Fenretinide for T-Cell Lymphoma

Recruiting at 9 trial locations

Overseen By Louis M Scarmoutzos, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: SciTech Development, Inc.

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: CNS disease, Hepatitis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

46 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot take drugs that strongly affect CYP3A enzymes, like some antibiotics and antifungals, for at least four weeks before starting the trial. If you need to take these drugs during the trial, you must stop the trial medication immediately.

What evidence supports the effectiveness of the drug fenretinide for treating T-cell lymphoma?

Fenretinide has shown complete responses in early-phase clinical trials for T-cell lymphomas and neuroblastoma, and it has demonstrated activity in ovarian cancer. It is a synthetic retinoid that induces cell death even in resistant cancer cell lines, making it a promising drug for various cancers. ^{1 2 3 4 5}

Is fenretinide generally safe for humans?

Fenretinide has been studied in humans and mice, showing no harmful side effects at certain levels in mice and a favorable safety profile in humans. However, there is a report of a serious eye-related side effect (retinal hemorrhage) in a patient with a blood cancer, suggesting that it may not be safe for everyone. ^{6 7 8 9 10}

What makes the drug fenretinide unique for treating T-cell lymphoma?

Fenretinide is unique because it works by generating reactive oxygen species (ROS) and dihydroceramides (DHCers), which can kill cancer cells. It has shown complete responses in early trials for T-cell lymphomas, and its effectiveness may be enhanced by a new delivery method that improves its absorption in the body. ^{1 11 12 13 14}

What is the purpose of this trial?

This study evaluates a fenretinide phospholipid suspension for the treatment of T-cell non-Hodgkin's lymphoma (NHL).

Research Team

Dipenkumar Modi, M.D.

Principal Investigator

Barbara Ann Karmanos Cancer Institute

Ryan Wilcox, MD

Principal Investigator

University of Michigan

Christiane Querfeld, MD

Principal Investigator

City of Hope Medical Foundation

Ali Moiin, MD

Principal Investigator

SciTech Development, Inc.

Oleg E Akilov, M.D., Ph.D.

Principal Investigator

University of Pittsburgh Medical Center (UPMC)

Ann F Mohrbacher, M.D.

Principal Investigator

University of Southern California

Barbara Pro, M.D.

Principal Investigator

Columbia University

Auris Huen, MD

Principal Investigator

M.D. Anderson Cancer Center

Brad Haverkos, M.D.

Principal Investigator

University of Colorado, Denver

Aaron R Mangold, M.D.

Principal Investigator

Mayo Clinic

Eligibility Criteria

Adults with specific types of T-cell non-Hodgkin's lymphoma who have not responded to at least two previous treatments can join. They should be relatively healthy, able to perform daily activities, and have a life expectancy over 6 months. Pregnant or breastfeeding women, HIV patients on certain therapies, and those with active hepatitis or CNS disease cannot participate.

Inclusion Criteria

I have at least one tumor that can be measured.

My lymphoma is at a specific stage and affects the skin or lymph nodes.

My condition has not improved or has returned after treatment.

Exclusion Criteria

I have previously been treated with fenretinide.

I have or had a brain or spinal cord disease.

I do not have any uncontrolled illnesses.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Accelerated Phase 1a

Up to 9 patients receive escalating doses of ST-001 nanoFenretinide to determine safety and pharmacology

5 days per cycle, every 21 days

Standard Phase 1a

Up to 15 patients receive ST-001 nanoFenretinide in a 3+3 design to determine the maximum tolerated dose

5 days per cycle, every 21 days

Phase 1b

20 patients receive ST-001 nanoFenretinide at the maximum tolerated dose to further assess safety and efficacy

5 days per cycle, every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Fenretinide

Trial Overview The trial is testing ST-001 nanoFenretinide, a new form of the drug fenretinide delivered in tiny particles designed for treating T-cell NHL. Participants will receive this treatment to see how well it works against their cancer.

