Study of Tirabrutinib (ONO-4059) in Patients With Primary Central Nervous System Lymphoma (PROSPECT Study)

Primary CNS Lymphoma Clinical Trial

Official title:

An Open-label Phase II Study to Investigate the Efficacy, Safety, and Pharmacokinetics of Tirabrutinib in Patients With Primary Central Nervous System Lymphoma (PCNSL)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04947319
• Other study ID #: ONO-4059-09
• Status: Recruiting
• Phase: Phase 2
• Start date: December 29, 2021
• Est. completion date: March 31, 2027

Study information

• Verified date: May 2024
• Source: Ono Pharmaceutical Co. Ltd
• Contact: Ono Pharma USA, Inc.
• Phone: 6179044500
• Email: PROSPECTstudy[@]ono-pharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A), and tirabrutinib in combination with one of two different high dose methotrexate based regimens (methotrexate/ temozolomide/rituximab or rituximab/methotrexate/procarbazine/ vincristine) as first line therapy in patients with newly diagnosed, treatment naïve PCNSL (Part B)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 112
• Est. completion date: March 31, 2027
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria (Part A)

1. Written informed consent by the patient prior to screening

2. Patients aged = 18 years on the day of consenting to the study

3. Pathologic diagnosis of PCNSL

4. Relapse or refractory PCNSL with at least one prior high dose methotrexate (HD-MTX) based therapy for PCNSL

5. Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced magnetic resonance imaging (MRI) performed within 14 days before starting tirabrutinib treatment

6. Eastern Cooperative Oncology Group performance score (ECOG PS) of 0, 1 or 2

7. Life expectancy of at least 3 months

8. Adequate bone marrow, renal, and hepatic function Inclusion Criteria (Part B)

1. Written informed consent by the patient prior to screening

2. Patients aged = 18 years on the day of consenting to the study

3. Pathologic diagnosis of PCNSL within the past 3 months

4. No prior anti-tumor treatments for PCNSL

5. Patients who, in the opinion of the Investigator, are suitable to receive treatment with a high dose methotrexate containing regimen

6. Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced MRI performed within 14 days before starting study treatment

7. ECOG PS of 0, 1 or 2

8. Life expectancy of at least 6 months

9. Adequate bone marrow, renal, and hepatic function Exclusion Criteria (Part A)

1. Intraocular PCNSL with no brain lesion

2. Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents

3. Patient with non-B cell PCNSL

4. Patient with systemic presence of lymphoma

5. Prior chemotherapy within 21 days, nitrosourea within 42 days, an antibody drug with anticancer activity (e.g., rituximab) within 28 days, prior radiotherapy within 14 days, prior major invasive surgery within 28 days, or allogeneic stem cell transplant within 6 months before starting tirabrutinib treatment

6. Prior BTK inhibitor treatment

7. Prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, before starting tirabrutinib treatment

8. Concomitant systemic corticosteroid on an ongoing basis within 14 days before starting

tirabrutinib treatment, with the exception of the following:

• Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL
• Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone) for patients with lesions of the brain or spinal cord or both

9. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment

10. Concomitant warfarin, any other warfarin derivative anticoagulant, vitamin K antagonists, novel oral anticoagulants, or antiplatelet therapy on an ongoing basis within 7 days before starting tirabrutinib treatment

11. Active malignancy, other than PCNSL requiring systemic therapy

12. Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments

13. Patient with bleeding diathesis

14. Patients with a history of moderate or severe hepatic impairment

15. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval

16. Active infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has had, within 28 days before starting tirabrutinib treatment, an infection (other than nail trichophytosis) that requires hospitalization or an intravenous antibiotic

17. Prior history of hypersensitivity or anaphylaxis to tirabrutinib

18. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis

19. Medical history of organ allografts

20. Tests positive for HIV-1 antibody and HIV-2 antibody, human T-lymphotropic virus 1 antibody, hepatitis B (HB) antigen, or hepatitis C virus (HCV) antibody. Tests positive for HBs antibody or hepatitis B virus core protein antibody and has a result of at least detectable in a hepatitis B virus deoxyribonucleic acid assay despite testing negative for HBs antigen.

21. Patient is unable to swallow tablets; has malabsorption, malabsorption syndrome, or a comorbidity that affects gastric function; has undergone complete resection of the stomach or small intestine; has ulcerative colitis or symptomatic inflammatory bowel disease; or has partial or complete intestinal obstruction.

