GS-US-401-1757 A Phase 1b Dose Escalation and Dose Expansion Study
Research type
Research Study
Full title
A Phase 1b Dose Escalation and Dose Expansion Study of ONO/GS-4059 Combined with Idelalisib in Subjects with B-cell Malignancies Current protocol: 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
IRAS ID
183471
Contact name
Martin Dyer
Contact email
Sponsor organisation
Gilead Sciences
Eudract number
2015-000834-30
Clinicaltrials.gov Identifier
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Summary of Research
The purpose of this study is to characterize the safety and tolerability of ONO/GS4059 combined with idelalisib in subjects with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), or nongerminal center Bcell like diffuse large Bcell lymphoma (nonGCB DLBCL).
Idelalisib is currently approved by the FDA in the United States and European Union for the treatment of relapsed Follicular Lymphoma, Small Lymphocytic Lymphoma, and relapsed Chronic Lymphocytic Lymphoma.
In this study, there will be 48 patients in the dose escalation phase or one of approximately 90 subjects patients in the dose expansion phase depending on the start date of the study. The study will take place at about 25 centres in the United States, European Union, Japan and Canada. This study will last approximately 3 years.Current protocol:
The purpose of this study is to characterise the safety and tolerability of tirabrutinib combined with idelalisib or entospletinib (also known as ENTO, and GS-9973) in patients with relapsed or refractory B-cell lymphoproliferative malignancies.Idelalisib is currently approved by the FDA in the US and European Union for the treatment of relapsed Follicular Lymphoma, Small Lymphocytic Lymphoma, and relapsed Chronic Lymphocytic Lymphoma.
Entospletinib will be discontinued by 31 Dec 2020. This is based on the limited clinical efficacy seen across the development program for entosplentinib. Sponsor will provide entospletinib for a limited period of time to enable patients to transition to other therapies.
There are 376 patients in this study. The study will take place at about 25 centres in the US and European Union.
This study will have a maximum treatment period of 10 years.
(Initial protocol V1.0: Maximum treatment period of 2 years, Protocol Amendment V5.1: Maximum treatment period extended to 4 years, Protocol Amendment V8.1: Maximum treatment period extended by 6 years to 10 years)Summary of Results
What is B-cell malignancy?
B-cell malignancy or B-cell cancer refers to cancers that originate from B cells, which are a type of white blood cells that make antibodies. Antibodies are proteins that help the body fight infections. B-cell cancers include various types of cancers like chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Waldenström's macroglobulinemia (WM). Existing treatments do not always work well for people with relapsed (r) or refractory (r) B- cell cancers. Relapsed means cancer has come back, and refractory means cancer has stopped responding to the treatment. Therefore, new treatment options are needed for these types of cancers.
In this study, the researchers tested tirabrutinib in combination with other drugs like idelalisib, entospletinib, and obinutuzumab. Tirabrutinib (also known as ONO/GS-4059) is a cancer treatment drug that was previously being developed by Gilead in collaboration with Ono Pharmaceuticals. Idelalisib is an approved medicine for treating B-cell cancer. Entospletinib is a cancer drug that was also previously under development for cancer treatment. Obinutuzumab is a monoclonal antibody used with other medicines to treat cancers like CLL and FL. Monoclonal antibodies are proteins made in the laboratory to target cancer cells.
What was the purpose of the study?
The purpose of this study was to check how safe and well-tolerated tirabrutinib was when given with other drugs to treat people with r/r B-cell cancers. The study also checked the effectiveness of tirabrutinib combinations and its long-term safety.
The main questions the researchers wanted to answer in this study were:
• How many participants had dose-limiting toxicities (DLTs) in Combinations 1 to 4 or Group 5, if any? DLTs were unwanted medical events that were serious enough to stop further increase in the dose. This was checked to find a safe dose of tirabrutinib to be given with other drugs.
