ONO-4059-02

24 evidence topics · 6 sources

Objective

Long-term follow-up assessments

“The secondary endpoints included investigator-assessed ORR, best overall response (BOR), duration of response (DOR), time to response, progression-free survival (PFS), and overall survival (OS).” (opens the source at this quote in a new tab)

Location and study date

Study sites and initiation

“This was an exploratory analysis of an ongoing multicenter, open-label, uncontrolled phase I/II study conducted across 10 sites in Japan from October 2017.” (opens the source at this quote in a new tab)

Enrollment period

“Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively.” (opens the source at this quote in a new tab)

Study design

Trial design

“open-label, uncontrolled phase I/II study” (opens the source at this quote in a new tab)

Eligibility criteria

Eligibility and exclusions

“Eligible patients were those with age ≥ 20 years; histologically diagnosed, previously treated relapsed/refractory PCNSL; a brain lesion with the major axis > 1.0 cm; a KPS score ≥ 70; and expected lifetime ≥ 3 months.” (opens the source at this quote in a new tab)
“Patients without B-cell type PCNSL and those with systemic lesions were excluded.” (opens the source at this quote in a new tab)

Treatment

Dose groups and treatment duration

“In the ONO-4059-02 open-label, single-arm, phase 1/2 study (Japanese Registry of Clinical Trials identifier, jRCT2080223590), patients with relapsed/refractory PCNSL were administered oral tirabrutinib q.d. at a dose of 320 or 480 mg, or 480 mg under fasted condition.” (opens the source at this quote in a new tab)
“The treatment was continued over 28-day cycles until disease progression or unacceptable toxicities were observed.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using IPCG overall response rate as the primary endpoint

Central response assessment

“The primary endpoint was the overall response rate (ORR) assessed by a central independent review committee, according to the International PCNSL Collaborative Group guidelines” (opens the source at this quote in a new tab)

Histological support from one trial participant

“An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib.” (opens the source at this quote in a new tab)

Validation as a surrogate for survival

No evidence found.

Statistical analysis description

Number of participants (Planned and analyzed)

Planned phase I and phase II enrollment

“The planned number of patients for enrollment was 3 or 6 for each cohort (320 or 480 mg) in the phase 1 part and 15 in the phase 2 part.” (opens the source at this quote in a new tab)

Actual enrollment

“Forty-four patients were enrolled” (opens the source at this quote in a new tab)

Description of analysis sets

Safety and efficacy analysis sets

“Safety was assessed in all patients who received ≥ 1 dose of study treatment.” (opens the source at this quote in a new tab)
“Within the safety set, those who had ≥ 1 measurable lesion before the start of treatment and had ≥ 1 centrally assessed BOR were assessed for the efficacy endpoints.” (opens the source at this quote in a new tab)
“Two-sided 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method.” (opens the source at this quote in a new tab)

Quality-of-life analysis population and statistical testing

“The analysis population consisted of 44 patients from the full analysis set.” (opens the source at this quote in a new tab)
“The mixed model for repeated measures was used to evaluate the systematic transition of scale change, in which time points (cycles) and participants were used as a repeated fixed factor and a random factor, respectively.” (opens the source at this quote in a new tab)
“The scale changes from baseline over time were evaluated with adjusted P-value using Dunnett’s multiple comparison method and the statistical significance level was set to be .05.” (opens the source at this quote in a new tab)

Results

Participant disposition

Treatment continuation and subsequent therapy

“The number of patients who continued treatment with tirabrutinib for 6 months, 1, 2, or 3 years was 20, 15, 8, and 6, respectively.” (opens the source at this quote in a new tab)
“A total of 42 patients (95.5%) terminated treatment (including those who completed study treatment) and 2 patients received ongoing treatment with marketed tirabrutinib.” (opens the source at this quote in a new tab)
“Of 42 patients who terminated tirabrutinib treatment, 32 (72.7%) started to receive subsequent treatment, including 28 (63.6%) who had disease progression under the treatment with tirabrutinib.” (opens the source at this quote in a new tab)

Baseline characteristics

Age, performance status, and prior treatment

“In the overall population, the median age was 60.0 years (range, 29–86) and the median for KPS scores was 80.0 (range, 70–100).” (opens the source at this quote in a new tab)
“The median number of previous lines of treatment was 2.0 (range, 1–14).” (opens the source at this quote in a new tab)

Efficacy results

Initial response assessment

“Independent review committee assessed overall response rate (ORR) at 64%” (opens the source at this quote in a new tab)

Three-year follow-up

“The median DOR was 9.2 (95% CI: 1.7–17.2) months in the overall population” (opens the source at this quote in a new tab)
“The 3-year OS rate was 56.7% in the overall population” (opens the source at this quote in a new tab)

Long-term progression-free survival

“The 3-year PFS rate was 13.9% in the overall population” (opens the source at this quote in a new tab)

Radiological response in the autopsy case

“The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

Performance status and quality-of-life findings

“Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.” (opens the source at this quote in a new tab)

Reported quality-of-life trajectory

“The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3–17 and remained relatively constant thereafter until cycle 23.” (opens the source at this quote in a new tab)

Safety results

Initial fatal adverse events

“One patient had grade 5 AEs (pneumocystis jirovecii pneumonia and ILD)” (opens the source at this quote in a new tab)

Long-term adverse-event incidence

“Any-grade AEs occurred in 38 patients (86.4%) and grade ≥ 3 AEs occurred in 23 patients (52.3%).” (opens the source at this quote in a new tab)
“The most frequent any-grade AEs were rash (36.4%), neutropenia (27.3%), leukopenia (25.0%), and lymphopenia (18.2%).” (opens the source at this quote in a new tab)

Study limitations

Summary

The study was uncontrolled and enrolled 44 participants with KPS scores of at least 70. Results therefore do not establish comparative efficacy or directly characterize participants with lower performance status. Subsequent therapy was reported for 32 participants, limiting attribution of long-term overall survival to tirabrutinib alone. Quality-of-life analyses were exploratory, were not planned when the protocol was fixed, and lacked follow-up after tirabrutinib discontinuation. The autopsy publication describes a participant from this trial, not an independent efficacy cohort.

Exploratory quality-of-life analysis and missing follow-up

“This was an exploratory analysis because the statistical analysis was not planned when the protocol was fixed.” (opens the source at this quote in a new tab)
“Follow-up data on KPS and QoL after tirabrutinib discontinuation were not obtained, preventing an examination of changes compared to the continuation group.” (opens the source at this quote in a new tab)