Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination With Other Targeted Anti-cancer Therapies in Adults With B-cell Malignancies

Phase 1

Terminated

Conditions: B-cell Malignancies

Interventions: Drug: Tirabrutinib
Drug: Idelalisib
Drug: Entospletinib
Drug: Obinutuzumab

Registration Number: NCT02457598

Lead Sponsor: Gilead Sciences

Brief 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 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 203

Inclusion Criteria

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
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

Key

Exclusion Criteria

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID)	Tirabrutinib	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.
Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID)	Idelalisib	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.
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD)	Tirabrutinib	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.
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD)	Entospletinib	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.
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD)	Tirabrutinib	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.
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD)	Entospletinib	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.
Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD)	Tirabrutinib	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.
Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD)	Entospletinib	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.
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD)	Tirabrutinib	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.
Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg)	Obinutuzumab	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.
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD)	Entospletinib	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.
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD)	Tirabrutinib	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.
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD)	Entospletinib	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.
Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD)	Tirabrutinib	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.
Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD)	Entospletinib	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.
Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg)	Tirabrutinib	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.
Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg)	Idelalisib	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.
Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg)	Tirabrutinib	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.
Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg)	Entospletinib	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.
Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg)	Obinutuzumab	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.
Group V Single Agent Tirabrutinib	Tirabrutinib	Participants will receive tirabrutinib 80 mg tablet QD orally, for each 28-day cycle up to 194 weeks.
Group VI Single Agent Tirabrutinib: CLL	Tirabrutinib	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.
Group VI Single Agent Tirabrutinib: NHL	Tirabrutinib	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.
Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID)	Tirabrutinib	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.
Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID)	Idelalisib	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.
Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID)	Tirabrutinib	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.
Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID)	Idelalisib	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.
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID)	Tirabrutinib	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.
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID)	Idelalisib	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.
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD)	Tirabrutinib	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.
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD)	Idelalisib	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.
Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD)	Tirabrutinib	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.
Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD)	Idelalisib	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Dose Limiting Toxicities (DLTs)	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	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	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)	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.

Secondary Outcome Measures

Name	Time	Method
PK Parameter: Cmax of Entospletinib When Given in Combination With Tirabrutinib	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	Cmax was defined as the maximum observed concentration of drug.
PK Parameter: AUCtau of Entospletinib When Given in Combination With Tirabrutinib	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
ORR: Percentage of Participants With Complete Response (CR) or Partial Response (PR) in the Dose Escalation and Expansion Phase	Up to 281 weeks	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.
Progression Free Survival (PFS) During the Dose Escalation Phase and Dose Expansion Phase	Up to 281 weeks	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.
Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase	Up to 281 weeks	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
PK Parameter: Cmax of Tirabrutinib 80 mg	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	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.
PK Parameter: AUCtau of Idelalisib When Given in Combination With Tirabrutinib	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
PK Parameter: Cmax of Idelalisib When Given in Combination With Tirabrutinib	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	Cmax was defined as the maximum observed concentration of drug.
PK Parameter: AUCtau of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
PK Parameter: Cmax of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	Cmax was defined as the maximum observed concentration of drug.
Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase	Up to 281 weeks	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.
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	Up to 281 weeks	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.
Pharmacokinetic (PK) Parameter: AUCtau of Tirabrutinib 80 mg	Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose	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.

Trial Locations

Locations (15): Georgetown University Medical Center
🇺🇸
Washington, District of Columbia, United States
Indiana University Health Goshen Center for Cancer Care
🇺🇸
Goshen, Indiana, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
CHRU de Lille, Hopital Claude Huriez
🇫🇷
Lille, France
Hopital Saint Eloi
🇫🇷
Montpellier, France
Chu Haut Leveque
🇫🇷
Pessac, France
Centre Hospitalier de Lyon Sud
🇫🇷
Pierre Benite, France
Institut Universitaire du Cancer-Oncopole I.U.C.T-O
🇫🇷
Toulouse, France
Cambridge University Hospitals NHS Foundation Trust
🇬🇧
Cambridge, United Kingdom
Cardiff and Vale Health Board, Clinical Research Facility
🇬🇧
Cardiff, United Kingdom
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Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States