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

Study Overview
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Brief Summary
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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)

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

Conditions
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Refractory Primary Central Nervous System Lymphoma, Primary CNS Lymphoma

Intervention / Treatment
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* Drug: Tirabrutinib
* Drug: Tirabrutinib
* Drug: Tirabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Part A) Written informed consent by the patient prior to screening Patients aged ≥ 18 years on the day of consenting to the study Pathologic diagnosis of PCNSL Relapse or refractory PCNSL with at least one prior high dose methotrexate (HD-MTX) based therapy for PCNSL 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 Eastern Cooperative Oncology Group performance score (ECOG PS) of 0, 1 or 2 Life expectancy of at least 3 months Adequate bone marrow, renal, and hepatic function Inclusion Criteria (Part B) Written informed consent by the patient prior to screening Patients aged ≥ 18 years on the day of consenting to the study Pathologic diagnosis of PCNSL within the past 3 months No prior anti-tumor treatments for PCNSL Patients who, in the opinion of the Investigator, are suitable to receive treatment with a high dose methotrexate containing regimen Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced MRI performed within 14 days before starting study treatment ECOG PS of 0, 1 or 2 Life expectancy of at least 6 months Adequate bone marrow, renal, and hepatic function Exclusion Criteria (Part A) Intraocular PCNSL with no brain lesion Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents Patient with non-B cell PCNSL Patient with systemic presence of lymphoma 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 Prior BTK inhibitor treatment 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 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 Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment 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 Active malignancy, other than PCNSL requiring systemic therapy Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments Patient with bleeding diathesis Patients with a history of moderate or severe hepatic impairment QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval 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 Prior history of hypersensitivity or anaphylaxis to tirabrutinib Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis Medical history of organ allografts 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. 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. Women who are pregnant or lactating Patient is found incapable of giving consent due to dementia or another such condition Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator. Exclusion Criteria (Part B) Intraocular PCNSL with no brain lesion 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 Patients with a history of intolerable toxicity, hypersensitivity, anaphylaxis to the selected backbone regimen medications Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents Patient with non-B cell PCNSL Patient with systemic presence of lymphoma 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 Prior BTK inhibitor treatment 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 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 Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment 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 Active malignancy, other than PCNSL requiring systemic therapy Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments Patient with bleeding diathesis Patients with a history of moderate or severe hepatic impairment QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval 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 Prior history of hypersensitivity or anaphylaxis to tirabrutinib Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis Medical history of organ allografts 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. 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. Women who are pregnant or lactating Patient is found incapable of giving consent due to dementia or another such condition Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A)<br>Patients with relapsed or refractory PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib monotherapy. | Drug: Tirabrutinib<br>* 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.<br>* Other names: ONO-4059;|
| Experimental: Tirabrutinib + MTR in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 1)<br>Patients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + methotrexate/temozolomide/rituximab (MTR) | Drug: Tirabrutinib<br>* 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.<br>* Other names: ONO-4059;|
| Experimental: Tirabrutinib + R-MPV in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 2)<br>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<br>* 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.<br>* Other names: ONO-4059;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B) |  | 29 days | 
| PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B) |  | 29 days | 
| PK parameters (AUC) of tirabrutinib in the plasma (Part A and B) |  | 29 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton's Tyrosine Kinase Inhibitor, BTKi, tirabrutinib, ONO-4059, PROSPECT