Participant Groups

Group I: Phase 1 Experimental Treatment 1 Intervention

Accelerated Phase 1a + Standard Phase 1a + Phase 1b Accelerated Phase 1a Up to 9 patients for accelerated phase 1a (single patient cohort); dose levels of ST-001 nanoFenretinide (mg/m\^2/day X 5 days every 21 days): Dose Level 1 1.25 (1 patient) Dose Level 2 2.5 (1 patient) Dose Level 3 5.0 (1 patient) Dose Level 4 10 (1 patient) Dose Level 5 20 (1 patient) Dose Level 6 40 (1 patient) Dose Level 7 80 (1 patient) Dose Level 8 160 (1 patient) Dose Level 9 320 (1 patient) Standard Phase 1a Up to 15 patients for standard phase 1a (3+3 design); dose level (mg/m2/day X 5 days every 21 days): Dose Level 10 640 (3-6 patients) Dose Level 11 896 (3-6 patients) Dose Level 12 1,254 (3-6 patients) Dose Level 13 1,756 (3-6 patients) Phase 1b 20 patients for phase 1b at the maximum tolerated dose (MTD)

Fenretinide is already approved in United States for the following indications:

Approved in United States as Fenretinide for:

• Orphan drug designation for the treatment of B-cell lymphoma

Who Is Running the Clinical Trial?

SciTech Development, Inc.

Lead Sponsor

Trials

1

Recruited

50+

SciTech Development, LLC

Lead Sponsor

Trials

1

Recruited

50+

Rush University Medical Center

Collaborator

Trials

448

Recruited

247,000+

Findings from Research

The compound 4-HPR demonstrated significant cytotoxic effects, killing over 99.9% of cancer cells in nine out of fifteen tested cell lines, indicating its strong potential as an anti-cancer treatment.

Both 4-HPR and its metabolite oxoHPR showed comparable effectiveness in increasing reactive oxygen species and inducing apoptosis, while the other metabolites, cis-HPR and MPR, were less effective, suggesting that maximizing exposure to 4-HPR is crucial for its therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia. Song, MM., Makena, MR., Hindle, A., et al.[2020]

Fenretinide (4HPR) showed significant effectiveness in increasing survival time in mice with human ovarian carcinoma when administered directly into the abdominal cavity, unlike oral administration which was ineffective.

When combined with cisplatin, 4HPR enhanced the antitumor activity of the chemotherapy drug, suggesting it could be a promising treatment option for epithelial ovarian tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. Formelli, F., Cleris, L.[2013]

In a phase I-II study involving 32 patients with B-cell non-Hodgkin lymphoma, the combination of fenretinide and rituximab was well tolerated, with no dose-limiting toxicities observed, indicating a favorable safety profile.

The treatment resulted in a modest overall response rate of 24%, with a median duration of response lasting 47 months, suggesting that while the efficacy may be limited, the remissions achieved can be prolonged.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma. Cowan, AJ., Stevenson, PA., Gooley, TA., et al.[2018]

Fenretinide, a vitamin A analogue, has shown promising results in preventing breast cancer recurrence and new cases in patients, with 2969 stage I breast cancer patients involved in trials.

The drug is less toxic than other vitamin A analogues, accumulates preferentially in breast tissue, and has been effective in preventing local recurrences of oral leukoplakia, indicating its potential for broader cancer prevention applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide. Costa, A., Formelli, F., Chiesa, F., et al.[2013]

Fenretinide (4HPR) is a synthetic retinoid that shows promise as an anti-tumor agent with fewer side effects compared to traditional retinoids like all-trans retinoic acid (ATRA).

It has the unique ability to induce apoptosis in cancer cells that are resistant to ATRA, suggesting it may work through different mechanisms than classical retinoids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenretinide and its relation to cancer. Ulukaya, E., Wood, EJ.[2013]

Intravenous fenretinide (4-HPR) is being tested in a phase I clinical trial for patients with hematologic malignancies, but it may cause significant side effects, such as acute large subretinal and intraretinal hemorrhage, as seen in a patient with hairy cell leukemia.

