Featured Clinical Study

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

Study Sponsor:  ONO Pharma USA, Inc.

Study Number:  ONO-4059-09

Tumor Type: Primary Central Nervous System Lymphoma

Age Group:  Adults

Gender:  Female & Male

Study Phase:  Phase 2

ABTA Published Date:  01/20/2023  

GENERAL OVERVIEW

Study Overview

This study will evaluate tirabrutinib treatment in patients with Primary Central Nervous System Lymphoma (PCNSL). 

Tirabrutinib will be taken orally, either as a single therapy (relapsed/refractory) or in combination (newly diagnosed) with a standard chemotherapy regimen, until disease progression, unacceptable adverse reactions are observed, or you or your doctor decide to stop treatment.

Study Objective

This study will evaluate tirabrutinib treatment in patients with Primary Central Nervous System Lymphoma (PCNSL). 

If you have PCNSL that has not responded to or returned after prior treatment, you will be in Part A of the study. This part of the study will look at the safety and effectiveness of tirabrutinib when given without any additional chemotherapy. 

If you have been newly diagnosed with PCNSL and have not yet received any treatment, you will be in Part B of the study. This part of the study will look at the safety and effectiveness of tirabrutinib when given together with standard of care chemotherapy regimens used to treat newly diagnosed patients.

Possible Risks & Side Effects

Parts A and B:

Tirabrutinib potential side effects:

  • Low blood cell counts including: Neutropenia (low number of white blood cells, which can make it easier to become sick); anemia (low number of red blood cells, which can make you feel tired); and thrombocytopenia (low number of platelets, which can make it harder for your blood to clot\easier to bleed)
  • Allergic reaction (hypersensitivity) which may include skin rash
  • Infections including: pneumonia (caused by bacterial or fungal infection, in the lungs); urinary tract infections; viral infection (shingles); and Sepsis (body’s extreme response to blood infection). Some people died as a result infections.
  • Disorders of the skin: Rash, Petechiae (tiny red spots on skin), purpura (skin eruptions with larger red spots), erythema multiforme (a severe skin rash)
  • Blood in the urine (hematuria)
  • Bleeding events including minor hemorrhagic events (bruising) and major hemorrhagic events (bleeding within the gut and brain)
  • Liver function abnormalities (which can indicate damage to the liver)
  • Interstitial lung disease: an inflammatory disease of the lung which can make it difficult to breathe effectively. Deaths have been reported with interstitial lung disease.
  • Heart failure
  • Stevens-Johnson Syndrome/toxic epidermal necrosis (a severe skin reaction most commonly caused by some medications or infections). Some people die as a result of this condition, but it is treatable if caught early.

Study procedures and assessments potential risks:

  • The potential risks of the study procedures and assessments will be provided by your doctor
 

Part B Only:

  • The potential side-effects of the standard of care treatment regimens will be provided by your doctor

ELIGIBILITY

Inclusion Criteria (Part A)

  • Written informed consent
  • Aged ≥ 18 years
  • Pathologic diagnosis of PCNSL
  • Relapse or refractory PCNSL with at least one prior high dose methotrextrate 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
  • At least able to walk and capable of all selfcare, up and about more than 50% of waking hours
  • Life expectancy of at least 3 months
  • Adequate bone marrow, kidney, and liver function

Inclusion Criteria (Part B)

  • Written informed consent
  • Aged ≥ 18 years
  • 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
  • At least able to walk and capable of all selfcare, up and about more than 50% of waking hours
  • Life expectancy of at least 6 months
  • Adequate bone marrow, kidney, and liver function

Exclusion Criteria (Part A)

  • Intraocular (within the eye) 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
  • Taking a 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
  • Taking 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 disorder
  • Patients with a history of moderate or severe liver impairment
  • QTcF (heart rate measurement) > 480 milliseconds or requirement for ongoing treatment with 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 tissue graft
  • 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.

