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

B-cell Malignancies Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02457598
• Other study ID #: GS-US-401-1757
• Secondary ID: 2015-000834-30
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: June 16, 2015
• Est. completion date: December 2025

Study information

• Verified date: December 2023
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 203
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• B-cell Malignancies
• Neoplasms

Intervention

Drug:
• Tirabrutinib
Capsules or tablets administered orally
• Idelalisib
Tablets administered orally twice daily
• Entospletinib
Tablets administered orally
• Obinutuzumab
Administered intravenously

Locations

Country	Name	City	State
France	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
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Cardiff and Vale Health Board, Clinical Research Facility	Cardiff
United Kingdom	Leeds Teaching Hosptials NHS Trust, Dept of Haematology	Leeds
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Plymouth Hospitals NHS Trust	Plymouth
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United States	Indiana University Health Goshen Center for Cancer Care	Goshen	Indiana
United States	Oregon Health and Science University	Portland	Oregon
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  France,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase		Up to 28 days
Primary	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
Primary	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
Primary	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	Overall Response Rate (ORR) During the Dose Escalation Phase and Dose Expansion Phase		Up to 6 years from the date of Protocol Amendment 8
Secondary	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
Secondary	Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase		Up to 6 years from the date of Protocol Amendment 8
Secondary	Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase		Up to 6 years from the date of Protocol Amendment 8
Secondary	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
Secondary	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
Secondary	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

External Links

•   Gilead Clinical Trials Website