• How many participants achieved complete or partial response in Combinations 1 to 4 and Group 5 for each disease type? A complete response means all tumors have disappeared, while a partial response means the tumors have shrunk and no new tumors have appeared. Together they are called objective response.
• How many participants had any unwanted medical events (also called Adverse Events [AEs]) during the study? AEs were any unwanted signs or symptoms that participants had during the study. They may or may not be caused by the study treatment. An AE is considered “serious” if it i) results in death, ii) is life-threatening, iii) is considered by the study doctor to be medically important, iv) causes lasting problems v) requires hospital care, vi) causes a birth defect.
• Researchers also checked what side effects participants had during the study, if any. Side effects were the AEs that the study doctors thought might be caused by the study treatment.
Who took part in the study?
The study began in June 2015 and ended in September 2024. The study closed earlier than planned as the researchers did not see any benefit of adding tirabrutinib to other drugs as a treatment for B-cell cancers.
The study enrolled 203 participants in France, the United States, and the United Kingdom. The participants were between the ages of 30 to 91 years. Out of 203 participants, 128 (63%) participants were men and 75 (37%) were women. All participants are now off-study.
This study enrolled people if they:
• Were men or women aged 18 years or above
• Had confirmed FL, MZL, SLL, CLL, MCL, DLBCL, or WM
• Received treatment for B-cell cancers in the past, but it failed
• Received tirabrutinib in another Gilead study (GS-US-401-1787)
What happened during the study?
This was an open-label, Phase 1b study. Open-label means the participant, the study doctor, and the study staff knew the treatments the participants were taking. Phase 1b means the researchers tested tirabrutinib combinations in a larger number of people with B-cell cancers.
The study had 3 parts: Dose-escalation, Dose-expansion, and Long-term Safety Monitoring (LTSM).
Dose-escalation: In this part, 4 different drug combinations were used. Combination 1 tested different doses of tirabrutinib with idelalisib. Combination 2 tested different doses of tirabrutinib with entospletinib. This was done to find a safe dose combination.
Once the safe dose combinations were determined, the study further tested the safety of both combinations with the third drug, obinutuzumab in Combinations 3 and 4.
Dose-expansion: In this part, more participants were enrolled in Combinations 1 to 4 to test the safety and effectiveness of tirabrutinib combinations as well as a single agent in participants with CLL.
LTSM: In this part, participants from this study and another tirabrutinib study were enrolled to assess the long-term safety of tirabrutinib.
What treatments did participants take?
Participants took the study treatments in 28-day cycles. A cycle is the interval between the end of one treatment to the start of the next. Below is the summary of treatments the participants took in each group:
• Combination 1 (54 participants): Tirabrutinib tablet (20-160 mg) + idelalisib capsule (50/100 mg), orally (by mouth), once a day (QD) or twice a day (BID).
• Combination 2 (101 participants): Tirabrutinib tablet (40-160 mg) + entospletinib tablet (200/400 mg), QD.
• Combination 3 (6 participants): Tirabrutinib tablet, 80 mg + idelalisib capsule, 100 mg, orally, QD + Obinutuzumab 1000 mg as a slow injection into a vein.
• Combination 4 (7 participants): Tirabrutinib tablet, 80 mg + entospletinib tablet, 400 mg, orally QD + Obinutuzumab 1000 mg as a slow injection into a vein.
• Group 5 (29 participants): Tirabrutinib tablet, 80 mg, orally, QD.
• Group 6 (6 participants, 3 with other types of B-cell cancers and 3 with CLL): Tirabrutinib tablet as the same dose level they were taking in Combinations 1 to 4 or Group 5 or other tirabrutinib Gilead study.
Participants took the treatment until the end of the study. The treatments were stopped if participants’ disease got worse, they had unacceptable side effects, they decided to leave the study, they died, or the study was stopped by the sponsor.
What were the results of the study?
This is a summary of the main results from this study.
How many participants had DLTs in Combinations 1 to 4 or Group 5, if any?