Exclusion Criteria (Part B)

  • Intraocular (within the eye) 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, or 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
  • Taking 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
  • Taking 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 disorder
  • Patients with a history of moderate or severe liver impairment
  • QTcF (heart rate measurement) > 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 tissue grafts
  • 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 stomach 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

STUDY DETAILS

Patient Participation Requirements

Part A (R/R PCNSL):

Signed informed consent; in-clinic visits (more frequently at the beginning of the study/treatment, followed by visits every 28 days beginning at cycle 2); confirmed eligibility based on; confirmed diagnosis, medical history, height/weight/disposition, eye exam, vital signs, electrocardiogram (ECG), laboratory tests (blood, urine, cerebrospinal fluid (CSF), bone marrow exam, and saliva/nail clippings), neuro-psychological assessments, and medical imaging (fluorodeoxyglucose (FDG)-positron emission tomography (PET), computerized tomography (CT), x-ray, MRI, 2D-echocardiography).

Part B (newly diagnosed PCNSL):

Similar to Part A, except in-clinic visits are more frequent for the first 4 cycles (induction), followed by visits every 28 days beginning at cycle 5.

Study Compensation

Reasonable and customary expenses (e.g. transportation, meals, parking) may be reimbursed or a patient stipend may be provided according to each hospital’s policy. Overnight stays may be reimbursed on a case-by-case basis.

Study Data

Tirabrutinib is an oral drug that is expected to effectively treat PCNSL in some patients.

In March 2020, tirabrutinib (80 mg tablets) was approved in Japan for the treatment of relapsed or refractory (R/R) PCNSL. I

In a study (ONO-4059-02) similar to this one, 63.6% of study patients with R/R PCNSL who were treated with tirabrutinib experienced a beneficial response. Relapsed or refractory means a lack of response or disease progression on last prior therapy.

Mechanism of Action

The study will be conducted in 2 parts. Part A will investigate tirabrutinib as a single treatment for relapsed or refractory (R/R) PCNSL and Part B is an exploratory part to investigate tirabrutinib in combination with one of two commonly used high-dose methotrexate (HD-MTX) regimens as the first treatment in newly diagnosed PCNSL patients.

Tirabrutinib is an oral drug that is expected to effectively treat PCNSL in some patients. Tirabrutinib acts by blocking an enzyme called Bruton’s tyrosine kinase (BTK). Some cancer cells use BTK to grow and thrive in your body. Tirabrutinib blocks BTK and interferes with the growth of cancer cells. Tirabrutinib is a highly potent, second-generation, selective BTK inhibitor.

Part A (R/R PCNSL) – In March 2020, tirabrutinib monotherapy (used alone) was granted marketing authorization in Japan for the treatment of relapsed or refractory (R/R) PCNSL because, in a study (ONO-4059-02) similar to this US study, 63.6% of study patients with R/R PCNSL who were treated with tirabrutinib monotherapy experienced a beneficial response.

Tirabrutinib, at an assigned dose, will be taken orally, once a day on an empty stomach. Tirabrutinib treatment may be continued until disease progression or clinically unacceptable toxicity is observed by your study doctor.

Part B (newly diagnosed PCNSL) – In the US, high-dose methotrexate based regimens are the mainstay of treatment in patients with newly diagnosed PCNSL. These regimens include methotrexate/temozolomide/rituximab and rituximab/methotrexate/procarbazine/vincristine. Recently, another BTK inhibitor in combination with high-dose methotrexate based regimens has shown clinical efficacy in newly diagnosed PCNSL patients.

Tirabrutinib, at an assigned dose, will be taken orally, once a day on an empty stomach in combination with a standard chemotherapy induction regimen containing methotrexate, which may contain rituximab, temozolomide, vincristine, and procarbazine as chosen by your study doctor. Tirabrutinib with chemotherapy treatment will be continued for 4 induction cycles (28-days/cycle), or until disease progression or clinically unacceptable toxicity is observed. Following induction, if your study doctor decides not to continue with treatment, you may continue to receive tirabrutinib, at an assigned dose, until disease progression, unacceptable adverse reactions are observed, or your doctor decides to stop treatment.

Grommes C, Tang SS, Wolfe J, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019;133(5):436-45.

