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

Sponsor
Ono Pharmaceutical Co. Ltd (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04947319
Collaborator
(none)
112
Enrollment
30
Locations
3
Arms
54
Anticipated Duration (Months)
3.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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/ temozolimide/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
Phase 2

Study Design

Study Type:
Interventional
Anticipated 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 :
Dec 29, 2021
Anticipated Primary Completion Date :
May 31, 2024
Anticipated Study Completion Date :
Jul 1, 2026

Arms and Interventions

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 Names:
  • 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 Names:
  • 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 Names:
  • ONO-4059

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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

    3. Incidence and severity of AEs and 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.

    4. 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 Outcome Measures

    1. Duration of response (DOR) (Part A and B) [2 years]

      EDuration 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) [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) [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.

    4. 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.

    5. 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.

    6. Laboratory abnormality profile of tirabrutinib as measured by incidence and severity of clinical laboratory abnormalities (Part A and B) [2 years]

    7. 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.

    8. PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B) [29 days]

    9. PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B) [29 days]

    10. PK parameters (AUC) of tirabrutinib in the plasma (Part A and B) [29 days]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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 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. 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

    1. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment

    2. 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

    3. Active malignancy, other than PCNSL requiring systemic therapy

    4. Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments

    5. Patient with bleeding diathesis

    6. Patients with a history of moderate or severe hepatic impairment

    7. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval

    8. 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

    9. Prior history of hypersensitivity or anaphylaxis to tirabrutinib

    10. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis

    11. Medical history of organ allografts

    12. 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.

    13. 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.

    14. Women who are pregnant or lactating

    15. Patient is found incapable of giving consent due to dementia or another such condition

    16. 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

    1. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment

    2. 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

    3. Active malignancy, other than PCNSL requiring systemic therapy

    4. Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments

    5. Patient with bleeding diathesis

    6. Patients with a history of moderate or severe hepatic impairment

    7. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval

    8. 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

    9. Prior history of hypersensitivity or anaphylaxis to tirabrutinib

    10. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis

    11. Medical history of organ allografts

    12. 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.

    13. 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.

    14. Women who are pregnant or lactating

    15. Patient is found incapable of giving consent due to dementia or another such condition

    16. Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 City of Hope Comprehensive Breast Cancer Center Duarte California United States 91010
    2 Cedar Sinai Medical Cancer Hollywood California United States 90046
    3 University of California, Irvine Irvine California United States 92868
    4 Stanford University Palo Alto California United States 94304
    5 University of Colorado Denver Aurora Colorado United States 80045
    6 Yale Cancer Center New Haven Connecticut United States 06510
    7 Georgetown University, Lombardi Comprehensive Cancer Center Washington District of Columbia United States 20037
    8 Piedmont Healthcare Atlanta Georgia United States 30318
    9 Emory University - Winship Cancer Institute Atlanta Georgia United States 30322
    10 Northwestern University Chicago Illinois United States 60611
    11 Norton Cancer Institute - St. Matthews Louisville Kentucky United States 40207
    12 Maine Medical Partners Neurology (Maine Neurology) Scarborough Maine United States 04074
    13 Massachusetts General Hospital Boston Massachusetts United States 02114
    14 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
    15 Dana-Farber Cancer Institute - Brigham & Women's Hospital Boston Massachusetts United States 02215
    16 University Of Michigan Ann Arbor Michigan United States 41809
    17 Henry Ford Hospital Detroit Michigan United States 48202
    18 The University of Kansas Cancer Center (KUCC) (Kansas City Cancer Center (KCCC)) - North Kansas City Missouri United States 64154
    19 Memorial Sloan Kettering Basking Ridge New Jersey United States 07920
    20 Hackensack University Medical Center - John Theurer Cancer Hackensack New Jersey United States 07601
    21 Levine Cancer Center Charlotte North Carolina United States 28204
    22 Cleveland Clinic Cleveland Ohio United States 44106
    23 Ohio State University Columbus Ohio United States 43210
    24 Providence Health Cancer Center Portland Oregon United States 97239
    25 Penn State Hershey Bone and Joint Institute Hershey Pennsylvania United States 17033
    26 Hillman Cancer Center, University of Pittsburgh Pittsburgh Pennsylvania United States 15213
    27 Lifespan Rhode Island Hospital Providence Rhode Island United States 02903
    28 University of Tennessee Cancer Institute Knoxville Tennessee United States 27920
    29 The University of Utah - Huntsman Cancer Institute (HCI) Salt Lake City Utah United States 84112
    30 The University of Vermont - Fletcher Allen Health Care Burlington Vermont United States 05401

    Sponsors and Collaborators

    • Ono Pharmaceutical Co. Ltd

    Investigators

    • Study Director: Arata Aoi, Ono Pharma USA Inc

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Ono Pharmaceutical Co. Ltd
    ClinicalTrials.gov Identifier:
    NCT04947319
    Other Study ID Numbers:
    • ONO-4059-09
    First Posted:
    Jul 1, 2021
    Last Update Posted:
    Jun 21, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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 (BTK) Inhibitor, tirabrutinib, ONO-4059, PROSPECT, relapsed, refractory, first line
    Additional relevant MeSH terms:
    Lymphoma

    Study Results

    No Results Posted as of Jun 21, 2022