Clinical trial NCT02457598: Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination With Other Targeted Anti-cancer Therapies in Adults With B-cell Malignancies
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: B-cell Malignancies
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-05-29
Enrollment: 203
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Enrollment and treatment were parallel in different combinations used in the study.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 28 days
measure: 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
timeFrame: Week 12
measure: ORR: Percentage of Participants With CR or PR in Participants With CLL at Week 24
timeFrame: Week 24
measure: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
timeFrame: First dose up to last dose date (up to 441 weeks) plus 30 days
Secondary outcomes:
measure: ORR: Percentage of Participants With Complete Response (CR) or Partial Response (PR) in the Dose Escalation and Expansion Phase
timeFrame: Up to 281 weeks
measure: Progression Free Survival (PFS) During the Dose Escalation Phase and Dose Expansion Phase
timeFrame: Up to 281 weeks
measure: Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase
timeFrame: Up to 281 weeks
measure: Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase
timeFrame: Up to 281 weeks
measure: 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
timeFrame: Up to 281 weeks
measure: Pharmacokinetic (PK) Parameter: AUCtau of Tirabrutinib 80 mg
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: Cmax of Tirabrutinib 80 mg
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: AUCtau of Idelalisib When Given in Combination With Tirabrutinib
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: Cmax of Idelalisib When Given in Combination With Tirabrutinib
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: AUCtau of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: Cmax of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: AUCtau of Entospletinib When Given in Combination With Tirabrutinib
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
measure: PK Parameter: Cmax of Entospletinib When Given in Combination With Tirabrutinib
timeFrame: Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose
Other outcomes:
Locations:
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Goshen
country: United States
facility: Indiana University Health Goshen Center for Cancer Care
state: Indiana
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Lille
country: France
facility: CHRU de Lille, Hopital Claude Huriez
city: Montpellier
country: France
facility: Hopital Saint Eloi
city: Pessac
country: France
facility: Chu Haut Leveque
city: Pierre Benite
country: France
facility: Centre Hospitalier de Lyon Sud
city: Toulouse
country: France
facility: Institut Universitaire du Cancer-Oncopole I.U.C.T-O
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale Health Board, Clinical Research Facility
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hosptials NHS Trust, Dept of Haematology
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Morschhauser 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.
citation: Salles, 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.
citation: 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.
citation: Walter 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.
citation: Morschhauser, 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.
citation: 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.
citation: Yahiaoui 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.