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

• ClinicalTrials.gov Identifier: NCT04947319
• Recruitment Status: Recruiting
• First Posted: July 1, 2021
• Last Update Posted: May 3, 2024
• Sponsor: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Ono Pharmaceutical Co. Ltd

Tracking Information

• First Submitted Date: June 16, 2021
• First Posted Date: July 1, 2021
• Last Update Posted Date: May 3, 2024
• Actual Study Start Date: December 29, 2021
• Estimated Primary Completion Date: March 31, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 30, 2023)

• Overall response rate (ORR) (Part A) [ Time Frame: 1 year ]
  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.
• Tirabrutinib dose estimate (Part B) [ Time Frame: 1 month ]
  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
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during induction (Part B) [ Time Frame: 4 months ]
  Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.
• Complete response rate (CRR) (Part B) [ Time Frame: 4 months ]
  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.

Original Primary Outcome Measures (submitted: June 23, 2021)

Overall response rate (ORR) [ Time Frame: 1 year ]

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.

Current Secondary Outcome Measures (submitted: March 30, 2023)

• Duration of response (DOR) (Part A and B) [ Time Frame: 2 years ]
  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.
• Time to response (TTR) (Part A and B) [ Time Frame: 1 year ]
  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.
• Best overall response (BOR) (Part A and B) [ Time Frame: 1 year ]
  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.
• Change in corticosteroid dose (Part A) [ Time Frame: 2 years ]
  Descriptive statistics will be calculated for the actual corticosteroid dose and the change from baseline at each assessment point.
• Incidence and severity of AEs and SAEs (Part A and B) [ Time Frame: 2 years ]
  Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.
• Laboratory abnormality profile of tirabrutinib as measured by incidence and severity of clinical laboratory abnormalities (Part A and B) [ Time Frame: 2 years ]
  Results of laboratory tests
• ECG parameters by 12 lead ECG (Part A and B) [ Time Frame: 2 years ]
  Heart rate, RR and QT intervals, QTc (QTcF, QTcB), PR interval, and QRS width.
• PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B) [ Time Frame: 29 days ]
• PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B) [ Time Frame: 29 days ]
• PK parameters (AUC) of tirabrutinib in the plasma (Part A and B) [ Time Frame: 29 days ]

Original Secondary Outcome Measures (submitted: June 23, 2021)

• Duration of response (DOR) [ Time Frame: 2 year ]
  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.
• Time to response (TTR) [ Time Frame: 1 year ]
  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.
• Best overall response (BOR) [ Time Frame: 1 year ]
  Best overall response based on 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.
• Change in corticosteroid dose [ Time Frame: 2 year ]
  Descriptive statistics will be calculated for the actual corticosteroid dose and the change from baseline at each assessment point.
• Incidence and severity of AEs and SAEs [ Time Frame: 2 year ]
  Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.
• Laboratory abnormality profile of tirabrutinib as measured by incidence and severity of clinical laboratory abnormalitiesclinical laboratory abnormalities [ Time Frame: 2 year ]
• ECG parameters by 12 lead ECG [ Time Frame: 2 years ]
  Heart rate, RR and QT intervals, QTc (QTcF, QTcB), PR interval, and QRS width.
• PK parameters (Cmax) of tirabrutinib in the plasma [ Time Frame: 29 days ]
• PK parameters (Tmax) of tirabrutinib in the plasma [ Time Frame: 29 days ]
• PK parameters (AUC) of tirabrutinib in the plasma [ Time Frame: 29 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Tirabrutinib (ONO-4059) in Patients With Primary Central Nervous System Lymphoma (PROSPECT Study)
• 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)
• Brief 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)
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Refractory Primary Central Nervous System 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.
  Other Name: ONO-4059
• Drug: 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.

  Other Name: ONO-4059
• Drug: 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.

  Other Name: ONO-4059

Study Arms

• Experimental: Tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A)
  Patients with relapsed or refractory PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib monotherapy.
  Intervention: Drug: Tirabrutinib
• Experimental: Tirabrutinib + MTR in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 1)
  Patients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + methotrexate/temozolomide/rituximab (MTR)
  Intervention: Drug: Tirabrutinib
• Experimental: Tirabrutinib + R-MPV in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 2)
  Patients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + rituximab/methotrexate/procarbazine/vincristine (R-MPV)
  Intervention: Drug: Tirabrutinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 23, 2022): 112
• Original Estimated Enrollment (submitted: June 23, 2021): 44
• Estimated Study Completion Date: March 31, 2027
• Estimated Primary Completion Date: March 31, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Ono Pharma USA, Inc.; 6179044500; PROSPECTstudy@ono-pharma.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04947319
• Other Study ID Numbers: ONO-4059-09
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ono Pharmaceutical Co. Ltd
• Original Responsible Party: Same as current
• Current Study Sponsor: Ono Pharmaceutical Co. Ltd
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Project Leader; Ono Pharma USA Inc

• PRS Account: Ono Pharmaceutical Co. Ltd
• Verification Date: May 2024