 weeks
Pharmacokinetic (PK) Parameter: AUCtau of Tirabrutinib 80 mg
AUCtau was defined as concentration of drug over time. Area under the concentration verses time curve over the dosing interval (AUctau). The data for AUCtau is reported for tirabrutinib 80 mg as monotherapy and in combination with idelalisib 50 mg and 100 mg and entospletinib 200 mg and 400 mg.
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Tirabrutinib 80 mg
Cmax was defined as the maximum observed concentration of drug. The data for Cmax is reported for tirabrutinib 80 mg as monotherapy and in combination with idelalisib 50 mg and 100 mg and entospletinib 200 mg and 400 mg.
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: AUCtau of Idelalisib When Given in Combination With Tirabrutinib
AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Idelalisib When Given in Combination With Tirabrutinib
Cmax was defined as the maximum observed concentration of drug.
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: AUCtau of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib
AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib
Cmax was defined as the maximum observed concentration of drug.
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: AUCtau of Entospletinib When Given in Combination With Tirabrutinib
AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Entospletinib When Given in Combination With Tirabrutinib
Cmax was defined as the maximum observed concentration of drug.
Measured: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2015 (estimated)
- Study start16 Jun 2015
- Primary completion25 Sep 2024
- Study completion25 Sep 2024
Why it stopped: The goal of the study was to improve tolerability while maintaining or increasing efficacy. The results of this study showed no efficacy advantage although the combinations were well tolerated.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for B-cell MalignanciesStudies of the same condition, open and under way.
- More trials run by Gilead SciencesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Enrollment and treatment were parallel in different combinations used in the study.
- Masking
- None (open label)
- Enrolment
- 203 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gilead Sciences
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Gilead Study Director, Study director, Gilead Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02457598
- Sponsor's protocol ID
- GS-US-401-1757
- Other IDs
- 2015-000834-30, 2015
- Status last verified
- May 2025
- First submitted
- 27 May 2015
- Last updated
- 17 Jun 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, Karlin L, Dyer MJS, Mitra SS, Yi PC, Humeniuk R, Huang X, Zhou Z, Bhargava P, Jurgensmeier JM, Fegan CD. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020 Jun 15;26(12):2810-2818. doi: 10.1158/1078-0432.CCR-19-3504. Epub 2020 Mar 10.
PubMed 32156743Morschhauser F, Dyer MJS, Walter HS, Danilov AV, Ysebaert L, Hodson DJ, Fegan C, Rule SA, Radford J, Cartron G, Bouabdallah K, Davies AJ, Spurgeon S, Rajakumaraswamy N, Li B, Humeniuk R, Huang X, Bhargava P, Jurgensmeier JM, Salles G. Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma. Leukemia. 2021 Jul;35(7):2108-2113. doi: 10.1038/s41375-020-01108-x. Epub 2020 Dec 17. No abstract available.
PubMed 33328591Salles, G., Dyer, MJS,. Hodson, DJ., et-al. Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Entospletinib in Patients with B-Cell Lymphoma. Blood 2018; 132 (Supplement 1): 5344.
Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, Quittet P, Shah N, Hutchinson CV, Honda H, Duffy K, Birkett J, Jamieson V, Courtenay-Luck N, Yoshizawa T, Sharpe J, Ohno T, Abe S, Nishimura A, Cartron G, Morschhauser F, Fegan C, Salles G. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016 Jan 28;127(4):411-9. doi: 10.1182/blood-2015-08-664086. Epub 2015 Nov 5.
PubMed 26542378Walter HS, Salles GA, Dyer MJ. New Agents to Treat Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jun 2;374(22):2185-6. doi: 10.1056/NEJMc1602674. No abstract available.
PubMed 27248633Morschhauser, F., Radford, J., Ysebaert, L., et-al. Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Idelalisib in Patients with B-Cell Lymphoma. Blood 2018; 132 (Supplement 1): 5345.
Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip S, Karlin L, Jones C, Herbaux C, Quittet P, Shah N, Hutchinson CV, Fegan C, Yang Y, Mitra S, Salles G, Dyer MJS. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 May 18;129(20):2808-2810. doi: 10.1182/blood-2017-02-765115. Epub 2017 Apr 4. No abstract available.
