Abstract
IMPORTANCE: Patients with relapsed or refractory (r/r) cutaneous T-cell lymphoma (CTCL) have limited treatment options. Combining agents that target complementary oncogenic pathways may enhance efficacy while maintaining tolerability. OBJECTIVE: To evaluate the safety and efficacy of linperlisib, a PI3Kδ inhibitor, combined with chidamide, a histone deacetylase inhibitor, in patients with r/r CTCL. DESIGN, SETTING, AND PARTICIPANTS: This prospective, single-arm, phase 1 nonrandomized clinical trial with a 3 + 3 dose-escalation phase followed by dose expansion was conducted at a tertiary referral hospital in China from May 1, 2023, to March 6, 2025, with a median follow-up of 8.9 months (range, 1-21 months). It included patients with histologically confirmed advanced CTCL. All had an Eastern Cooperative Oncology Group performance status of 0 to 2 and received a median (range) of 3 (1-7) prior systemic therapies. Patients were enrolled consecutively based on eligibility. INTERVENTIONS: Oral linperlisib administered once daily in escalating doses (40 mg, 60 mg, or 80 mg) plus chidamide, 20 mg, twice weekly. Treatment continued until progression, unacceptable toxic effects, or withdrawal. MAIN OUTCOMES AND MEASURES: Primary outcomes were dose-limiting toxic effects, maximum tolerated dose, and objective response rate. Secondary outcomes included safety, progression-free survival, and disease control rate. RESULTS: Of 22 patients (19 [86.4%] with mycosis fungoides, 3 [13.6%] with Sézary syndrome), 10 were female individuals (45.5%), and the median (range) age was 44 (27-71) years. No dose-limiting toxic effects were observed. The recommended phase 2 dose of linperlisib was 80 mg. The most common treatment-related adverse events were nausea (8 [36.4%]), pruritus (7 [31.8%]), and skin rash (6 [27.3%]), mostly grade 1 to 2. Grade 3 adverse events occurred in 5 patients (22.7%); no grade 4 to 5 events were reported. The objective response rate was 59.1% (13 of 22; 95% CI, 38.7%-76.7%), including 2 complete responses and 11 partial responses. The disease control rate was 86.4% (19 of 22), and the median progression-free survival was 5.4 months. CONCLUSIONS AND RELEVANCE: This nonrandomized clinical trial found that plus chidamide showed a manageable safety profile and promising activity in r/r CTCL. This all-oral combination may represent a new therapeutic option for advanced CTCL, particularly in mycosis fungoides. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06037239.