ST-001 nanoFenretinide, an intravenous phospholipid nanoparticle formulation of the synthetic retinoid fenretinide, generated an objective response rate (ORR) of 28% (7 of 25 patients) in previously treated cutaneous T-cell lymphoma (CTCL), according to phase 1a data from a first-in-human study (NCT04234048) presented at the 6th World Congress of Cutaneous Lymphomas.1
The 7 responses comprised 5 partial responses (PRs), 1 unconfirmed PR, and 1 complete response (CR). The objective response rate reached approximately 28% in all treated patients (n = 25) and approximately 42% among the 12 patients treated at the completed dose levels 11 and 12 (896 mg/m² per day and 1254 mg/m² per day, respectively). Four of the 7 responses were durable through 8 cycles, which was the maximum permitted on study.
What are the unmet needs for patients with relapsed/refractory CTCL?
Advanced mycosis fungoides and Sézary syndrome carry high morbidity and mortality, and relapsed/refractory CTCL is clinically heterogeneous and difficult to treat; in a validation of the ISCL/EORTC staging system, advanced clinical stage, increased age, male sex, elevated lactate dehydrogenase, and large-cell transformation were linked with reduced survival.2 Patients continue to relapse after retinoids, HDAC inhibitors, brentuximab vedotin (Adcetris), chemotherapy, interferon, and other approved agents, leaving a need for options that are active, durable, and not broadly immunosuppressive.
Early Promise for ST-001 nanoFenretinide in Pretreated CTCL
- ST-001 nanoFenretinide achieved a 28% objective response rate in heavily pretreated patients with cutaneous T-cell lymphoma, with responses increasing to 42% at higher dose levels.
- Several responses were durable through the maximum 8 treatment cycles, with rapid tumor responses observed as early as the first on-study assessment.
- ST-001 demonstrated a manageable safety profile with no treatment-related deaths, supporting continued evaluation in an upcoming phase 1b trial.
Fenretinide is a synthetic retinoid with cytotoxic activity, but poor water solubility and oral bioavailability limited its earlier development. An intravenous oil-in-water emulsion produced durable complete and PRs in heavily pretreated T-cell lymphoma in a prior phase 1 study, although active doses were accompanied by grade 4 hypertriglyceridemia.3
ST-001 is a second-generation, triglyceride-free phospholipid nanoparticle formulation designed to deliver higher fenretinide exposure. An earlier readout of the current trial was reported at the 2024 ASH Annual Meeting.4
How was the ST-001 nanoFenretinide phase 1a trial designed?
The first-in-human, phase 1a study (NCT04234048; SciTech protocol ST-001-010) enrolled patients with relapsed/refractory T-cell non-Hodgkin lymphoma, including CTCL (mycosis fungoides and Sézary syndrome) and noncutaneous subtypes (angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, and follicular T-cell lymphoma).
The trial utilized a Simon 4B accelerated dose-escalation design that permitted intrapatient dose escalation. ST-001 was given as a 4-hour continuous intravenous infusion daily for 5 days, repeated every 3 weeks (1 cycle), for up to 8 cycles. Primary objectives included the maximum tolerated dose, toxicity profile, and tolerability. Secondary objectives included antitumor activity and recommended treatment dose, as well as pharmacokinetic and pharmacodynamic analyses.
Among the 25 patients with CTCL, the median age was 60 years (range, 29-83), and 60% were male. Most had mycosis fungoides (84%), and 16% had Sézary syndrome. The median baseline modified Severity-Weighted Assessment Tool (mSWAT) score was 42.8 (range, 9.7-400). The population was heavily pretreated: 92% of patients had received at least 3 prior lines of therapy, most commonly bexarotene, methotrexate, brentuximab vedotin, and HDAC inhibitors, interferon, topical steroids, radiation, and photopheresis.
What efficacy did ST-001 nanoFenretinide show in CTCL?
Responses tended to emerge early, particularly at the higher dose levels. “If patients are responding, they are responding quite fast,” said Oleg E. Akilov, MD, PhD, an associate professor at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania. He noted that improvement was sometimes visible by the first on-study assessment: “So this is week three, so usually when they come for assessment for a second time, so even after the first infusion, you can see responses in that curve.”