PubMed 28377400Yahiaoui A, Meadows SA, Sorensen RA, Cui ZH, Keegan KS, Brockett R, Chen G, Queva C, Li L, Tannheimer SL. PI3Kdelta inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kdelta and BTK inhibitors. PLoS One. 2017 Feb 8;12(2):e0171221. doi: 10.1371/journal.pone.0171221. eCollection 2017.
PubMed 28178345
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib (ONO/GS-4059) in Combination With Other Targeted Anti-cancer Therapies in Subjects With B-cell Malignancies
- ClinicalTrials.gov ID
- NCT02457598
- Acronym / sponsor ID
- GS-US-401-1757
- Conditions
- B-cell Malignancies
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The goal of the study was to improve tolerability while maintaining or increasing efficacy. The results of this study showed no efficacy advantage although the combinations were well tolerated.
- Enrolment
- 203 participants (actual)
- Lead sponsor
- Gilead SciencesIndustry (pharma, biotech, devices)
- Study start
- 16 Jun 2015 (actual)
- Primary completion
- 25 Sep 2024 (actual)
- Study completion
- 25 Sep 2024 (actual)
- First posted
- 29 May 2015 (estimated)
- Results
- Posted 17 Jun 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objectives of this study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of tirabrutinib (ONO/GS-4059) in combination with other targeted anti-cancer therapies and to evaluate the long-term safety of tirabrutinib as a monotherapy and in combination with other targeted anti-cancer therapies in adults with relapsed or refractory B-cell lymphoproliferative malignancies.
This study consists of three parts: Dose Escalation, Dose Expansion, and Long-term Safety Monitoring. During the Dose Escalation phase, participants will be sequentially enrolled in a standard 3 + 3 dose escalation study design, to receive oral tirabrutinib combined with idelalisib entospletinib +/- obinutuzumab. The Dose Expansion Phase will enroll additional participants with a single B-cell lymphoproliferative malignancy disease type to further evaluate efficacy, safety, tolerability, PK, and pharmacodynamics. The Long-term Safety Monitoring phase will evaluate the long-term safety of tirabrutinib both as a monotherapy and in combination with other anti-cancer therapies. As of Amendment 9, all participants currently on the study who have no clinical evidence of disease progression will transition into long-term safety monitoring. Participants from the ongoing Study GS-US-401-1787 and participants who came off Study GS-US-401-1757 and Study GS-US-401-1787 but continued to receive treatment via named patient use (or individual expanded use) will be enrolled into the long-term safety monitoring group (Group VI). Participants enrolled in Group VI will continue the same treatment regimen in Study GS-US-401-1787 or named patient use (or individual expanded use). As of Protocol Amendment 8, the maximum treatment duration for any participant is an additional 6 years from the date of this amendment (ie. until November 2025). As of Amendment 9, entospletinib will be provided until 31 December 2020 to participants who are currently receiving entospletinib. Participants treated with entospletinib as part of a combination regimen with tirabrutinib will stop receiving entospletinib by 31 December 2020 but may continue to be treated with tirabrutinib monotherapy. Idelalisib will be provided as 50 mg tablets until 31 December 2020 and 100 mg tablets until study completion. Participants assigned to the 50 mg tablet will be given the option, at the investigator's discretion, to switch to 100 mg once daily idelalisib dose.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 17
- Model description
- Enrollment and treatment were parallel in different combinations used in the study.
