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Fenretinide Drug Applications in Pediatric Cancer

Louis M. Scarmoutzos, Ph.D.

A Brief Overview

Pediatric Cancer

Pediatric cancer [1-3], also known as childhood cancer, is a term generally used to describe the types of cancer found in children under the age of 15. This definition of childhood cancer sometimes includes adolescents aged 15–19 years old. The drug fenretinide has been widely used as an experimental treatment in childhood cancer.

 

Cancer is relatively uncommon in children. Most cancers develop in adults, particularly in older adults. Cancer in children is not always treated like adult cancers and pediatric oncology is the branch of medicine focused on the care of children with cancer.

 

The smaller number of pediatric cancer patients compared to adult cancer patients has limited investment and drug development in pediatric cancer therapy. The combination of a limited pediatric patient population coupled with the high costs of bringing a drug to market has resulted in a limited number of FDA approved pediatric cancer drugs compared to the number of cancer drugs available to adult patients.

In order to close the gap between pediatric and adult cancer drug availability, the FDA has implemented a pediatric priority review voucher (PRV) program. Under this program, the FDA awards priority review vouchers to sponsors of rare pediatric disease drug product applications that meet certain specified criteria. Most pediatric cancer indications satisfy the FDA criteria for the PRV program. 

Since its inception in 2012, the pediatric PRV program has incentivized drug development for pediatric cancers and today there are about 60 drugs approved for childhood cancers [1]. The PRV program has also given rise to an active market where these PRV vouchers are sold or exchanged for millions of dollars.

You can download a brief overview of the FDA voucher program to learn more about the pediatric PRV program. Both fenretinide and ST-001 nanoFenretinde drug candidates, if approved by the FDA, would qualify for the PRV program for the cancer indications provided below.

Cancer in children can occur anywhere in the body and most of the time there is no known cause for these pediatric cancers. The types of cancers that occur most often in children are different from those seen in adults. In the United State, the most common types of cancer in children and adolescents are leukemias, brain and central nervous system (CNS) tumors, and lymphomas.

 
Fenretinide

 

Fenretinide is the active ingredient (AI) in SciTech's lead drug candidate ST-001 nanoFenretinide. ST-001 nanoFenretinide is a nanoparticle formulation containing an enhanced bioavailable form of fenretinide for intravenous (IV) infusion. Fenretinide, a drug with a well-documented safety profile [4], has shown promise in the treatment of a number of pediatric cancers.

Promising fenretinide drug applications includes its use in a number of pediatric cancers such as alveolar rhabdomyosarcoma (ARMS), diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, hepatoblastoma, leukemia, neuroblastoma, rhabdoid tumors, solid tumors, head and neck squamous cell carcinoma (HNSCC), and non-Hodgkin's lymphoma (NHL) as highlighted below.

 

Several of the pediatric studies highlighted below include fenretinide as one of the components in a multiple or combination treatment regimen (co-therapy). Fenretinide drug combinations in clinical studies include its use with other therapeutic agents such as vincristine, safingol and ketoconazole. Fenretinide combinations in preclinical studies include its use with radiation, genistein, lenalidomide, ponatinib, pazopanib, diphenylhydantoin and the benzamide ABT-751. 

Fenretinide appears promising as both a monotherapy and a combination therapy in the treatment of several pediatric cancer indications. However, fenretinide has not gained FDA drug approval and is currently unavailable as a cancer treatment in the U.S. or, for that matter, anywhere else in the world. This lack of commercialization is most likely due to fenretinide's limited bioavailability and patentability. These obstacles have been recently addressed and overcome by SciTech Development and others. 

Efforts directed towards enhancing fenretinide's bioavailability include the use of several approaches and drug delivery systems (DDS) such as lipid emulsions [5], cyclodextrins [6], liposomes [7,8], polymeric micelles [9], ion-pair stabilized lipid matrix [10], gelatin matrix [11], lym-x-sorb (LXS) lipid matrix [12], and fenretinide-PEG (polyethylene glycol) conjugates [13].

SciTech Development's proprietary drug delivery platform (SDP) has enhanced fenretinide's bioavailability in its patented lead drug candidate ST-001 nanoFenretinide which combines SDP plus fenretinide in a phospholipid nanoparticle formulation for intravenous drug administration [14].

