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

Background and Significance: Fenretinide (4-hydroxyretinamide) is a vitamin A analog that exhibits both retinoid and unique non-retinoid pharmacology, which explains its broad therapeutic activity in laboratory models of various disease and in several clinical conditions, including multiple cancer types. In a recently reported trial of intravenous fenretinide in hematologic malignancies, responses were reported in cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) (Mohrbacher et al, PMID 28420721), including a sustained complete response in a Sézary Syndrome (SS) patient who did not benefit from bexarotene (Crandon and Yancey, PMID 19349262), thereby confirming lack of retinoid cross-resistance. Unfortunately, this trial used a low strength (2-mg per cc), triglyceride emulsion formulation that was neither practical (120-hour continuous infusion) nor well tolerated (the predicted hypertriglyceridemia was a common dose-limiting toxicity (DLT), and a low challenge dose was introduced to identify patients eligible for treatment). In contrast, ST-001 is an intentionally designed, phospholipid-based, nanoparticle formulation of high-strength (12.5-mg per cc) capable of achieving the previously reported, clinically active blood levels of fenretinide using a practical 4-hour infusion (outpatient setting). The clinical development objectives of this first-in-human Trial in Progress are (i) confirm that ST-001 achieves previously reported clinically active blood levels of fenretinide without any formulation liabilities, (ii) determine the pharmacological behavior of intravenous fenretinide delivered by this novel approach for delivery of poorly soluble drugs, (iii) and determine the safety profile, toxicity, DLT, and recommended treatment dose to evaluate disease activity and response rates in the follow-on Phase 1b trial in CTCL, AITL, and any other peripheral T-cell lymphoma (PTCL) type that responds during Phase 1a.

Study Design and Methods:

• innovative study design: open label, multicenter Phase 1a study that begins with accelerated, 100% dose escalation cohorts of single patients (Simon 4B design, Simon et al, PMID 9262252), which allows intra-patient dose escalation after two, well-tolerated cycles at the previous dose level; the study design switches to a classical 3+3 design and more gradual dose escalation upon occurrence of grade 2 Adverse Events or at dose level 10 when biological effects are expected from the predicted blood levels of fenretinide
• clinical trial registration number: NCT04234048 (IND #135475)
• description of the study population: patients with stage 1b-4 relapsed/refractory T-cell non-Hodgkin lymphoma after inadequate response to first line treatment
• general location of participating centers: multicenter, US-based trial
• major inclusion criteria: ≥18 years old (consenting, male or female), histologically/cytologically confirmed diagnosis (including PTCL, CTCL, AITL, and follicular T), life expectancy ≥ 6 months, 0-1 ECOG performance status
• exclusion criteria: triglycerides >300-mg/dL, clinically significant clinical chemistry, hematology, ophthalmology, or neurology abnormalities, or any other serious medical condition (active infection)
• study treatment: 4-hour intravenous infusion daily for 5 days, repeated every 3 weeks (outpatient)
• primary endpoints: maximum tolerated dose and recommended Phase 1b treatment dose of ST-001
• secondary endpoints: toxicity, adverse events, and clinical activity of ST-001
• pharmacokinetic endpoints: characterization of peak drug levels at end of infusion on cycle 1 days 1 and 4 to investigate potential drug accumulation, and detection of circulating drug metabolites that would indicate tissue delivery of fenretinide
• pharmacodynamic endpoints: specific biomarker responses to ST-001 in the CTCL tumor microenvironment
• statistical methods: descriptive statistics of dose-dependent clinical activity by histology and pharmacokinetic/pharmacodynamic behavior of fenretinide adminstered as ST-001