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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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B-cell Malignancies

Intervention / Treatment
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* Drug: Tirabrutinib
* Drug: Idelalisib
* Drug: Entospletinib
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Key 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tirabrutinib + Idelalisib (Combination I)<br>Dose Escalation: Participants will receive a single dose of tirabrutinib on Day 1 of Cycle 1 and tirabrutinib 20 mg + idelalisib 50 mg on Day 2 and remainder of Cycle 1. For all subsequent cycles, participants will receive tirabrutinib 20 mg + idelalisib 50 mg. Based on DLTs observed in subsequent cohorts, additional participants will be enrolled and administered escalating dose of tirabrutinib up to 160 mg + idelalisib up to 100 mg to determine the maximum tolerated dose (MTD) of tirabrutinib either once daily or twice daily. Dose Expansion: Additional participants will receive tirabrutinib + idelalisib for an additional 6 years from the date of Protocol Amendment 8. | Drug: Tirabrutinib<br>* Capsules or tablets administered orally<br>* Other names: ONO/GS-4059;Drug: Idelalisib<br>* Tablets administered orally twice daily<br>* Other names: CAL-101;|
| Experimental: Tirabrutinib + Entospletinib (Combination II)<br>Dose Escalation: Participants will receive a single dose of tirabrutinib 40 mg on Day 1 of Cycle 1 and tirabrutinib 40 mg + entospletinib 200 mg on Day 2 and remainder of Cycle 1. For all subsequent cycles, participants will receive tirabrutinib 40 mg + entospletinib 200 mg. Based on DLTs observed in subsequent cohorts, additional participants will be enrolled and administered escalating dose of tirabrutinib up to 160 mg + entospletinib up to 400 mg to determine the maximum tolerated dose (MTD) of tirabrutinib either once daily or twice daily. Dose Expansion: Additional participants will receive tirabrutinib + entospletinib for an additional 6 years from the date of Protocol Amendment 8. | Drug: Tirabrutinib<br>* Capsules or tablets administered orally<br>* Other names: ONO/GS-4059;Drug: Entospletinib<br>* Tablets administered orally<br>* Other names: GS-9973;|
| Experimental: Tirabrutinib + Idelalisib + Obinutuzumab (Combination III)<br>Dose escalation: Participants will receive tirabrutinib + idelalisib + obinutuzumab 1000 mg at 8 doses (tirabrutinib and idelalisib doses will depend on results of Combination I data). Based on DLTs observed, additional participants will be enrolled to determine the maximum tolerated dose (MTD) of tirabrutinib either once daily or twice daily. Dose Expansion: Additional participants will receive tirabrutinib + idelalisib + obinutuzumab for an additional 6 years from the date of Protocol Amendment 8. | Drug: Tirabrutinib<br>* Capsules or tablets administered orally<br>* Other names: ONO/GS-4059;Drug: Idelalisib<br>* Tablets administered orally twice daily<br>* Other names: CAL-101;Drug: Obinutuzumab<br>* Administered intravenously<br>|
| Experimental: Tirabrutinib + Entospletinib + Obinutuzumab (Combination IV)<br>Dose escalation: Participants will receive tirabrutinib + entospletinib + obinutuzumab 1000 mg at 8 doses (tirabrutinib and entospletinib doses will depend on results of Combination II data). Based on DLTs observed, additional participants will be enrolled to determine the maximum tolerated dose (MTD) of tirabrutinib either once daily or twice daily. Dose Expansion: Additional participants will receive tirabrutinib + idelalisib + obinutuzumab for an additional 6 years from the date of Protocol Amendment 8. | Drug: Tirabrutinib<br>* Capsules or tablets administered orally<br>* Other names: ONO/GS-4059;Drug: Entospletinib<br>* Tablets administered orally<br>* Other names: GS-9973;Drug: Obinutuzumab<br>* Administered intravenously<br>|
| Experimental: Single Agent Tirabrutinib (Combination V)<br>Participants with relapsed or refractory chronic lymphocytic leukemia (CLL) may be enrolled to receive tirabrutinib 80 mg once daily. | Drug: Tirabrutinib<br>* Capsules or tablets administered orally<br>* Other names: ONO/GS-4059;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase |  | Up to 28 days | 
| Overall Response Rate (ORR) at Week 12 During the Dose Expansion Phase for Non-CLL Participants | Overall response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) as assessed by disease type. | Week 12 | 
| Overall Response Rate (ORR) at Week 24 During the Dose Expansion Phase for CLL Participants | Overall response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) as assessed by disease type. | Week 24 | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events for the Long-term Safety Phase |  | Up to 6 years from the date of Protocol Amendment 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) During the Dose Escalation Phase and Dose Expansion Phase |  | Up to 6 years from the date of Protocol Amendment 8 | 
| Progression Free Survival (PFS) During the Dose Escalation Phase and Dose Expansion Phase | PFS is defined as the interval from the start of the study therapy to the earlier of the first documentation of definite disease progression or death from any cause. | Up to 6 years from the date of Protocol Amendment 8 | 
| Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase |  | Up to 6 years from the date of Protocol Amendment 8 | 
| Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase |  | Up to 6 years from the date of Protocol Amendment 8 | 
| For Participants with Chronic Lymphocytic Leukemia (CLL) Only: Proportion of Participants who Achieve Minimal Residual Negative Disease (< 1 leukemia cell/10,000 leukocytes) During the Dose Escalation Phase and Dose Expansion Phase |  | Up to 6 years from the date of Protocol Amendment 8 | 
| Plasma Pharmacokinetic (PK) Parameter: AUCtau of tirabrutinib, Idelalisib, Idelalisib Metabolite GS-563117, and Entospletinib During the Dose Escalation Phase and Dose Expansion Phase | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12 (optional), 24 hours postdose | 
| Plasma Pharmacokinetic (PK) Parameter: Cmax of tirabrutinib, Idelalisib, Idelalisib Metabolite GS-563117, and Entospletinib During the Dose Escalation Phase and Dose Expansion Phase | Cmax is defined as the maximum observed concentration of drug. | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12 (optional), 24 hours postdose |