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 website: https://www.theprospectstudy.com/
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) – Closed to enrollment
- 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) – Closed to enrollment
- 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) – Closed to enrollment
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) –Closed to enrollment– 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