References

1. https://www.cancer.gov/types/childhood-cancers and https://www.cancer.gov/about-cancer/treatment/drugs/childhood-cancer-fda-approved-drugs 

2. https://www.cancer.net/cancer-types/childhood-cancer

3. https://www.cancer.org/cancer/cancer-in-children/types-of-childhood-cancers.html

4. Costa, A., Malone, W., Perloff, M., Buranelli, F., Campa, T., Dossena, G., Barbieri, A et al. (1989). "Tolerability of the synthetic retinoid fenretinide (HPR)". European Journal of Cancer and Clinical Oncology, 25(5), 805-808. https://doi.org/10.1016/0277-5379(89)90124-7

5. Xinli Liu, Barry Maurer, Tomas Frgala, John Page, Patricia Noker, Ronna Fulton, Matthew Ames, Joel Reid, Shanker Gupta, Rao Vishnuvajjala, Joseph Tomaszewski, Karen Schweikart, C Reynolds; "Preclinical toxicology and pharmacokinetics of intravenous lipid emulsion fenretinide." Mol Cancer Ther 1 November 2007; 6 (11_Supplement): C159.  https://aacrjournals.org/mct/article/6/11_Supplement/C159/240578

6. Orienti, I., Francescangeli, F., De Angelis, M.L. et al. "A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors." Cell Death Dis 10, 529 (2019). https://doi.org/10.1038/s41419-019-1775-y

7. Di Paolo D, Pastorino F, Zuccari G, Caffa I, Loi M, Marimpietri D, Brignole C, Perri P, Cilli M, Nico B, Ribatti D, Pistoia V, Ponzoni M, Pagnan G. "Enhanced anti-tumor and anti-angiogenic efficacy of a novel liposomal fenretinide on human neuroblastoma." J Control Release. 2013 Sep 28;170(3):445-51.https://doi.org/10.1016/j.jconrel.2013.06.015. Epub 2013 Jun 19. PMID: 23792118.

8. Bensa V, Calarco E, Giusto E, Perri P, Corrias MV, Ponzoni M, Brignole C, Pastorino F. "Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors. Pharmaceuticals." 2021; 14(9):854. https://doi.org/10.3390/ph14090854

9. Okuda T, Kawakami S, Higuchi Y, Satoh T, Oka Y, Yokoyama M, Yamashita F, Hashida M. "Enhanced in vivo antitumor efficacy of fenretinide encapsulated in polymeric micelles." Int J Pharm. 2009 May 21;373(1-2):100-6. doi: 10.1016/j.ijpharm.2009.01.019. Epub 2009 Jan 31. PMID: 19429294 https://www.sciencedirect.com/science/article/abs/pii/S0378517309000416.

10. Orienti, I., Salvati, V., Sette, G. et al. "A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells." J Exp Clin Cancer Res 38, 373 (2019). https://doi.org/10.1186/s13046-019-1383-9

11. Orienti, I., Meco, D., Francesco, A.M., Cusano, G., Popoli, P., Potenza, R.L., Armida, M., Falconi, M., Teti, G., Gotti, R., Zucchetti, M., & Riccardi, R. (2015). "Nanoencapsulation of Fenretinide in Glucosamine Butyrate - Gelatin Matrices as a Mean to Improve its Oral Bioavailability." Journal of Nanomedicine & Nanotechnology, 6, 1-6. https://www.walshmedicalmedia.com/open-access/nanoencapsulation-of-fenretinide-in-glucosamine-butyrate--gelatinmatrices-as-a-mean-to-improve-its-oral-bioavailability-2157-7439-1000292.pdf

12. Kummar S, Gutierrez ME, Maurer BJ, Reynolds CP, Kang M, Singh H, Crandon S, Murgo AJ, Doroshow JH. "Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas." Anticancer Res. 2011 Mar;31(3):961-6. PMID: 21498721; PMCID: PMC7357208. https://pubmed.ncbi.nlm.nih.gov/21498721/

13. Yutong Wang, Yanfang Ding, Changyuan Wang, Meng Gao, Youwei Xu, Xiaodong Ma, Xinyi Ma, Hongxia Cui & Lei Li (2020) Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy, Pharmaceutical Development and Technology, 25:8, 962-970.  https://doi.org/10.1080/10837450.2020.1765377

14. "Liposomal Nanoparticles and Other Formulations of Fenretinide for Use in Therapy and Drug Delivery" U.S. Patent No. 8709379

Fenretinide Molecule Structure

Fenretinide (4-HPR)

PRECLINICAL STUDIES

Listed below are several select publications concerning preclinical investigations of fenretinide alone or as a combination therapy in the treatment of a number of pediatric cancers. These childhood cancers include alveolar rhabdomyosarcoma (ARMS), diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, hepatoblastoma, leukemia, neuroblastoma and rhabdoid tumors. The references provided below include selected excerpts from the published preclinical studies.