The researchers checked the safety and tolerability of various doses of tirabrutinib with other drugs in 197 participants in Combinations 1 to 4 and Group 5. DLTs were reported in 1 out of 54 (5%) participants in Combination 1 who received tirabrutinib + idelalisib. Participants in Combinations 2 to 4, and Group 5 did not experience any dose-limiting toxicities (DLTs).
How many participants achieved complete or partial response in Combinations 1 to 4 and Group 5 for each disease type?
The researchers assessed participants for complete or partial response to treatment at Week 12 among participants with non-CLL and at Week 24 among participants with CLL.
Below is the summary of participants with complete or partial response:
Combination 1: Tirabrutinib + idelalisib (40 non-CLL and 14 with CLL participants)
- Week 12: Out of 40 participants with non-CLL who achieved response were: 1 out of 10 (10%) with FL; 0 out of 1 with MCL, 1 out of 2 (50%) with SLL, 2 out of 5 (40%) with MZL, 4 out of 5 (80%) with WM, 3 out of 17 (18%) with DLBCL.
- Week 24: 11 out of 14 (79%) participants with CLL, achieved response.
Combination 2: Tirabrutinib + entospletinib (91 non-CLL and 10 CLL participants)
- Week 12: Out of 91 participants with non-CLL who achieved response were: 6 out of 26 (23%) with FL; 6 out of 11 (55%) with MCL, 0 out of 2 with SLL, 2 out of 5 (40%) with MZL, 3 out of 8 (38%) with WM, 8 out of 39 (21%) with DLBCL.
- Week 24: 4 out of 10 (40%) participants with CLL, achieved objective response.
Combination 3: Tirabrutinib + idelalisib + obinutuzumab (6 participants with non-CLL)
- Week 12: Out of 6 participants with non-CLL who achieved response were: 1 out of 4 (25%) with FL; 1 out of 1 (100%) with MCL and MZL each.
Combination 4: Tirabrutinib + entospletinib + obinutuzumab (7 participants with non-CLL)
- Week 12: Out of 7 participants with non-CLL participants who achieved response were: 2 out of 5 (40%) with FL; 1 out of 2 (50%) with MZL.
Group 5: Week 24: 23 out of 29 (79%) participants with CLL achieved objective response.
The participants with CLL had the greatest response at Week 24 compared to the response in participants in other groups with other B-cell cancers.
Participants in Group 6 were assessed only for the long-term safety of tirabrutinib.
How many participants had AEs during the study?
Almost all participants had some AEs during the study. Of 203 participants, 26 out of 54 (48%) participants in Combination 1, 47 out of 100 (47%) participants in Combination 2, 4 out of 6 (67%) participants in Combination 3, all 7 (100%) participants in Combination 4, 10 out of 29 (35%) participants in Group 5 and 2 out of 6 (33%) participants in Group 6 had serious AEs.
Overall, participants in Combination 4 who took tirabrutinib + entospletinib + obinutuzumab had a higher number of serious AEs than any other groups.
What side effects did participants have during the study?
Below is a summary of the side effects for all study participants.
Out of 203 participants, 165 (81%) had side effects, 43 (21%) had serious side effects, and 24 (12%) discontinued the study drug due to side effects. None of the participants died due to any side effects. All serious side effects in the study were each reported in only 1 participant. The most common (top 2) non-serious side effects that occurred in more than 25% of total participants were diarrhea and low number of white blood cells (neutropenia).
The non-serious side effects were the side effects that were not serious in nature and did not meet the definition of ‘serious side effects’. There were other non-serious side effects, but those occurred in fewer participants. Some participants may have had more than 1 serious or non-serious side effect.
This summary was created and approved by Gilead Sciences in February 2025. The information in this summary does not include any information available after this date.
Thank you!REC name
West of Scotland REC 1
REC reference
15/WS/0135
Date of REC Opinion
25 Aug 2015
REC opinion
Further Information Favourable Opinion