Pharmacokinetic sampling showed that fenretinide reached high concentrations and could be traced in the skin shortly after the end of infusion, and fenretinide Cmax approached approximately 200 µM at higher doses, with an exploratory association with response. Investigators are continuing to refine dosing: “We’re still looking for the magic dose, where we can have good balance between response and tolerability,” Akilov said.
One illustrative case was a patient with stage IVA Sézary syndrome who achieved a PR at 896 mg/m² per day (dose level 11), with a 95.3% reduction in mSWAT, after prior methotrexate, romidepsin, durvalumab (Imfinzi), and mogamulizumab (Poteligeo). The patient came off study in a confirmed PR after completing the maximum 8 cycles. The fenretinide Cmax was 82 µM at the end of infusion on cycle 1, day 1, and a metabolite appeared in the blood by the end of infusion, consistent with rapid tissue delivery.
What did the safety analysis of ST-001 show?
Treatment-related adverse effects (TRAEs) were dose related, with no treatment-related deaths and no cytopenias, sepsis, or cardiac or neurologic toxicity. At 1.25 to 640 mg/m² per day, no significant grade 3 or higher TRAEs occurred except for one grade 3 ulceration over CTCL lesions at 20 mg/m².
At 896 mg/m² per day, single grade 3 events of bone pain, back pain, hypercholesterolemia, and acute kidney injury were reported (n = 1 each). At 1254 mg/m² per day, hypercholesterolemia occurred in 4 patients (grade 4 in 3; grade 3 in 1), along with single grade 3 events of nausea, vomiting, hepatobiliary disorder, and aspartate aminotransferase or alanine aminotransferase increase. Hypercholesterolemia was reversible within the 21-day cycle and was not reported at off-study visits.
Eye-related TRAEs increased with dose, but no grade 3 or higher ocular events occurred; all were grade 1 except for four grade 2 events observed at doses of at least 1254 mg/m². “Patients [experience] ocular issues, but those effects disappear after discontinuation of the drug,” Akilov said. AE-related discontinuations were rare, limited to one consent withdrawal at 1254 mg/m² for grade 2 night blindness.
What are the next steps for ST-001 in CTCL?
Dose level 13 has been completed, and phase 1a enrollment is closed, with 3 patients continuing on treatment. A dose-scheduling study is enrolling into a weekly schedule (dose level 12W) to investigate the safety and clinical activity of weekly dosing.
A phase 1b trial is planned with a 6-month induction, 6 months of weekly maintenance, and a 6-month observation period. The primary end point is stable disease accompanied by pruritus response, confirmed PR, or confirmed CR. The protocol is under review by a central institutional review board (IRB) and local IRBs and is filed under an investigational new drug (IND) application with the FDA.
“It’s going to be induction for 6 months, it’s going to be five days interval, after that we’re going to switch on just weekly, once a week injection, and there’s going to be observation,” Akilov concluded.
Disclosures: Akilov reported serving as a consultant for SciTech Development, Inc. Several coauthors reported employment with, equity ownership in, or consultancy for SciTech Development, Inc.
References
- Akilov OE, Christine Q, Auris H, et al. Preliminary clinical activity of ST-001 nanoFenretinide in previously treated CTCL: first-in-human phase 1a trial results. Presented at: 6th World Congress of Cutaneous Lymphomas; June 25-27, 2026; Montréal, Canada.
- Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28(31):4730-4739. doi:10.1200/JCO.2009.27.7665
- Mohrbacher AM, Yang AS, Groshen S, et al. Phase I study of fenretinide delivered intravenously in patients with relapsed or refractory hematologic malignancies: a California Cancer Consortium trial. Clin Cancer Res. 2017;23(16):4550-4555. doi:10.1158/1078-0432.CCR-17-0234
- Moiin A, Donekal Y, Scarmoutzos L, et al. First-in-human phase 1a clinical trial of the investigational new drug ST-001, a novel nano-phospholipid dispersion formulation of fenretinide, in relapsed/refractory T-cell non-Hodgkin lymphoma. Blood. 2024;144(suppl 1):4453. doi:10.1182/blood-2024-211734
