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Clinical Trial
. 2025 Apr;43(10):1198-1209.
doi: 10.1200/JCO-24-01549. Epub 2024 Dec 19.

Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma

Francine M Foss  1 , Youn H Kim  2 , H Miles Prince  3 , Oleg E Akilov  4 , Christiane Querfeld  5 , Lucia Seminario-Vidal  6   7 , David C Fisher  8 , Timothy M Kuzel  9   10 , Costas K Yannakou  11   12 , Larisa J Geskin  13 , Tatyana Feldman  14 , Lubomir Sokol  15 , Pamela Blair Allen  16 , Nam Hoang Dang  17 , Fernando Cabanillas  18 , Henry K Wong  19 , Chean Eng Ooi  20 , Dongyuan Xing  21 , Nicholas Sauter  20 , Preeti Singh  21 , Myron Czuczman  21 , Madeleine Duvic  22
Affiliations
Clinical Trial

Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma

Francine M Foss et al. J Clin Oncol. 2025 Apr.

Abstract

Purpose: Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL).

Patients and methods: In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. The primary efficacy end point was objective response rate (ORR) using the Global Response Score. Secondary end points were duration of response (DOR), time to response (TTR), skin tumor burden, and safety and tolerability.

Results: The PEAS included 69 patients (median age, 64.0 years). The ORR was 36.2% (95% CI, 25.0 to 48.7), including 8.7% with complete response. The median DOR was 8.9 months (95% CI, 5.0 to not estimable), and the median (Q1-Q3) TTR was 1.4 (0.7-2.1) months. A total of 84.4% of patients showed decreased skin tumor burden, with 48.4% showing a ≥50% decrease. Treatment-emergent adverse events (TEAEs) of special interest, most of which were grade 1 or 2, included infusion reaction (73.9%), hypersensitivity (68.1%), hepatotoxicity (36.2%), and capillary leak syndrome (20.3% [grade ≥3, 5.8%]). Other common TEAEs were nausea (43.5%) and fatigue (31.9%).

Conclusion: Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.

Trial registration: ClinicalTrials.gov NCT01871727.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Myron Czuczman

Employment: Citius Pharmaceuticals

Stock and Other Ownership Interests: Citius Pharmaceuticals

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Study design. The lead-in study included patients with stage IA-IVB CTCL. The main study included patients with stage IA-IVA CTCL; however, the main study inclusion criteria were later amended to exclude all stage IV patients and include only stage IA-IIIB to match the patient population in historical reference study of denileukin diftitox (ie, Prince et al). Enrollment in the main study commenced after ≥one objective investigator assessment was recorded and the MTD was established. The main study comprised three phases: pretreatment, treatment, and extension. The pretreatment phase included the screening and baseline periods. The screening period was from day –28 to treatment initiation (C1D1); during this time, informed consent was obtained, and eligibility criteria were ascertained for all patients. The baseline period was from day –7 to treatment initiation. The treatment phase included the treatment and follow-up periods. The follow-up period included tumor assessment until treatment discontinuation because of PD. The extension phase started after primary data analysis cutoff and includes follow-up data only. A sample size of approximately 70 stage I-III patients was estimated assuming that the lower limit of the two-sided 95% CI of ORR exceeding 25% indicates clinical benefit in persistent and recurrent CTCL, as per FDA guidance. C, cycle; CTCL, cutaneous T-cell lymphoma; D, day; FDA, US Food and Drug Administration; GRS, Global Response Score; MTD, maximum tolerated dose; ORR, objective response rate; PD, progressive disease.
FIG 2.
FIG 2.
Swimmer plot per Global Response Score for responders—PEAS. This figure displays the best overall response, duration of treatment, and DOR for each of the 25 confirmed responders in the PEAS. Treatment is represented by solid bars that are color-coded for CTCL stage at baseline. Vertical dashed lines mark time points at 24 weeks after the first dose of study drug (eight cycles of therapy) and 52 weeks to mark 1 year on study. Blue diamonds indicate the time of initial CR, and black triangles indicate the time of initial PR. Arrowheads at the right edge of the colored (green, pink, or orange) bars indicate that treatment was ongoing at the data cutoff date; arrowheads at the right end of the lines (blue or black) indicate that DOR was censored. Black dots at the right end of the lines (black) indicate the end of response (ie, time of progressive disease, start of new anticancer therapy, or all-cause death). BOR, best overall response; CR, complete response; CTCL, cutaneous T-cell lymphoma; DOR, duration of response; ID, patient identifier; PEAS, primary efficacy analysis set; PR, partial response.
FIG 3.
FIG 3.
Waterfall plot for skin tumor burden (mSWAT score)—primary efficacy analysis set. This plot represents each patient's percent change in mSWAT score from baseline to postbaseline nadir. Of 69 patients, 64 who had baseline and ≥one postbaseline mSWAT scores were included. mSWAT, modified severity weighted assessment tool.
FIG 4.
FIG 4.
Occurrence over the treatment period of (A) CLS and (B) infusion reactions by grade and cycle. On the basis of CTCAE, the criteria for CLS were a preferred term of CLS and/or TEAEs in at least two of three categories assessing hypotension, edema, and hypoalbuminemia within a cycle. Instructions on dose modifications and interruptions were provided for these TEAEs. CLS, capillary leak syndrome; CTCAE, Common Terminology Criteria for Adverse Events; TEAE, treatment-emergent adverse events.
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