| Arm | Type | Receives |
|---|---|---|
| Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID) | Experimental | Drug: Tirabrutinib, Drug: IdelalisibParticipants will receive tirabrutinib 20 mg tablet once daily (QD) for up to 209 weeks and idelalisib 50 mg tablet twice daily (BID) orally for up to 120 weeks. Both drugs will be administered for 28-day cycles. |
| Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID) | Experimental | Drug: Tirabrutinib, Drug: IdelalisibParticipants will receive tirabrutinib 40 mg tablet QD for up to 251 weeks and idelalisib 50 mg tablet BID orally, for up to 245 weeks. Both drugs will be administered for 28-day cycles. |
| Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID) | Experimental | Drug: Tirabrutinib, Drug: IdelalisibParticipants will receive tirabrutinib 80 mg tablet QD for up to 212 weeks and idelalisib 50 mg tablet BID orally, for up to 26 weeks. Both drugs will be administered for 28-day cycles. |
| Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD) | Experimental | Drug: Tirabrutinib, Drug: IdelalisibParticipants will receive tirabrutinib 80 mg tablet QD for up to 227 weeks and idelalisib 100 mg tablet QD orally, for up to 227 weeks. Both drugs will be administered for 28-day cycles. |
| Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD) | Experimental | Drug: Tirabrutinib, Drug: IdelalisibParticipants will receive tirabrutinib 160 mg tablet QD for up to 151 weeks and idelalisib 100 mg tablet QD orally, for up to 151 weeks. Both drugs will be administered for 28-day cycles. |
| Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID) | Experimental | Drug: Tirabrutinib, Drug: IdelalisibParticipants will receive tirabrutinib 20 mg tablet BID for up to 207 weeks and idelalisib 50 mg tablet BID orally, for up to 207 weeks. Both drugs will be administered for 28-day cycles. |
| Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD) | Experimental | Drug: Tirabrutinib, Drug: EntospletinibParticipants will receive tirabrutinib 40 mg tablet QD for up to 250 weeks and entospletinib 200 mg tablet QD orally, for up to 250 weeks. Both drugs will be administered for 28-day cycles. |
| Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD) | Experimental | Drug: Tirabrutinib, Drug: EntospletinibParticipants will receive tirabrutinib 80 mg tablet QD for up to 234 weeks and entospletinib 200 mg tablet QD orally, for up to 220 weeks. Both drugs will be administered for 28-day cycles. |
| Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD) | Experimental | Drug: Tirabrutinib, Drug: EntospletinibParticipants will receive tirabrutinib 150 mg tablet QD for up to 103 weeks and entospletinib 200 mg tablet QD orally, for up to 88 weeks. Both drugs will be administered for 28-day cycles. |
| Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD) | Experimental | Drug: Tirabrutinib, Drug: EntospletinibParticipants will receive tirabrutinib 40 mg tablet QD for up to 119 weeks and entospletinib 400 mg tablet QD orally, for up to 119 weeks. Both drugs will be administered for 28-day cycles. |
| Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD) | Experimental | Drug: Tirabrutinib, Drug: EntospletinibParticipants will receive tirabrutinib 80 mg tablet QD for up to 232 weeks and entospletinib 400 mg tablet QD orally, for up to 229 weeks. Both drugs will be administered for 28-day cycles. |
| Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD) | Experimental | Drug: Tirabrutinib, Drug: EntospletinibParticipants will receive tirabrutinib 160 mg tablet QD for up to 44 weeks and entospletinib 400 mg tablet QD orally, for up to 44 weeks. Both drugs will be administered for 28-day cycles. |
| Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg) | Experimental | Drug: Tirabrutinib, Drug: Idelalisib, Drug: ObinutuzumabParticipants will receive tirabrutinib 80 mg tablet QD for up to 199 weeks; Idelalisib 100 mg tablet QD orally for up to 199 weeks, and single dose of obinutuzumab 1000 mg intravenously (IV) for up to 22 weeks. Both drugs will be administered for 28-day cycles. |
| Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg) | Experimental | Drug: Tirabrutinib, Drug: Entospletinib, Drug: ObinutuzumabParticipants will receive tirabrutinib 80 mg tablet QD for up to 196 weeks; entospletinib 400 mg tablet QD orally for up to 196 weeks and single dose of obinutuzumab 1000 mg IV for up to 22 weeks. Both drugs will be administered for 28-day cycles. |
| Group V Single Agent Tirabrutinib | Experimental | Drug: TirabrutinibParticipants will receive tirabrutinib 80 mg tablet QD orally, for each 28-day cycle up to 194 weeks. |
| Group VI Single Agent Tirabrutinib: CLL | Experimental | Drug: TirabrutinibParticipants with CLL who received tirabrutinib in this or a previous tirabrutinib study will continue to receive tirabrutinib at the original dose (between the range of 40 - 400 mg), tablet QD, for each 28-day cycle up to 441 weeks. Participants will be monitored for the long-term safety of tirabrutinib in this group. |
| Group VI Single Agent Tirabrutinib: NHL | Experimental | Drug: TirabrutinibParticipants with NHL who received tirabrutinib in this or a previous tirabrutinib study will continue to receive tirabrutinib at the original dose (between the range of 60 - 480 mg), tablet QD, for each 28-day cycle up to 441 weeks. Participants will be monitored for the long-term safety of tirabrutinib in this group. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Diagnosis of follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL) (meeting International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria 2008), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), or non-germinal center B-cell lymphoma (GCB) diffuse large B-cell lymphoma (DLBCL) as documented by medical records on World Health Organization (WHO) criteria