22. Women who are pregnant or lactating

23. Patient is found incapable of giving consent due to dementia or another such condition

24. Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator. Exclusion Criteria (Part B)

1. Intraocular PCNSL with no brain lesion

2. Patients for whom the selected backbone regimen medications (i.e, methotrexate/temozolomide/rituximab for MTR and rituximab/methotrexate/procarbazine/vincristine for R-MPV) are contraindicated

3. Patients with a history of intolerable toxicity, hypersensitivity, anaphylaxis to the selected backbone regimen medications

4. Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents

5. Patient with non-B cell PCNSL

6. Patient with systemic presence of lymphoma

7. Prior chemotherapy within 21 days, nitrosourea within 42 days, an antibody drug with anticancer activity (e.g., rituximab) within 28 days, prior radiotherapy within 14 days, prior major invasive surgery within 28 days, or allogeneic stem cell transplant within 6 months before starting tirabrutinib treatment

8. Prior BTK inhibitor treatment

9. Prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, before starting tirabrutinib treatment

10. Concomitant systemic corticosteroid on an ongoing basis within 14 days before starting

tirabrutinib treatment, with the exception of the following:

• Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL
• Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone) for patients with lesions of the brain or spinal cord or both

11. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment

12. Concomitant warfarin, any other warfarin derivative anticoagulant, vitamin K antagonists, novel oral anticoagulants, or antiplatelet therapy on an ongoing basis within 7 days before starting tirabrutinib treatment

13. Active malignancy, other than PCNSL requiring systemic therapy

14. Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments

15. Patient with bleeding diathesis

16. Patients with a history of moderate or severe hepatic impairment

17. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval

18. Active infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has had, within 28 days before starting tirabrutinib treatment, an infection (other than nail trichophytosis) that requires hospitalization or an intravenous antibiotic

19. Prior history of hypersensitivity or anaphylaxis to tirabrutinib

20. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis

21. Medical history of organ allografts

22. Tests positive for HIV-1 antibody and HIV-2 antibody, human T-lymphotropic virus 1 antibody, HBs antigen, or HCV antibody. Tests positive for HBs antibody or hepatitis B virus core protein antibody and has a result of at least detectable in a hepatitis B virus deoxyribonucleic acid assay despite testing negative for HBs antigen.

23. Patient is unable to swallow tablets; has malabsorption, malabsorption syndrome, or a comorbidity that affects gastric function; has undergone complete resection of the stomach or small intestine; has ulcerative colitis or symptomatic inflammatory bowel disease; or has partial or complete intestinal obstruction.

24. Women who are pregnant or lactating

25. Patient is found incapable of giving consent due to dementia or another such condition

26. Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.

Related Conditions & MeSH terms

• Lymphoma
• Primary CNS Lymphoma

Intervention

Drug:
• Tirabrutinib
Part A: Tirabrutinib 480 mg, taken orally, once a day on an empty stomach. Tirabrutinib treatment may be continued until disease progression or clinically unacceptable toxicity is observed.
• Tirabrutinib
Part B, Arm 1 - Tirabrutinib 320 mg or 480 mg, taken orally, once a day on an empty stomach in combination with an MTR induction regimen. Tirabrutinib with MTR treatment will be continued for 4 induction cycles (28-day/cycle), or until disease progression or clinically unacceptable toxicity is observed. For patients not receiving consolidation treatment following induction, tirabrutinib 480 mg will be continued until disease progression, unacceptable toxicities are observed, or the Investigator decides to stop treatment.
• Tirabrutinib
Part B, Arm 2 - Tirabrutinib 320 mg or 480 mg, taken orally, once a day on an empty stomach in combination with an R-MPV induction regimen. Tirabrutinib with R-MPV treatment will be continued for 4 induction cycles (28-day/cycle), or until disease progression or clinically unacceptable toxicity is observed. For patients not receiving consolidation treatment following induction, tirabrutinib 480 mg will be continued until disease progression, unacceptable toxicities are observed, or the Investigator decides to stop treatment.

