Trial in Progress: A Phase 3, Randomized, Open-Label Study Comparing the Efficacy and Safety of the Combination of Beleodaq-CHOP or Folotyn-Cop to the CHOP Regimen Alone in Newly Diagnosed Patients with Peripheral T- Cell Lymphoma - Crescendo

Background: Pralatrexate (Fol) and belinostat (Bel) have each demonstrated monotherapy activity in one or more subtypes of peripheral T-cell lymphoma (PTCL) and are approved for treatment of relapsed or refractory PTCL. CHOP remains a standard of care in the frontline setting for PTCL. Here, we describe the Phase 3 CRESCENDO trial, designed to determine if adding either Fol or Bel to first-line chemotherapy improves outcomes in newly diagnosed PTCL.

Study Design/Methods: CRESCENDO is a 2-part, Phase 3, randomized, open-label trial to determine optimal dose of Fol and Bel within the treatment regimen (Part 1, dose optimization), then evaluate efficacy and safety of these agents at optimal doses in combination with C(H)OP compared with CHOP alone (Part 2), Clinicaltrials.gov NCT06072131. We anticipate enrolling 504 patients who meet the inclusion criteria: 18yrs with newly diagnosed, previously untreated PTCL (including PTCL-NOS, angioimmunoblastic T-cell lymphoma, ALK- negative ALCL [for which brentuximab vedoitin (Bv) cannot be used due to unavailability or tolerance], follicular T cell lymphoma and others [extra-nodal natural killer/T-cell lymphoma, nasal type; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; and subcutaneous panniculitis-like T-cell lymphoma]) based on local pathology review, with measurable disease, ECOG performance status ≤2, and eligible to receive Bel or Fol, and a standard CHOP regimen (cyclophosphamide 750 mg/m² IV, Day 1; doxorubicin 50 mg/m² IV, Day 1; vincristine 1.4 mg/m² (maximum 2 mg) IV, Day 1; and prednisone 100 mg daily PO, Days 1-5). Cutaneous T cell lymphomas or ALCLs eligible for Bv are excluded.

The primary objective of Part 1 is to identify one of two dose-levels, each for Bel and Fol that is optimal in polychemotherapy for Part 2, based on safety and ORR at 3 months. In Part 1, Bel and Fol will be separately added to C(H)OP regimens (standard CHOP or COP [CHOP without doxorubicin, to minimize risk of mucositis and cytopenia]). Following a 28-day screening period, patients will be randomized to 5 groups, 20 patients each: Groups 1a/1b receive Bel 600 or 1000 mg/m² by IV infusion over 30 min on Days 1-5 of each of 6 cycles in combination with CHOP (Bel-CHOP); Groups 2a/2b receive Fol 20 or 30 mg/m² by IV push over 3-5 min on Days 1 and 8 of each of 6 cycles in combination with COP (Fol-COP); and Group 3 receives CHOP alone. Each group will receive 6 cycles of therapy, with cycles lasting 21 days. Recommended doses for Part 2 will be determined by an Independent Data Monitoring Committee (IDMC) based on tolerability, efficacy and compliance when 75 patients in Part 1 have completed planned treatment. The IDMC will also convene for an interim analysis and determination of study continuation after 120 PFS events.

The primary objective for Part 2 is to compare the progression-free survival (PFS), defined as months from randomization to first documented progressive disease (PD) or death, whichever occurs first, of patients with newly diagnosed PTCL treated for up to 6 cycles with each of the 3 regimens. PFS will be determined using Investigator assessments and a one-sided log-rank test will be used. The totality of scans will be centrally reviewed by a Blinded Independent Review Committee. Secondary objectives include comparison of overall survival (OS) and objective response rate (ORR) by treatment, compliance, duration of response, and pharmacokinetics/pharmacodynamics. Assuming target treatment superiority (HR of 0.7), 80% power and 2.5% one-sided type I error rate, a 4-year linear enrollment period and minimum 2-year follow-up with an estimated 10% drop-off rate, 143 patients are needed per arm. Therefore, in Part 2, 429 patients will be randomized 1:1:1 into 3 arms (Group 1: Bel-CHOP; Group 2: Fol-COP; Group 3: CHOP), stratified by histology (nodal vs extra-nodal subtype), Prognostic Index for T-Cell Lymphoma (Group 1/2 vs 3/4), and region (US vs ex-US), excluding patients in Part 1. After completion of study treatment, patients may proceed to bone marrow transplant at the physician's discretion. Long-term survival follow-up will also be completed by phone every 6 months, until a 5-year median follow-up of the population is reached.

Tumor assessments will be performed every 3 cycles and end-of-treatment visit, then every 3 months for 3 years for patients with CR, PR or SD, and every 6 months thereafter until PD or death. Part 1 recruitment began Q1 of 2024.

Atmuri:Acrotech Biopharma: Current Employment. Iyer:Seagen: Research Funding; Acrotech: Research Funding; Merck: Research Funding; CRISPR: Research Funding; Dren-Bio: Research Funding; Innate: Research Funding; Pfizer: Research Funding; IMPaRT.ai: Current equity holder in private company.