Clinical trial NCT04947319: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Refractory Primary Central Nervous System Lymphoma
Primary CNS Lymphoma
Keywords: Bruton's Tyrosine Kinase Inhibitor, BTKi, tirabrutinib, ONO-4059, PROSPECT
Lead sponsor: Ono Pharmaceutical Co. Ltd
Sponsor class: INDUSTRY
First posted: 2021-07-01
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)


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.

Primary outcomes:
measure: Overall response rate (ORR) (Part A)
timeFrame: 1 year
measure: Tirabrutinib dose estimate (Part B)
timeFrame: 1 month
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during induction (Part B)
timeFrame: 4 months
measure: Complete response rate (CRR) (Part B)
timeFrame: 4 months
Secondary outcomes:
measure: Duration of response (DOR) (Part A and B)
timeFrame: 2 years
measure: Time to response (TTR) (Part A and B)
timeFrame: 1 year
measure: Best overall response (BOR) (Part A and B)
timeFrame: 1 year
measure: Change in corticosteroid dose (Part A)
timeFrame: 2 years
measure: Incidence and severity of AEs and SAEs (Part A and B)
timeFrame: 2 years
measure: Laboratory abnormality profile of tirabrutinib as measured by incidence and severity of clinical laboratory abnormalities (Part A and B)
timeFrame: 2 years
measure: ECG parameters by 12 lead ECG (Part A and B)
timeFrame: 2 years
measure: PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B)
timeFrame: 29 days
measure: PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B)
timeFrame: 29 days
measure: PK parameters (AUC) of tirabrutinib in the plasma (Part A and B)
timeFrame: 29 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic- Phoenix
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Breast Cancer Center
state: California
city: Hollywood
country: United States
facility: Cedar Sinai Medical Cancer
state: California
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Georgetown University, Lombardi Comprehensive Cancer Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic- Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami-Sylvester Cancer Center
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Pembroke Pines
country: United States
facility: Moffitt Cancer Center- Miami
state: Florida
city: Atlanta
country: United States
facility: Piedmont Healthcare
state: Georgia
city: Atlanta
country: United States
facility: Emory University - Winship Cancer Institute
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute - St. Matthews
state: Kentucky
city: Scarborough
country: United States
facility: Maine Medical Partners Neurology (Maine Neurology)
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute - Brigham & Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University Of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic- Rochester
state: Minnesota
city: Kansas City
country: United States
facility: The University of Kansas Cancer Center (KUCC) (Kansas City Cancer Center (KCCC)) - North
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center - John Theurer Cancer
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center (RPCCC) (Roswell Park Cancer Institute (RPCI))
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University School of Medicine
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence Health Cancer Center
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hillman Cancer Center, University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Lifespan Rhode Island Hospital
state: Rhode Island
city: Knoxville
country: United States
facility: University of Tennessee Cancer Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Research Institute (HMRI)
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: The University of Utah - Huntsman Cancer Institute (HCI)
state: Utah
city: Burlington
country: United States
facility: The University of Vermont - Fletcher Allen Health Care
state: Vermont
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Ono Pharmaceutical Co. Ltd
name: Project Leader
role: STUDY_DIRECTOR
References: