Background and Significance: Cutaneous T-cell lymphoma (CTCL) is a rare, incurable non-Hodgkin lymphoma characterized by progressive Th2 immune skewing, loss of tumor surveillance, and chronic skin inflammation. Interferon-alpha (IFN-α) has long demonstrated immunomodulatory and antitumor effects in CTCL, with historical response rates between 30–80%, but is limited by short half-life, frequent dosing, and dose-limiting toxicities (DLTs). Pegylated IFN-α2a (Pegasys) has become a mainstay for systemic treatment in CTCL due to improved tolerability and biweekly administration; however, recent supply shortages in the U.S. have limited access, creating a significant treatment gap. Ropeginterferon alfa-2b (P1101) is a monopegylated IFN-α-2b with a longer half-life, reduced dosing frequency, and improved pharmacokinetics. It is FDA-approved for polycythemia vera and may permit sustained IFN exposure at higher doses. No studies have evaluated P1101 in CTCL. This trial seeks to define the recommended Phase 2 dose (RP2D) of P1101 in CTCL patients who have failed skin-directed therapies and to explore associated immune biomarkers.

Study Design and Methods: This is a Phase I/Ib, open-label, single-center, investigator-initiated trial (ClinicalTrials.gov: NCT07047885) conducted at Moffitt Cancer Center (Tampa, FL, USA). Eligible patients have stage IA–IIIB CTCL (WHO-EORTC criteria), including Mycosis Fungoides, Lymphomatoid Papulosis, and other rare variants, with no evidence of large cell transformation at screening. Patients with stage IA–IB must have an inadequate response to ≥2 lines of skin-directed therapy, where “inadequate response” is defined as any of the following: a. persistent clinically significant lesions or symptoms, b. Unacceptable toxicity, or c. Disease progression. Those with stage IIA–IIIB must have less than a complete response after phototherapy, extracorporeal photopheresis (ECP), or total skin electron beam therapy (TSET). Patients must have adequate organ function and no uncontrolled psychiatric, infectious, ophthalmic, or autoimmune comorbidities.

The Phase I dose-escalation cohort will enroll up to 18 patients using a Bayesian Optimal Interval (BOIN) design with three target dose levels: 250 mcg, 350 mcg, and 500 mcg P1101 administered subcutaneously every 2 weeks. Intra-patient dose titration is allowed. DLTs are defined as grade ≥3 non-hematologic or grade ≥4 hematologic adverse events (CTCAE v5.0) within 6 weeks or 14 days after reaching the target dose. A Bayesian continuous toxicity monitoring algorithm halts accrual if the posterior probability of exceeding the 25% DLT threshold surpasses 80%.

The expansion phase will enroll up to 20 additional patients at the RP2D. RP2D selection will integrate safety (DLTs, AE profile), preliminary efficacy signals (mSWAT, time to response, patient-reported outcomes), and immunologic biomarker trends. An interim futility analysis will occur after 10 patients in the expansion cohort have completed ≥24 weeks of therapy.

Biomarker studies include serial blood and optional skin biopsies to analyze treatment-related changes in circulating T cells, NK cells, LGLs, and cytokines. Whole blood, PBMC, and plasma samples will be collected at baseline, during therapy, and at progression. Gene expression and immune profiling will explore predictors of response.

This is the first prospective study of Ropeginterferon alfa-2b in CTCL in U.S. It aims to define a biologically active, immunomodulatory dose with sufficient tolerability for extended administration.

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2025
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