Several of the preclinical studies report an enhanced or synergistic effect when fenretinide is combined with the antimitotic sulfonamide ABT-751, the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA or vorinostat), lenalidomide, ceramide modulators or radiation.

Although not clinical studies, together these preclinical research studies highlight the promise and potential of fenretinide as a monotherapy or a combination treatment in several pediatric cancers. Furthermore, these studies provide guidance as to a treatment protocol as well as provide support and justification of moving the fenretinide therapy into the clinic.

Alveolar rhabdomyosarcoma (aRMS)

 

Brack, E., Wachtel, M., Wolf, A. et al. Fenretinide induces a new form of dynamin-dependent cell death in pediatric sarcoma. Cell Death Differ 27, 2500–2516 (2020). https://doi.org/10.1038/s41418-020-0518-z
Conclusions: "... Taken together, our data identify a new form of cell death mediated through the production of ROS (reactive oxygen species ) by fenretinide treatment, highlighting the value of this compound for treatment of sarcoma patients including FP-RMS (fusion positive RMS).”

 

Eva Brack, Marco Wachtel, Beat W. Schaefer. Characterization of the mode of action of Fenretinide treatment in alveolar rhabdomyosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 700. doi:10.1158/1538-7445.AM2017-700  Conclusions: "...Taken together, our data show that Fenretinide shows high potential for the treatment of aRMS, inducing several forms of cell death mediated through the production of ROS. These properties open the search for additional compounds acting in a combinatorial manner."

Brack Eva, Bender Sabine, Wachtel Marco, Pruschy Martin, Schäfer Beat W., Fenretinide Acts as Potent Radiosensitizer for Treatment of Rhabdomyosarcoma Cells. Front. Oncol., Vol. 11, 15 June 2021, https://doi.org/10.3389/fonc.2021.664462     Conclusions: "... Our data suggest that fenretinide acts in combination with IR (ionizing radiation) to induce cell death in FP-RMS cells and therefore might represent a novel radiosensitizer for the treatment of this disease.”

Herrero Martín D, Boro A, Schäfer BW. Cell-based small-molecule compound screen identifies fenretinide as potential therapeutic for translocation-positive rhabdomyosarcoma. PLoS One. 2013;8(1):e55072. doi: 10.1371/journal.pone.0055072. Epub 2013 Jan 25. PMID: 23372815; PMCID: PMC3555977.  Conclusions: "...These results are similar to earlier reports for two other pediatric tumors, namely neuroblastoma and Ewing sarcoma, where fenretinide is under clinical development. Our results suggest that fenretinide might represent a novel treatment option also for translocation-positive rhabdomyosarcoma."

Diffuse Intrinsic Pontine Glioma (DIPG)

 

Tsoli, M., Yeung, N., Valvi, S., Joshi, S., Franshaw, L., Shen, H., Liu, J., & Ziegler, D. (2017). DIPG-05. Combination of Synthetic Retinoid Fenretinide with Receptor Tyrosine Kinase Inhibitor Ponatinib as a Potential New Approach Against Diffuse Intrinsic Pontine Glioma. Neuro-Oncology, 19(Suppl 4), iv5–iv6. https://doi.org/10.1093/neuonc/nox083.020   Conclusions: "... We performed a high throughput screen (HTS) of 3500 clinically available compounds, which identified fenretinide among the top 33 most active agents against DIPG…  Preliminary results indicate that delivery of fenretinide with irradiation could extend the survival of mice. This novel and potentially effective DIPG treatment strategy is readily translatable to clinical trial."

