A Multicenter, Open-Label, Phase 3, Randomized Controlled Trial of Duvelisib Versus Investigator’s Choice of Gemcitabine or Bendamustine in Patients with Relapsed/Refractory Nodal T Cell Lymphoma with T Follicular Helper Phenotype

Background and Significance:

Peripheral T cell lymphomas (PTCL) are a rare, heterogeneous group of aggressive lymphomas that represent 10-15% of all non-Hodgkin lymphomas. Patients with newly diagnosed PTCL are commonly treated with anthracycline-based combination chemotherapy; however, the majority will develop relapsed/refractory (R/R) disease. Currently, no agent is approved in the EU or UK for treatment of patients with R/R PTCL, except brentuximab vedotin (BV) for anaplastic large-cell lymphoma (ALCL). Approvals of single agents for PTCL (except for BV) in the US were based on single arm studies.

Primary nodal subtypes of PTCL comprise a majority of PTCL in North America and Europe and include PTCL-not otherwise specified (NOS) (34%), angioimmunoblastic T cell lymphoma (AITL) (16-29%), and ALCL (16-24%). The AITL cell of origin, a T follicular helper (TFH) cell, has a set of recurrent gene mutations frequently found in cases of AITL and PTCL-NOS. Due to similarities in clinical, immunophenotypic and genetic characteristics, the 5^th edition of the WHO classification of lymphoid neoplasms groups AITL, PTCL-NOS with TFH phenotype, and follicular T cell lymphoma under the category nodal T follicular helper cell lymphoma (nTFHL).

Duvelisib (DUV), an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms, is approved in the US, EU, and UK for treatment of adult patients with R/R CLL (and for SLL in the US) after ≥2 prior systemic therapies (and for refractory follicular lymphoma after ≥2 prior systemic therapies in the EU and UK). In January 2023, the European Commission issued an orphan drug designation to DUV for treatment of adult patients with PTCL.

In the PRIMO study (NCT03372057), outcomes with DUV in patients with R/R PTCL were objective response rate (ORR) 48.0%, median progression-free survival (mPFS) 3.45 mo, and median overall survival (mOS) 12.35 mo. In patients with AITL, outcomes were ORR 62.2%, mPFS 8.34 mo, and mOS 18.07 mo.

The TERZO™ study (NCT06522737; EU CT: 2024-516605-23-00) will evaluate efficacy and safety of DUV versus investigator’s choice of gemcitabine (GEM) or bendamustine (BEN), two standard of care regimens commonly used in clinical practice in patients with R/R nTFHL.

Study Design and Methods:

TERZO is a multicenter, open-label, phase 3, randomized study expected to enroll 124 patients (at nearly 45 EU/UK sites) with R/R nTFHL who have progressed on ≥1 line of systemic anticancer therapy. Study duration will be 48 months; patients will be randomized 1:1 and stratified by number of prior therapies and AITL score.

Arm 1: DUV 75 mg orally twice daily (BID) for cycles 1 and 2, and DUV 25 mg BID for cycles 3+, in 28-day cycles. Arm 2: either GEM 1200 mg/m² IV on Day (D)1, 8, and 15 of each 28-day cycle (up to 6 cycles) or BEN 90-120 mg/m² IV on D1 and 2 of each 21-day cycle (up to 6 cycles).

Primary endpoint: Independent Review Committee-assessed PFS; key secondary endpoint: OS; additional secondary endpoints: investigator (INV)-assessed PFS, ORR, complete response rate, duration of response, safety, quality-of-life, percent of patients proceeding to stem cell transplant (SCT), and INV-assessed PFS in patients proceeding to SCT; exploratory endpoints: AITL vs non-AITL outcomes, whole exome sequencing, circulating DNA, and AITL score.

Eligibility criteria include adults with R/R nTFHL, ≥1 prior line of systemic therapy, measurable disease, ECOG performance status ≤2, and no prior history of allogeneic SCT or PI3K inhibitor use.

DUV monotherapy has demonstrated activity in R/R PTCL, with more pronounced effect in AITL. TERZO will test the hypothesis that DUV monotherapy is associated with improved outcomes compared with GEM or BEN in patients with R/R nTFHL.