A Phase 1a/1b Trial of ST-001, a Fenretinide Phospholipid Suspension for 4-Hour Intravenous Infusion in Relapsed/Refractory T-Cell Non-Hodgkin's Lymphoma

A phase 1a/1b trial is planned for specific types of T-cell non-Hodgkin's lymphoma (T-NHL) using a new formulation of fenretinide for intravenous (IV) administration (ST-001, IND# 135475). Despite documented anticancer properties, clinical development of fenretinide has been hampered by poor bioavailability of the oral preparations and poor water solubility for IV infusion although some progress has been made. A phase 1 clinical trial of a 20% soy oil-in-water emulsion containing 2mg/mL of fenretinide, administered via 24-hour daily infusions x5 q3wks, demonstrated activity in mycosis fungoides /Sézary syndrome (MF/SS) and in angioimmunoblastic T-cell lymphoma (AITL) (Mohrbacher et al 2017). However, all doses exhibiting disease activity were associated with grade 4 hypertriglyceridemia. ST-001 from SciTech Development, LLC is a second generation, triglyceride-free, phospholipid-based nano-dispersion formulation of higher potency fenretinide (12.5mg/mL) suitable for IV infusion. The SciTech Delivery Vehicle (SDV) is composed of 4 clinically acceptable phospholipids (DPPC, DOPC, DMPC, and DMPG) which, in the presence of fenretinide, form lamellar bilayer structures <200nm in diameter. Pharmacokinetic (PK) studies showed that IV administration of ST-001 in the Sprague-Dawley rat model achieved fenretinide blood levels required for in vitro cytotoxicity to human cancer cell lines (including T- and B-NHL).

The planned US multicenter phase 1a trial utilizes an Accelerated Titration (Simon) 4B design, with 100% dose escalation in single-patient cohorts until first instance of grade 3 or higher toxicity is encountered, at which point the trial reverts to a 'standard', 3 patient-cohort approach and 40% dose escalation. To maximize each patient's chance to be treated at a potentially active dose, intrapatient dose escalation is allowed for patients who remain on study and have no evidence of toxicity once the safety of the next dose level is established in a drug-naïve patient. The primary study objective is determining the maximum tolerated dose (MTD) of ST-001 in adult patients with T-NHL. Secondary objectives are to describe the toxicity profile of ST-001, observe and record anti-tumor activity of ST-001 in patients with T-NHL, describe the PK of ST-001 when given at the specified dose/schedule in this study, and evaluate potential mechanisms of action of ST-001 using pharmacodynamic (PD) biomarkers. Eligible patients will be 18 years or older with histologically confirmed diagnosis of MF/SS (stages IB-IV according to TNMB system), or Ann Arbor stage II-IV non-cutaneous peripheral T-cell NHL (PTCL), AITL, or follicular T-NHL (FTCL) as defined in the 2016 WHO classification of lymphoid malignancies. Patients must have received at least 2 prior systemic therapies, have good performance status, and acceptable organ function. The drug will be administered IV over 4 hours daily for 5 consecutive days as outpatient starting at a dose of 1.25mg/m²/day. Treatment will be repeated every 3 weeks for up to 8 cycles. Once MTD is determined, an expanded cohort (phase 1b) will be conducted at MTD for diseases that demonstrate efficacy signals in phase 1a; however, patients must have at least one measurable disease site to be eligible for 1b. Up to 44 patients are projected to be enrolled (24 for phase 1a, and 20 for 1b). All patients who receive at least one dose of ST-001 will be evaluated for safety and toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Patients with at least one measurable site of disease and have received at least one full cycle (5-day infusion) of ST-001 are eligible for response evaluation. Descriptive statistics will be used for PK analysis to characterize the range, median and mean of calculated values of clearance, volume of distribution, and half-lives of distribution and elimination phases across all evaluable patients. PD analysis will use each patient's baseline value as the control and normalize PD values as % change from baseline. Effect of ST-001 on specific immune functions including cytokines and immune effector cell function will be evaluated at baseline and after therapy. It is anticipated that ST-001 will demonstrate activity in T-NHL in the absence of excipients that contribute to triglyceride elevations.