ReSTART (JCOG2314)

15 evidence topics · 2 sources

Objective

Non-inferiority and functional objectives

“We designed a multicenter, randomized phase II/III trial (JCOG2314) to assess the non-inferiority of tirabrutinib to WBRT in overall survival and its potential to reduce functional deterioration and cognitive impairment.” (opens the source at this quote in a new tab)

Location and study date

Trial activation

“activated in January 2026” (opens the source at this quote in a new tab)

Participating centers and accrual period

“A total of 94 patients from 49 institutions will be enrolled over 4 years.” (opens the source at this quote in a new tab)

Study design

Randomized treatment assignment

“Eligible patients with refractory primary central nervous system lymphoma (PCNSL) are randomly assigned to receive either whole-brain radiotherapy (WBRT) or tirabrutinib.” (opens the source at this quote in a new tab)

Trial setting

“This is a multicenter (49 specialized centers), open-label, randomized controlled phase II/III trial.” (opens the source at this quote in a new tab)

Eligibility criteria

Selected eligibility criteria

“Histologically proven DLBCL from surgical resection or biopsy of an intracranial lesion.” (opens the source at this quote in a new tab)
“Age: 18 years or older.” (opens the source at this quote in a new tab)
“Eastern Cooperative Oncology Group performance status of 0–2, or 3 due to tumor-related neurological symptoms.” (opens the source at this quote in a new tab)
“No prior RT for PCNSL.” (opens the source at this quote in a new tab)

Treatment

Tirabrutinib treatment

“Tirabrutinib is administered orally at a dose of 480 mg once daily under fasting conditions.” (opens the source at this quote in a new tab)
“The treatment will be continued until disease progression, unacceptable toxicity, or any other protocol-defined reason for discontinuation.” (opens the source at this quote in a new tab)

Radiotherapy treatment

“Patients in the RT arm will receive WBRT followed by a local boost to the residual parenchymal lesions after induction therapy.” (opens the source at this quote in a new tab)
“In total, 40 Gy in 20 fractions will be delivered over ~4 weeks, consisting of 30 Gy in 15 fractions for WBRT (2 Gy per fraction, once daily, 5 days/week), and a subsequent local boost of 10 Gy in 5 fractions (2 Gy per fraction).” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using overall survival as the phase III primary endpoint

Overall survival definition and analysis role

“In phase III, the primary endpoint is OS in all randomized patients analyzed on an intent-to-treat basis.” (opens the source at this quote in a new tab)
“OS is defined as the time from randomization to death from any cause and will be censored on the last day of contact for a surviving patient.” (opens the source at this quote in a new tab)

Phase II continuation endpoint

“In phase II, the primary endpoint is the proportion of patients in the tirabrutinib arm who continue tirabrutinib without disease progression at 4 weeks after treatment initiation.” (opens the source at this quote in a new tab)

Quality-of-life measurement

“QOL score will be measured using EORTC QLQ-C30 and EORTC QLQ-BN20.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Sample size, margin, and power

“To account for potential loss to follow-up, the planned sample size for phase III is set at 94 patients, including those enrolled in phase II.” (opens the source at this quote in a new tab)
“a non-inferiority margin of 5 months (corresponding to a hazard ratio of 1.50)” (opens the source at this quote in a new tab)
“a power of 70% with a one-sided alpha level of 10%” (opens the source at this quote in a new tab)

Description of analysis sets

Analysis populations and phase II stopping rule

“All treated patients, including those who discontinued tirabrutinib for reasons other than disease progression, are included in the analysis population.” (opens the source at this quote in a new tab)
“In phase III, the primary endpoint is OS in all randomized patients analyzed on an intent-to-treat basis.” (opens the source at this quote in a new tab)
“Advancement to phase III will proceed only if at least 50% (≥5 of these 10 patients) remain on tirabrutinib without disease progression at 4 weeks.” (opens the source at this quote in a new tab)

Interim analysis

“We plan to conduct one interim analysis, considering multiplicity, using the Lan-DeMets method with the O’Brien and Fleming-type alpha spending function” (opens the source at this quote in a new tab)

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

No evidence found.

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

No evidence found.

Study limitations

Summary

The protocol describes an open-label comparison in induction-refractory PCNSL, not a completed efficacy analysis. The phase III plan includes 94 participants, a non-inferiority hazard-ratio margin of 1.50, 70% power, and a one-sided alpha of 10%. These design choices require consideration when interpreting any future non-inferiority finding. Overall survival and functional or cognitive outcomes must be distinguished from the phase II four-week treatment-continuation criterion.