Dataset Information

Phase 1/2 Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Relapsed/Refractory Primary Central Nervous System Lymphoma.

ABSTRACT:

Background

The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine kinase inhibitor were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).

Methods

Patients with relapsed/refractory PCNSL, Karnofsky performance status ?70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (QD) in phase 1 to evaluate dose-limiting toxicity (DLT) within 28 days using a 3+3 dose escalation design and with 480 mg QD under fasted conditions in phase 2.

Results

Forty-four patients were enrolled; 20, seven and 17 received tirabrutinib at 320, 480 and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ?3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee-assessed overall response rate (ORR) was 64%: 60% with five complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with four CR/CRu at 480 mg, and 53% with six CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1 and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild-types.

Conclusion

These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.

SUBMITTER: Narita Y

PROVIDER: S-EPMC7850159 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Phase I/II study of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma.

Narita Yoshitaka Y Nagane Motoo M Mishima Kazuhiko K Terui Yasuhito Y Arakawa Yoshiki Y Yonezawa Hajime H Asai Katsunori K Fukuhara Noriko N Sugiyama Kazuhiko K Shinojima Naoki N Kitagawa Junsaku J Aoi Arata A Nishikawa Ryo R

Neuro-oncology 20210101 1

<h4>Background</h4>The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).<h4>Methods</h4>Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 day ...[more]

PMID: 32583848

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Project description:BACKGROUND: Lenalidomide is an immunomodulator agent that exhibits efficacy in multiple myeloma and haematological malignancies including refractory/relapsed diffuse large B-cell (DLBC) systemic lymphoma. METHODS: Retrospective review of PCNSL patients treated with lenalidomide at the Pitié-Salpêtrière hospital. Inclusion criteria were: 1) immunocompetent status 2) pathologically proven diagnosis of DLBC-PCNSL, 3) recurrent or refractory disease after at least two prior chemotherapy treatments, including intravenous high-dose methotrexate and cytarabine based regimens, 4) lenalidomide administered orally, at a dose of 25 mg/day on days 1-21 of a 28-days cycle. MRI scans were performed monthly. Response was evaluated according to the IPCG criteria. RESULTS: Between June 2011 and March 2013, 6 patients (4 women and 2 men) met the inclusion criteria. Lenalidomide was given as 3rd line in four patients, as 4th line in one and 5th line in one. Median age was 73.5 years (range 64-78) and median Karnofsky Performance Status was 60 (range 40-70). Two patients achieved complete response (CR). Patient 1 received a total of 9 monthly cycles of lenalidomide without any steroids and is still in remission after a follow-up of 18 months from the start of the treatment. Patient 2 achieved a CR and was off-steroids at the time of CR, but relapsed during the 3rd cycle and died after 14 weeks. Patient 3 achieved a partial response after one cycle but died suddenly during the 2nd cycle. Patients 4, 5 and 6 progressed and died 2, 5 and 6 months respectively after the start of lenalidomide. One of them who suffered from an oculo-cerebral relapse demonstrated a partial ocular response while progressing in the brain. Apart from the sudden death of unknown cause, the treatment was well tolerated. None of the patients experienced any grade III or IV toxicity. CONCLUSIONS: These results suggest that lenalidomide exhibits activity in heavily pre-treated PCNSL and is well tolerated in elderly patients. Lenalidomide efficacy on PCNSL needs to be evaluated prospectively, alone or in association with other cytotoxic agents. A phase II trial combining rituximab and lenalidomide for recurrent PCNSL is on-going in France (NCT01956695).