STUDY LOCATIONS & CONTACTS

California

City of Hope Comprehensive Breast Cancer Center

1500 East Duarte Road

Duarte, CA 91010

 

Melissa Banez

626-218-8276

mbanez@coh.org

University of California, Irvine

101 The City Drive

South Irvine, CA 92868

Manisha Dandekar

714-456-6221

mdandeka@hs.uci.edu

Stanford University

801 Welch Road

Palo Alto, CA 94304

Kelly Tanner

650-724-5361

ketanner@stanford.edu

Cedar Sinai Medical Cancer

8700 Beverly Blvd AC1076

West Hollywood, CA 90046

Kortnee Calkins

310-423-1160

Kortnee.Calkins@cshs.org

Colorado

University of Colorado Denver

12631 East 17Th Avenue Mail Stop 8205

Aurora, CO 80045

Julie Compton

720-848-8312

Julie.Compton@cuanschutz.edu

District of Columbia

Georgetown University

Lombardi Comprehensive Cancer Center

3800 Reservoir Rd NW

Washington, DC 20037

Elizabeth Pendergrass

202-784-0038

eaw109@georgetown.edu

Georgia

Piedmont Healthcare

95 Collier Road, Suite 3025

Atlanta, GA 30318

Ali Arabnia

404-425-7943

Ali.Arabnia@piedmont.org

Maine

Maine Medical Partners Neurology

(Maine Neurology)

100 Campus Drive, Suite 103

Scarborough, ME 04074

Kimberly Caron

207-396-7559

kacaron@mmc.org

Massachusetts

Beth Israel Deaconess Medical Center

330 Brookline Ave.

Boston, MA 02215

Vivian Potter

617-975-7454

Vpotter@bidmc.harvard.edu

Dana-Farber Cancer Institute

Brigham & Women’s Hospital

450 Brookline Ave.

Boston, MA 02215

Alyssa Russ

617-732-7432

Alyssa_Russ@dfci.harvard.edu

Massachusetts General Hospital

10 Emerson Pl Ste 112

Boston, MA 02114

Patrick Mostyn

617-582-7303

PMOSTYN@mgh.harvard.edu

Michigan

University of Michigan

Rogel Cancer Center Building

1500 E Medical Center Dr

Ann Arbor, MI 41809

Nancy McCullough

734-936-8538

ntsai@med.umich.edu

New York

Hackensack University Medical Center

John Theurer Cancer Center

92 2nd St

Hackensack, NJ 07601

Danielle Blair

551-996-5809

dblair@hmhn.org

Memorial Sloan Kettering

Department of Neurology

160 East 53rd Street, Office 232

New York, NY 10022

Venissala Wongchai

203-824-2686

wongchv@mskcc.org

Ohio

Cleveland Clinic

10201 Carnegie Avenue

CA-LL-016

Cleveland, OH 44106

Marci Ciolfi

216-445-3407

ciolfim@ccf.org

Oregon

Providence Health Cancer Center

9205 SW Barnes Rd

Portland, OR 97239

Amy Huddleston

313-576-8727

huddlesa@ohsu.edu

Pennsylvania

Penn State Hershey Bone and Joint Institute

30 Hope Dr., Suite B

Hershey, PA 17033

Scott Stanley

717-531-0003 ext. 285799

sstanley2@pennstatehealth.psu.edu

Rhode Island

Lifespan Rhode Island Hospital

593 Eddy Street

Providence, RI 02903

Stephen Donnelly

401-444-3234

SDonnelly1@lifespan.org

Tennessee

University of Tennessee Cancer Institute

1924 Alcoa Hwy, Suite F344

Knoxville, TN 27920

Kristine Bollig

865-305-7469

klbollig@utmck.edu

Utah

The University of Utah

Huntsman Cancer Institute

2000 Circle Of Hope Drive

Salt Lake City, UT 84112

Allison Cohen

801- 587-9499

allison.cohen@hci.utah.edu

Vermont

The University of Vermont

Fletcher Allen Health Care

89 Beaumont Avenue

Burlington, VT 05401

Hannah Hatch

802-656-2967

Hannah.Hatch@uvmhealth.org