Results of a Phase I-II Study of Fenretinide and Rituximab for Patients with B-Cell Lymphomas
Authors: Cowan Andrew J. , Stevenson Philip , Gooley Ted A. , Frayo Shani L. , Oliveira George R. , Smith Stephen D. , Green Damian J. , Roden Jennifer E. , Pagel John M. , Wood Brent L , Press Oliver W , Gopal Ajay K. 
Published: October 2019

Abstract
Background:
Despite improved treatment options, indolent non-Hodgkin lymphoma (NHL) and Mantle Cell Lymphoma (MCL) remain incurable for most patients. Fenretinide (4-hydroxy(phenyl)retinamide; 4-HPR), an orally bioavailable synthetic retinoid, has been shown to induce apoptotic cell death in a variety of tumor types, presumably via intratumoral induction of oxygen free radicals. Our group has shown single-agent fenretinide anti-B-NHL activity as well as synergy with anti-CD20 antibody therapy when tested in vitro (Shan et al Clin Cancer Res. 2001) and in human xenograft models (Gopal et al, Blood 2004). These preclinical data support the first trial to evaluate this strategy of fenretinide and rituximab in patients with B-cell malignancies. Here we report results from a phase I-II study evaluating the safety and efficacy of fenretinide with rituximab for indolent NHL and MCL.
Methods:
This was an open-label, phase I/II study conducted at the Fred Hutchinson Cancer Research Center (FHCRC) and Seattle Cancer Care Alliance, Seattle, WA (ClinicalTrials.gov identifier: NCT00288067). The study was approved by the institutional review board at FHCRC and written informed consent was obtained from all patients. Major eligibility criteria included: CD20 positive lymphoid malignancy, radiographically measurable disease, ECOG PS ²2, and adequate organ function. The phase I portion evaluated the safety of dosing single agent fenretinide at 900 mg/m2 PO BID for days 1-5 of a 7 day cycle and allowed de-escalation for excess toxicity. The phase II portion added 375 mg/m2 IV rituximab weekly on weeks 5-9 then every 3 months. All patients could remain on therapy until disease progression or unacceptable toxicity. Response assessment occurred approximately every 3 months. Correlative studies included fenretinide pharmacokinetics, serum retinol concentrations, and evaluation of tumor expression of BCL-2 family proteins. Response was scored by standard criteria (Cheson 1999).
Results:
Thirty-two patients enrolled in the study: 7 patients in phase I, and 25 patients in phase II. The median age was 64 years (range, 40 - 78), 81% were male, and the median number of prior therapies was 1 (range, 0 - 10) with 22 (69%) having received prior rituximab and 8 (25%) with rituximab-refractory disease. Histologies included 13 CLL/SLL, 10 follicular (FL), 7 mantle cell (MCL), 1 lymphoplasmacytic, and 1 marginal zone. No dose limiting toxicities were observed in the phase I portion, and 900 mg/m2 was the dose level delivered in combination with rituximab for the phase II component. The most common treatment-related adverse events (AE) of any grade were reversible night blindness (n=18, 56%), other eye disorders (n=17, 53%), rash (n=12, 38%), and photosensitivity (n=8, 25%). The most common treatment related AEs of grade 3 or higher included: maculopapular rash, night blindness, and decreased lymphocyte count. Three patients (9%) discontinued treatment early due to toxicity (rash-2, GI toxicity-1). One patient with MCL in the phase I portion experienced stable disease (SD) lasting 35 months. In the phase II portion of the study, 5 (20%) patientÕs disease responded (Figure), with 2 (8%) achieving complete remission (both SLL/CLL), and 3 (12%) achieving partial remission (2 FL, 1 MCL). In addition 16 (64%) patients had SD. The median progression-free survival was 9 months (range, 6 - 31 months), and the median overall survival was not reached (range, 33 months to not reached). Median time to progression of responders was 14.5 months. The one-month median peak and trough concentrations of fenretinide were 11.45 µM and 2.5 µM, respectively. Correlative studies assessing Bcl-2, BAX, and apoptosis in the 13 patients with circulating tumor cells were not able to associate these data with response, or survival.
Discussion:
In this phase I/II study, the combination of fenretinide and rituximab was well tolerated with predictable, reversible toxicities with up to 4.5 years of continuous therapy. Though the ORR was modest (20%), the majority had of patients had disease control (ORR + SD=84%) which lasted for > 6 months. Further study of this novel combination should focus on identifying the subset of B-NHL that is most likely to respond or the rational addition of other agents to augment these anti-tumor effects.
Figure 1. Figure 1.

Disclosures
Pagel: Actinium Pharmacetuicals, Inc.: Equity Ownership. Gopal:Merck: Research Funding; Emergent/Abbott: Research Funding; Cephalon/Teva: Research Funding; BioMarin: Research Funding; Sanofi-Aventis: Honoraria; Millenium: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Piramal: Research Funding; Biogen Idec, BMS: Research Funding.