FDA Grants ODD to Tirabrutinib for Primary Central Nervous System Lymphoma

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Tirabrutinib has received orphan drug status from the FDA and is being studied in the phase 2 PROSPECT study for patients with primary central nervous system lymphoma.

The FDA has granted tirabrutinib (ONO-4059), a Bruton's tyrosine kinase (BTK) inhibitor, an orphan drug designation for the treatment of patients with primary central nervous system lymphoma (PCNSL), according to Ono Pharma USA.1

"We are extremely pleased that tirabrutinib has been granted orphan drug status for the treatment of PCNSL," said Kunihiko Ito, president and chief executive officer of Ono Pharma USA, in the press release. "The designation represents a milestone for ONO. Currently, ONO is carrying out a phase 2 trial of tirabrutinib in people with newly diagnosed or relapsed/refractory PCNSL, and we look forward to advancing clinical trials so that patients may have therapeutic options as soon as possible."

PCNSL is a rare and aggressive extra nodal non-Hodgkin lymphoma (NHL) limited to the brain parenchyma, spinal cord, eye, or leptomeninges, without systemic involvement. Currently, there are no approved therapies in the United States for the treatment of patients with PCNSL, as data is limited in this space. While there has been recent progress leading to the improvement of clinical outcomes for newly diagnosed patients with PCNSL after an induction treatment, about 20%-30% of patients are refractory to the initial treatment. Additionally, up to 60% of patients with PCNSL will eventually relapse.

Tirabrutinib is a highly potent selective BTK inhibitor which signals through the B-cell receptor (BCR) to regulate cellular proliferation and activation. This ultimately can promote survival, differentiation, and clonal expansion of B-cells.

In some B-cell malignancies, the BCR signaling pathway plays an important role. According to gene expression profiling data, the BCR signaling pathway is the most prominent pathway activated in chronic lymphocytic leukemia cells isolated from lymphatic tissues.

In March 2020, tirabrutinib was approved in Japan for the treatment of relapsed/refractory PCNSL. Following this approval, tirabrutinib was approved for this patient population in South Korea in November 2021 and in Taiwan in February 2022. Also in August 2020, the agent was approved for the treatment of patients with Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma in Japan.

Now, the open-label, phase 2 PROSPECT study (NCT04947319) is evaluating the safety and efficacy of tirabrutinib for patients with newly diagnosed or relapsed/refractory PCNSL.2

In part A, patients with relapsed or refractory PCNSL will receive oral tirabrutinib 480 mg which is taken once a day on an empty stomach. Tirabrutinib treatment may be continued until disease progression or clinically unacceptable toxicity is observed.

Then in part B, the first arm (arm 1) will receive tirabrutinib 320 mg or 480 mg, taken orally, 1 time a day on an empty stomach in combination with methotrexate/temozolomide/rituximab (Rituxan). In the second arm (arm 2), oral tirabrutinib 320 mg or 480 mg will be administered to patients once a day on an empty stomach in combination with a rituximab/methotrexate/procarbazine/vincristine induction regimen.

In both arm 1 and arm 2, regimens of tirabrutinib with methotrexate/temozolomide/rituximab or tirabrutinib with rituximab/methotrexate/procarbazine/vincristinewill continue for 4 induction cycles (28-day/cycle), or until disease progression or clinically unacceptable toxicity is observed.

Patients enrolled in part A of the trial are those aged 18 years and older with a pathologic diagnosis of PCNSL, measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced MRI performed within 14 days before starting tirabrutinib treatment, and ECOG performance status of 0-2, and a life expectancy of at least 3 months, and adequate bone marrow, renal, and hepatic function.

Inclusion in part B is open to patients with patients aged ≥ 18 years on the day of consenting to the study a pathologic diagnosis of PCNSL within the past 3 months who have had no prior anti-tumor treatments for PCNSL. Patients must be suitable to receive treatment with a high dose methotrexate containing regimen, have a measurable brain lesion, an ECOG performance status of 0-2, a life expectancy of at least 6 months, and adequate bone marrow, renal, and hepatic function.

The primary end points of the study include overall response rate in part A, tirabrutinib dose estimate and complete response rate in part B, and the incidence of adverse events (AEs) in both parts. The secondary end point for part A only is change in corticosteroid dose while the secondary end points for both parts include duration of response, time to response, best overall response, incidence of AEs, and pharmacokinetics.

The PROSPECT study is actively recruiting patients in California, Georgia, Kentucky, Maine, Massachusetts, Michigan, New Jersey, Ohio, Tennessee, and Utah, with more locations to follow. The estimated study completion date is July 1, 2026.

REFERENCES
Ono Pharma USA's tirabrutinib receives orphan drug designation from the FDA for the treatment of primary central nervous system lymphoma. News release. Ono Pharma, USA. March 23, 2023. Accessed March 23, 2023. https://prn.to/40bAWcd
Study of tirabrutinib (ONO-4059) in patients with primary central nervous system lymphoma (PROSPECT Study). ClinicalTrials.gov. June 21, 2022. Accessed March 23, 2023.
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