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

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

Study Description
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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)

Condition or disease Intervention/treatment Phase
Refractory Primary Central Nervous System Lymphoma Primary CNS Lymphoma Drug: Tirabrutinib Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : December 29, 2021
Estimated Primary Completion Date : March 31, 2027
Estimated Study Completion Date : March 31, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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Arm Intervention/treatment
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.
 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
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)
 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
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)
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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

  3. 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.

  4. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B) [ Time Frame: 29 days ]
  9. PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B) [ Time Frame: 29 days ]
  10. PK parameters (AUC) of tirabrutinib in the plasma (Part A and B) [ Time Frame: 29 days ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04947319


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

Locations
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Sponsors and Collaborators
Ono Pharmaceutical Co. Ltd
Investigators
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Study Director: Project Leader Ono Pharma USA Inc
More Information
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Additional Information:

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Responsible Party: Ono Pharmaceutical Co. Ltd
ClinicalTrials.gov Identifier: NCT04947319    
Other Study ID Numbers: ONO-4059-09
First Posted: July 1, 2021    Key Record Dates
Last Update Posted: May 3, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ono Pharmaceutical Co. Ltd:
Bruton's Tyrosine Kinase Inhibitor, BTKi, tirabrutinib, ONO-4059, PROSPECT
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
 Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases