Abstract
BackgroundFirst-line (1L) therapy for peripheral T-cell lymphoma (PTCL) is cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-based, and relapse/refractory (r/r) rates are high (75%) with limited therapeutic options thereafter; currently approved agents for r/r PTCL include belinostat and pralatrexate, with overall response rates (ORR) of <30% and progression free survival (PFS) between 2-4 months. The pivotal study JACKPOT8 part B, with the Janus kinase one (JAK1) selective inhibitor golidocitinib in r/r PTCL, demonstrated ORR of 44.3% with a median PFS and overall survival (OS) of 5.6 and 19.2 months, respectively. The most common ≥ grade 3 therapy-related adverse event (TRAE) was neutropenia (29%) which was clinically reversible, with discontinuation in only 9% (Song and Malpica et al, Lancet Oncology 2023). In the subgroup analysis of patients (pts) with T follicular helper (TFH) PTCL phenotype the ORR was 62% and median PFS was 9.5 months.
The current trial builds upon our prior experience with encouraging results of golidocitinib compared to other approved agents and the high failure rates after 1L CHOP-based therapy by designing a study evaluating the incorporation of golidocitinib into the frontline management of PTCL.
Study Design and MethodsWe are conducing a phase II, single-center, single-arm clinical trial evaluating the safety and efficacy of golidocitinib for pts with newly diagnosed PTCL (NCT06630091).
Eligibility criteria include pts who are 18y+ with newly diagnosed PTCL (enriched with 70% TFH subtype given golidocitinib's demonstrated activity in prior trials, and 30% PTCL, not otherwise specified subtype), Eastern Cooperative Oncology Group Performance Status 0-2, and measurable disease at baseline. Pts with prior lymphoma-directed therapy, anaplastic large cell lymphoma subtype, known CNS involvement with lymphoma and active viral infections are ineligible.
For induction, all pts will receive single agent golidocitinib at 150 milligrams (mg) orally once daily for six 21-day cycles. If there is progression of disease (PD), pts will receive subsequent standard of care therapy off study. Prior to cycle seven, all pts will be restaged with PET/CT and those achieving complete response (CR) will continue single agent golidocitinib at the previously described dose for six more cycles, while pts with partial response (PR) or stable disease (SD) will receive golidocitinib 150 mg every other day in combination with CHOP for six more cycles. Restaging PET/CT will be performed every three cycles with response criteria based on 2014 Lugano classification. Upon completion, maintenance will consist of golidocitinib 150 mg once daily (1) for up to one year in pts achieving post-induction CR, or (2) until PD, unacceptable toxicity/death, withdrawal of consent, or study termination in pts achieving PR/SD, with restaging PET/CT performed every four cycles. Survival follow up is planned for 2 years since the first dose.
The primary objective is to assess ORR after induction. The sample size is 30 pts, with a target ORR of 50%. The secondary objectives are CR rate (CRR) after induction and CRR/ORR after single agent induction lead-in, 2-year PFS, 2-year OS, duration of response and time to response rates, and safety and tolerability of golidocitinib as single agent or in combination with CHOP.
Toxicities will be graded according to the Common Terminology Criteria for Adverse Events version 5.0. Stopping boundaries are jointly based on response and serious TRAEs using Bayesian optimal phase 2 design, with study hold triggered by ≤ 7 responses for the first 15 enrolled pts and/or ≥ 1 serious TRAE for the first 10 and 20 enrolled pts.
Exploratory studies to determine biomarkers of response and mechanisms of resistance to JAK/STAT inhibition will include paired diagnosis and post-therapy tissue and blood samples assessed by immunohistochemistry, fluorescence in situ hybridization, cytokine panel, and an in-house 162-gene tumor-targeted sequencing panel, in addition to planned multi-omics with whole exome and bulk RNA sequencing.
This trial has been activated as of April 2025 and is currently enrolling. To our knowledge, this study is the first to explore a novel oral targeted agent for newly diagnosed pts with a subtype specific PTCL. The chemotherapy de-escalation and response-adapted design will potentially identify pts who may benefit from no chemotherapy or novel agent plus chemotherapy combination.