Locations

Country	Name	City	State
United States	University Of Michigan	Ann Arbor	Michigan
United States	Emory University - Winship Cancer Institute	Atlanta	Georgia
United States	Piedmont Healthcare	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	University of Alabama at Birmingham School of Medicine	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute - Brigham & Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center (RPCCC) (Roswell Park Cancer Institute (RPCI))	Buffalo	New York
United States	The University of Vermont - Fletcher Allen Health Care	Burlington	Vermont
United States	Levine Cancer Center	Charlotte	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	City of Hope Comprehensive Breast Cancer Center	Duarte	California
United States	Duke University School of Medicine	Durham	North Carolina
United States	Hackensack University Medical Center - John Theurer Cancer	Hackensack	New Jersey
United States	Penn State Hershey Cancer Center	Hershey	Pennsylvania
United States	Cedar Sinai Medical Cancer	Hollywood	California
United States	Houston Methodist Research Institute (HMRI)	Houston	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of California, Irvine	Irvine	California
United States	Mayo Clinic- Jacksonville	Jacksonville	Florida
United States	The University of Kansas Cancer Center (KUCC) (Kansas City Cancer Center (KCCC)) - North	Kansas City	Missouri
United States	University of Tennessee Cancer Institute	Knoxville	Tennessee
United States	University of Kentucky	Lexington	Kentucky
United States	Norton Cancer Institute - St. Matthews	Louisville	Kentucky
United States	University of Miami-Sylvester Cancer Center	Miami	Florida
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Columbia University Irving Medical Center	New York	New York
United States	Memorial Sloan Kettering	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Orlando Health	Orlando	Florida
United States	Stanford University	Palo Alto	California
United States	Moffitt Cancer Center- Miami	Pembroke Pines	Florida
United States	Abramson Cancer Center University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic- Phoenix	Phoenix	Arizona
United States	Hillman Cancer Center, University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Providence Health Cancer Center	Portland	Oregon
United States	Lifespan Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic- Rochester	Rochester	Minnesota
United States	The University of Utah - Huntsman Cancer Institute (HCI)	Salt Lake City	Utah
United States	Maine Medical Partners Neurology (Maine Neurology)	Scarborough	Maine
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Georgetown University, Lombardi Comprehensive Cancer Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Ono Pharmaceutical Co. Ltd

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate (ORR) (Part A)	Overall response rate is defined as the proportion of patients with a best overall response of Complete response (CR), Complete response - unconfirmed (CRu), or (=partial response (PR) as determined by an independent review committee according to the International PCNSL Collaborative Group (IPCG) criteria.	1 year
Primary	Tirabrutinib dose estimate (Part B)	Estimate of tirabrutinib dose in combination with each backbone induction regimen (MTR and R-MPV) based upon treatment related AEs, SAEs, and toxicities observed during the initial cycle of induction therapy in the dose-ranging phase	1 month
Primary	Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during induction (Part B)	Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.	4 months
Primary	Complete response rate (CRR) (Part B)	Complete response rate is defined as the proportion of patients with a best overall response of CR or CRu as determined by an independent review committee according to the IPCG criteria.	4 months
Secondary	Duration of response (DOR) (Part A and B)	Duration of response is defined as the time between the date of first response (CR, CRu, or PR) and the date of the first PD according to the IPCG criteria, or date of death due to any cause, whichever occurs first.	2 years
Secondary	Time to response (TTR) (Part A and B)	Time to response is defined as the time between the date of first administration of tirabrutinib and the date of first response (CR, CRu, or PR) as determined by IRC according to the IPCG criteria.	1 year
Secondary	Best overall response (BOR) (Part A and B)	Best overall response based on independent review committee (IRC) response determination is defined as the best response and is derived programmatically based upon the visit responses determined by IRC from the date of administration of tirabrutinib to the date of PD as determined by IRC or the date of initiation of subsequent anticancer therapy for PCNSL, whichever occurs first.	1 year
Secondary	Change in corticosteroid dose (Part A)	Descriptive statistics will be calculated for the actual corticosteroid dose and the change from baseline at each assessment point.	2 years
Secondary	Incidence and severity of AEs and SAEs (Part A and B)	Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.	2 years
Secondary	Laboratory abnormality profile of tirabrutinib as measured by incidence and severity of clinical laboratory abnormalities (Part A and B)	Results of laboratory tests	2 years
Secondary	ECG parameters by 12 lead ECG (Part A and B)	Heart rate, RR and QT intervals, QTc (QTcF, QTcB), PR interval, and QRS width.	2 years
Secondary	PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B)		29 days
Secondary	PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B)		29 days
Secondary	PK parameters (AUC) of tirabrutinib in the plasma (Part A and B)		29 days

External Links

•   Sponsor maintained study web address