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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04947319
Other study ID # ONO-4059-09
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
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
Health authority
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.

Study Design


Related Conditions & MeSH terms


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
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