Valvi, S., Masters Thesis, 2019, “Novel therapies for diffuse intrinsic pontine glioma", School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales (UNSW), http://handle.unsw.edu.au/1959.4/64571   Conclusions: "... This research represents the first report to highlight the cytotoxic activity of fenretinide against DIPG cells. Fenretinide was effective in vitro across a panel of DIPG cell lines… We were able to demonstrate that fenretinide’s cytotoxicity was related to apoptosis induction secondary to ROS production and caspase activation.”

Dannielle Upton, Santosh Valvi, Jie Liu, Nicole Yeung, Sandra George, Caitlin Ung, Aaminah Khan, Laura Franshaw, Anahid Ehteda, Han Shen, Isabella Orienti, Giovanna Farruggia, Patrick Reynolds, Maria Tsoli, David Ziegler, RARE-08. Potential New Therapies for Diffuse Intrinsic Pontine Gliomas Identified Through High Throughput Drug Screening, Neuro-Oncology, Volume 23, Issue Supplement_1, June 2021, Page i42, https://doi.org/10.1093/neuonc/noab090.169   Conclusions: "...We used two different fenretinide formulations which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG."

Ewing's Sarcoma

Myatt SS, et al, “p38MAPK-Dependent sensitivity of Ewing's sarcoma family of tumors to fenretinide-induced cell death” Clin Cancer Res. 2005 Apr 15;11(8):3136-48  https://www.ncbi.nlm.nih.gov/pubmed/15837770 .
Conclusions: "... The efficacy of fenretinide in preclinical models demands the evaluation of fenretinide as a potential therapeutic agent in Ewing's sarcoma family of tumors (ESFT).”

Karmakar, S., Choudhury, S., Banik, N., & Ray, S. (2011). N-(4-Hydroxyphenyl) Retinamide Potentiated Anti-Tumor Efficacy of Genistein in Human Ewing's Sarcoma Xenografts. World Journal Of Oncology, 0, 53-63. https://www.wjon.org/index.php/wjon/article/view/301/223   Conclusions: "...Results revealed that combination of 4-HPR (fenretinide) and GST (genistein) could be highly effective treatment for inhibiting Ewing’s sarcomas in vivo."

Sandeep Batra, C. Patrick Reynolds and Barry J. Maurer, Fenretinide Cytotoxicity for Ewing’s Sarcoma and Primitive Neuroectodermal Tumor Cell Lines Is Decreased by Hypoxia and Synergistically Enhanced by Ceramide Modulators, Cancer Res August 1 2004 (64) (15) 5415-5424; DOI: 10.1158/0008-5472.CAN-04-0377   Conclusions: "...We conclude the following: (a) 4-HPR was active against ESFT cell lines in vitro at concentrations achievable clinically, but activity was decreased in hypoxia; and (b) combining 4-HPR with ceramide modulators synergized 4-HPR cytotoxicity in normoxia and hypoxia."

Hepatoblastoma

Zhang, L., Huang, D., Shao, D., Liu, H., Zhou, Q., Gui, S. ... Wang, Y. (2018). Fenretinide inhibits the proliferation and migration of human liver cancer HepG2 cells by downregulating the activation of myosin light chain kinase through the p38‑MAPK signaling pathway. Oncology Reports, 40, 518-526. https://doi.org/10.3892/or.2018.6436  Conclusions: "... 4‑HPR inhibited the proliferation and migration of HepG2 cells, and p38‑MAPK plays an important role in regulating these 4‑HPR effects by reducing the activation of MLCK. The present study suggests that 4‑HPR may be a potent antimetastatic agent."

Leukemia

O'Donnell, P., Guo, WX., Reynolds, C. et al. N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. Leukemia 16, 902–910 (2002). https://doi.org/10.1038/sj.leu.2402485  Conclusions: "... 4-HPR was cytotoxic and increased ceramide in acute lymphoblastic leukemia (ALL) cell lines, but not in non-malignant lymphoid cell types."

Neuroblastoma

Song MM, Makena MR, Hindle A, Koneru B, Nguyen TH, Verlekar DU, Cho H, Maurer BJ, Kang MH, Reynolds CP. Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia. Anticancer Drugs. 2019 Feb;30(2):117-127. doi: 10.1097/CAD.0000000000000696. PMID: 30272587.  Conclusions: "...These data support focusing on achieving high 4-HPR exposures for maximizing antineoplastic activity."