- Prior treatment for FL, MZL, SLL, MCL, WM with ≥ 2 or for CLL or non-GCB DLBCL ≥ 1 chemotherapy-based or immunotherapy-based regimen, and not transplant eligible and have had either progressive disease (PD) or no response to previous treatment
- For diseases other than Waldenstrom's macroglobulinemia (WM), presence of radiographically measurable presence of ≥ 1 lesion that measures ≥ 2.0 cm in the longest dimension (LD) and ≥ 1.0 cm in the longest perpendicular dimension (LPD)
- Eastern Cooperative Oncology Group (ECOG) ≤ 2
- Platelets ≥ 50 x 10^9/L; Hb ≥ 8.0 g/dL; absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
Key exclusion criteria (6 listed)
- Hepatitis B surface antigen (HBsAG) positive or hepatitis B core antibody positive
- Hepatitis C virus (HCV) antibody positive
- History of long QT syndrome or whose corrected QT(QTc) interval measured (Fridericia method) at screening is prolonged (>450 ms)
- Long-term Safety Monitoring group only (Group VI):
- Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TirabrutinibAlso: ONO/GS-4059Capsules or tablets administered orally | Drug | Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD), Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID), Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID), Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID), Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD), Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID), Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD), Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD), Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD), Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD), Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD), Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD), Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg), Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg), Group V Single Agent Tirabrutinib, Group VI Single Agent Tirabrutinib: CLL, Group VI Single Agent Tirabrutinib: NHL |
| IdelalisibAlso: Zydelig®, GS-1101, CAL-101Tablets administered orally twice daily | Drug | Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD), Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID), Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID), Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID), Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD), Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID), Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg) |
| EntospletinibAlso: GS-9973Tablets administered orally | Drug | Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD), Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD), Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD), Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD), Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD), Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD), Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg) |
| ObinutuzumabAdministered intravenously | Drug | Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg), Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg) |
Primary outcome
Percentage of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Up to 28 days
A DLT was defined as a ≥ Grade 3 AE that was assessed as related to study drug that occurred during the 28-day DLT assessment period with protocol-defined allowed exceptions. Any treatment-emergent adverse event (TEAE) that was, in the opinion of the Clinical Trial Steering Committee, of potential clinical significance such that further dosing exposed participants to unacceptable risk, was considered a DLT.
Objective Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) at Week 12 in Participants With Non-Chronic Lymphocytic Leukemia (CLL) Type NHL
Time frame: Week 12
ORR for Waldenstrom Macroglobulinemia(WM):CR+VGPR+PR+MPR. CR: Absence of serum monoclonal IgM protein; normal serum IgM level: complete resolution of extramedullary disease, morphologically normal bone marrow/aspirate and trephine biopsy. Very good partial response (VGPR):Detectable monoclonal IgM; ≥90% reduction in serum IgM; Complete resolution of extramedullary disease; No new signs/symptoms. PR: Monoclonal immunoglobulin M (IgM) protein is detectable ≥50% but <90% reduction in serum IgM level from baseline; reduction of extramedullary disease; no new signs or symptoms of active disease. Minor response (MPR):Detectable monoclonal IgM; ≥25% but <50% reduction in serum IgM; No progression of extramedullary disease; No new signs/symptoms. Clopper-Pearson method was used in analysis. Data is reported by disease type: WM; Follicular Lymphoma (FL);Mantle Cell Lymphoma (MCL);Small Lymphocytic Lymphoma (SLL);Marginal Zone Lymphoma (MZL);Diffuse Large B-Cell Lymphoma (DLBCL) as applicable.
ORR: Percentage of Participants With CR or PR in Participants With CLL at Week 24
Time frame: Week 24
ORR was defined as the percentage of participants who achieved a complete response (CR) or partial response (PR). CR and PR are defined in outcome measure#2. Clopper-Pearson method was used in outcome measure analysis. Percentages were rounded off.
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
Time frame: First dose up to last dose date (up to 441 weeks) plus 30 days
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. TEAEs were defined as an AE that onset in the period from the first dose of study treatment to 30 days after the last dose of study treatment. Percentages were rounded off.
