Refractory Primary Central Nervous System Lymphoma, Primary CNS Lymphoma
Conditions
Keywords
Bruton's Tyrosine Kinase Inhibitor, BTKi, tirabrutinib, ONO-4059, PROSPECT
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)
Interventions
DRUGTirabrutinib
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.
Sponsors
Ono Pharmaceutical Co. Ltd
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) (Part A) | 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) | 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) | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| Duration of response (DOR) (Part A and B) | 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) | 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) | 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) | 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) | 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) | 2 years | Results of laboratory tests |
| ECG parameters by 12 lead ECG (Part A and B) | 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) | 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 | — |
Countries
United States
Contacts
STUDY_DIRECTORProject Leader
Ono Pharmaceutical Co. Ltd
Outcome results
None listed