Nancy E. Chen, N. Vanessa Maldonado, Vazgen Khankaldyyan, Hiroyuki Shimada, Michael M. Song, Barry J. Maurer, C. Patrick Reynolds; Reactive Oxygen Species Mediates the Synergistic Activity of Fenretinide Combined with the Microtubule Inhibitor ABT-751 against Multidrug-Resistant Recurrent Neuroblastoma Xenografts. Mol Cancer Ther 1 November 2016; 15 (11): 2653–2664. https://doi.org/10.1158/1535-7163.MCT-16-0156 Conclusions: "... Our data support clinical evaluation of 4-HPR combined with ABT-751 in recurrent and refractory neuroblastoma."

Roberta Carosio, Vito Pistoia, Isabella Orienti, Franca Formelli, Elena Cavadini, Salvatore Mangraviti, Paolo G Montaldo, Emanuela Ognio, Laura Emionite, Guendalina Zuccari, Enhanced anti-neuroblastoma activity of a fenretinide complexed form after intravenous administration, Journal of Pharmacy and Pharmacology, Volume 64, Issue 2, February 2012, Pages 228–236, https://doi.org/10.1111/j.2042-7158.2011.01403.x  Conclusions: "... DX-OL/4-HPR (4-HPR-loaded amphipilic dextrin) increased the lifespan and the long-term survival of treated mice over controls.

Orienti I, Nguyen F, Guan P, Kolla V, Calonghi N, Farruggia G, Chorny M, Brodeur GM. A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model. Drug Des Devel Ther. 2019 Dec 19;13:4305-4319. https://doi.org/10.2147/DDDT.S221909. PMID: 31908416; PMCID: PMC6930389. Conclusions: "...New nanomicelles containing the fenretinide–lenalidomide combination (FLnMs) provided superior antitumor efficacy in NB xenografts compared to nanomicelles containing fenretinide alone (FnMs). The enhanced efficacy of the combination was likely due to the antiangiogenic effect of lenalidomide added to the cytotoxic effect of fenretinide. This new nanomicellar combination is characterized by a low-toxicity profile and offers a novel therapeutic option for the treatment of high-risk tumors where the persistence of minimal residual disease (MRD) requires repeated administrations of therapeutic agents over long periods of time to avoid recurrent disease."
 

Rhabdoid Tumors

Kerl, K., Ries, D., Unland, R. et al. The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells. BMC Cancer 13, 286 (2013). https://doi.org/10.1186/1471-2407-13-286 Conclusions: "... Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors."

CLINICAL STUDIES

Of the dozen or so fenretinide pediatric clinical trials currently registered at ClinicalTrials.gov [15-25], only a handful of them have publicly reported the results of their clinical study [26-30]. The reported clinical results include fenretinide treatment of children with neuroblastoma and solid tumors; and are for treating patients ranging in age from 2 to 27 years old (median age 9 years old) in relatively small patient populations (17-62 patients). 

The reported Phase 1 clinical studies [26-28, 30, 31] primarily addressed maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide. A single Phase 2 study reports the response rate to oral fenretinide administered to children with recurrent or refractory neuroblastoma [29].

Graventa et al [26] report in their Phase I study of pediatric neuroblastoma a recommended fenretinide administration of up to 4000 mg/m2/day. An excessive number of fenretinide capsules or oil content intake from the capsules precluded additional dose escalation and, as a result, a MTD was not reached. After the first dose administration, average fenretinide peak plasma levels reached about 6 μmol/L (dose of 4000 mg/m2/day) and increased 2-fold after a 28-day treatment. The mean half-life of fenretinide plasma levels was 17 hours after the first dose and 25 hours after 28 daily doses of the treatment.

Commonly observed toxicities reported in the Graventa study include skin xerosis (dry skin) and nyctalopia (night blindness). At the highest dose (4000 mg/m2/day),  a single patient experienced reversible grade 2 hepatic toxicity consisting of elevated levels of transaminases; and, 3 patients developed diarrhea. All adverse reactions were rapidly resolved after discontinuing the treatment. 

Villablanca et al [27] report a pediatric MTD of oral capsular fenretinide of 2,475 mg/m2 per day in their Phase 1 study in children with solid tumors. The study reports that 10 μmol/L fenretinide plasma levels were achieved without significant toxicity. The observation of a significant variation in steady-state fenretinide plasma levels was reported as likely due to variable dietary fat consumption affecting fenretinide absorption; and, the gelatin capsule formulation may have contributed to poor fenretinide absorption.