13 secondary outcomes
ORR: Percentage of Participants With Complete Response (CR) or Partial Response (PR) in the Dose Escalation and Expansion Phase
Time frame: Up to 281 weeks
Progression Free Survival (PFS) During the Dose Escalation Phase and Dose Expansion Phase
Time frame: Up to 281 weeks
Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase
Time frame: Up to 281 weeks
Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase
Time frame: Up to 281 weeks
Percentage of Participants Who Achieved Minimal Residual Negative Disease (< 1 Leukemia Cell/10,000 Leukocytes) During the Dose Escalation Phase and Dose Expansion Phase in Participants With CLL
Time frame: Up to 281 weeks
Pharmacokinetic (PK) Parameter: AUCtau of Tirabrutinib 80 mg
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Tirabrutinib 80 mg
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: AUCtau of Idelalisib When Given in Combination With Tirabrutinib
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Idelalisib When Given in Combination With Tirabrutinib
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: AUCtau of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: AUCtau of Entospletinib When Given in Combination With Tirabrutinib
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
PK Parameter: Cmax of Entospletinib When Given in Combination With Tirabrutinib
Time frame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 32156743Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, Karlin L, Dyer MJS, Mitra SS, Yi PC, Humeniuk R, Huang X, Zhou Z, Bhargava P, Jurgensmeier JM, Fegan CD. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020 Jun 15;26(12):2810-2818. doi: 10.1158/1078-0432.CCR-19-3504. Epub 2020 Mar 10.
- Background: PubMed 33328591Morschhauser F, Dyer MJS, Walter HS, Danilov AV, Ysebaert L, Hodson DJ, Fegan C, Rule SA, Radford J, Cartron G, Bouabdallah K, Davies AJ, Spurgeon S, Rajakumaraswamy N, Li B, Humeniuk R, Huang X, Bhargava P, Jurgensmeier JM, Salles G. Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma. Leukemia. 2021 Jul;35(7):2108-2113. doi: 10.1038/s41375-020-01108-x. Epub 2020 Dec 17. No abstract available.
- BackgroundSalles, G., Dyer, MJS,. Hodson, DJ., et-al. Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Entospletinib in Patients with B-Cell Lymphoma. Blood 2018; 132 (Supplement 1): 5344.
- Background: PubMed 26542378Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, Quittet P, Shah N, Hutchinson CV, Honda H, Duffy K, Birkett J, Jamieson V, Courtenay-Luck N, Yoshizawa T, Sharpe J, Ohno T, Abe S, Nishimura A, Cartron G, Morschhauser F, Fegan C, Salles G. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016 Jan 28;127(4):411-9. doi: 10.1182/blood-2015-08-664086. Epub 2015 Nov 5.
- Background: PubMed 27248633Walter HS, Salles GA, Dyer MJ. New Agents to Treat Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jun 2;374(22):2185-6. doi: 10.1056/NEJMc1602674. No abstract available.
- BackgroundMorschhauser, F., Radford, J., Ysebaert, L., et-al. Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Idelalisib in Patients with B-Cell Lymphoma. Blood 2018; 132 (Supplement 1): 5345.
- Background: PubMed 28377400Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip S, Karlin L, Jones C, Herbaux C, Quittet P, Shah N, Hutchinson CV, Fegan C, Yang Y, Mitra S, Salles G, Dyer MJS. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 May 18;129(20):2808-2810. doi: 10.1182/blood-2017-02-765115. Epub 2017 Apr 4. No abstract available.
- Derived from this study: PubMed 28178345Yahiaoui A, Meadows SA, Sorensen RA, Cui ZH, Keegan KS, Brockett R, Chen G, Queva C, Li L, Tannheimer SL. PI3Kdelta inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kdelta and BTK inhibitors. PLoS One. 2017 Feb 8;12(2):e0171221. doi: 10.1371/journal.pone.0171221. eCollection 2017.
- Gilead Clinical Trials WebsiteLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gilead Study Director study director
Gilead Sciences
15 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tirabrutinib, Idelalisib and Entospletinib in people with B-cell Malignancies, run by Gilead Sciences at 15 sites in 3 countries.
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 14 inclusion and 6 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: stopped early, as of the sponsor's last update on 17 Jun 2025. 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 United Kingdom, France, United States. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 17 Jun 2025). 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?
Percentage of Participants With Dose Limiting Toxicities (DLTs) (time frame: Up to 28 days). The study lists 4 primary outcomes in all. 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 NCT02457598, which also lists 8 linked publications.
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 17 Jun 2025.