Overall toxicities reported in the Villablanca study were mild and rapidly reversible. The incidence of nyctalopia was lower than that reported in adults, and likely due to under-reporting by young children. Gastrointestinal adverse effects were more prominent in children consuming higher numbers of capsules.

In a Phase 1 dose escalation study of neuroblastoma, Mauer et al [30] report that an oral powder comprised of fenretinide (4-HPR) and Lym-X-Sorb (LXS), a lipid complex which enables fat absorption, obtained a several fold higher fenretinide plasma level than previous capsule formulations. The study reported minimal toxicity with evidence of anti-tumor activity. An MTD was not reached and the authors suggest a recommended Phase 2 daily dose of 4-HPR/LXS powder of 1500 mg/m2/day and report that no unexpected toxicities occurred. 

Formelli et al [28] evaluated the pharmacokinetics of fenretinide and its active metabolite 4-oxo-fenretinide in pediatric neuroblastoma patients. The authors report that their results support daily dosing with steady-state concentrations of fenretinide and its metabolite in line with inhibitory effects observed in preclinical studies. 

Only the results of a single Phase 2 study have been reported; namely, for fenretinide treatment of pediatric neuroblastoma [29]. Oral capsular fenretinide was administered to sixty-two patients for 7 days every 21 days (2,475 mg/m2/day or 1,800 mg/m2/day) for a maximum of 30 cycles of treatment. The authors of the study report that the clinical protocol criteria for efficacy was not met and low bioavailability may have limited fenretinide activity. The authors further state that of the 62 patients, one partial response (PR) and 13 prolonged stable disease (SD) were observed and toxicities were mild and reversible.

Finally, it is important to note a Phase 1 pediatric clinical trial report of a fatal drug interaction. Kang et al [31] report that a combination treatment comprised of intravenous administration of a fenretinide emulsion formulation, ceftriaxone (cephalosporin antibiotic), and acetaminophen (antipyretic/analgesic) in a pediatric neuroblastoma study resulted in a single fatality.

In the neuroblastoma study, the authors reported the fatality of a seven-year-old male patient due to hepatic acetaminophen toxicity between the three agents: fenretinide, ceftriaxone, and acetaminophen. None of the other 16 pediatric patients in the study experienced significant hepatic toxicity. The authors relay that fenretinide with the concomitant medications (con-meds) ceftriaxone and acetaminophen should be avoided.

 

The Kang et al study also reports measured fenretinide plasma levels of 17 μmol/L to 110 μmol/L (doses of 640 mg/m2/day to 1110 mg/m2/day). Due to an inadequate Phase 1 drug supply, the pediatric neuroblastoma study was terminated.

References*

* ClinicalTrials.gov  Accessed March 24, 2022

CONCLUSION

Fenretinide, a third-generation retinoid, is a synthetic derivative of vitamin A (retinol) that has shown promising anticancer activity in many preclinical studies of both pediatric and adult cancers. In the clinic, however, fenretinide's potential as an anticancer drug appears to have been severely hampered by its low bioavailability.

Clinical studies of fenretinide have rarely progressed past Phase 2 where its effectiveness as an anticancer drug was not unambiguously demonstrable, although having a well-documented safety profile. This lack of clinical efficacy is presumably due to the relatively low plasma concentrations of fenretinide in the body not being able to bring about a favorable therapeutic outcome, i.e., its inherently limited bioavailability.

 

The relatively mild toxicities and adverse side effects associated with fenretinide treatment are generally reversed upon cessation of the treatment. However, the administration of concomitant medications (con-meds) in fenretinide clinical trials needs to be carefully and continuously monitored.

Large pharmaceutical companies have been reluctant to further fenretinide's drug development and bring this promising drug to market. This is most likely due fenretinide's past history of clinical failures and associated negative connotations as well as limitations in its patentability. Fenretinide itself has long since come off-patent.

Several small companies (including SciTech Development) and academic researchers have kept the promise of fenretinide alive. Several patented new fenretinide formulations now exist that claim to successfully address the bioavailability limitations of fenretinide. It is now time to evaluate them in the clinic.