This case emphasizes the need for careful monitoring of retinal health in patients receiving fenretinide therapy, particularly those with existing blood disorders, due to the risk of multilayered retinal hemorrhage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenretinide-associated multilayered retinal hemorrhage in a patient with hairy cell leukemia. Salehi-Had, H., Puliafito, CA.[2013]

In a study using AKR/J mice, N-(4-Hydroxyphenyl)retinamide (4-HPR) significantly reduced the development of virus-induced T-lymphoma by 40% and 50% at dietary doses of 1 and 2 mmole/kg, respectively, over a 19-week period.

4-HPR was well-tolerated, achieving micromolar plasma levels without causing harmful side effects, suggesting its potential as a safe chemopreventive agent for lymphoid cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-(4-hydroxyphenyl)retinamide prevents development of T-lymphomas in AKR/J mice. Chan, LN., Zhang, S., Cloyd, M., et al.[2013]

In a study involving 14 women with suspected breast cancer, the synthetic retinoid 4-HPR was shown to accumulate significantly in breast tissue compared to plasma, especially at a dose of 200 mg/day, which is relevant for its potential use in breast cancer prevention.

The concentrations of 4-HPR in breast tissue at this dose were similar to levels that inhibit breast cancer cell growth in laboratory settings, suggesting that 4-HPR could be an effective preventive treatment, particularly for premenopausal women at risk for estrogen receptor-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide. Sabichi, AL., Modiano, MR., Lee, JJ., et al.[2016]

The study identified six metabolites of fenretinide (4-HPR) in both human and mouse plasma, with 4-HPR being oxidized to 4-oxo-4-HPR primarily through the CYP3A4 enzyme.

Co-administration of ketoconazole, a CYP3A4 inhibitor, significantly increased plasma levels of 4-HPR in mice by more than twofold, suggesting that this combination could enhance the bioavailability of 4-HPR in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. Cooper, JP., Hwang, K., Singh, H., et al.[2021]

The new compound 5-hydroxyphenyl butanoate retinamide (5-HPBR) showed 2- to 6-fold greater cytotoxicity against various cancer cell lines compared to its parent compound, fenretinide (4-HPR), indicating enhanced antitumor potential.

5-HPBR was found to induce apoptosis in cancer cells while showing no harmful effects on normal liver cells, suggesting a favorable safety profile alongside its increased efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent effect of 5-HPBR, a butanoate derivative of 4-HPR, on cell growth and apoptosis in cancer cells. Han, HS., Kwon, YJ., Park, SH., et al.[2016]

The novel LYM-X-SORB oral powder formulation of fenretinide significantly increases its bioavailability, achieving up to 4-fold higher plasma levels and 7-fold higher tissue levels compared to traditional corn oil capsules, based on studies in mice.

In murine models of neuroblastoma, the LYM-X-SORB oral powder formulation improved survival rates, indicating its potential effectiveness in cancer treatment and suitability for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved oral delivery of N-(4-hydroxyphenyl)retinamide with a novel LYM-X-SORB organized lipid complex. Maurer, BJ., Kalous, O., Yesair, DW., et al.[2013]

Fenretinide (4-HPR) has shown promising cytotoxic effects against cancer cells, but its initial oral capsule formulation had low bioavailability, leading to disappointing response rates in early clinical trials.

New formulations of 4-HPR, including an intravenous lipid emulsion (ILE) and an oral powder (LYM-X-SORB®), have significantly improved bioavailability, achieving higher plasma concentrations and resulting in multiple complete responses in patients with peripheral T cell lymphomas and recurrent neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of fenretinide as an antineoplastic drug: Pharmacology perspectives. Cooper, JP., Reynolds, CP., Cho, H., et al.[2018]

Fenretinide (4HPR) shows strong potential as a treatment for small-cell lung cancer (SCLC) by inducing cell death and generating reactive oxygen species, making it effective on its own and in combination with other chemotherapy drugs.

When combined with cisplatin or etoposide, 4HPR demonstrated more than additive effects in inhibiting cancer cell growth, suggesting that it could enhance the efficacy of standard treatments for SCLC with minimal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of fenretinide plus chemotherapeutic agents in small-cell lung cancer cell lines. Kalemkerian, GP., Ou, X.[2015]

Fenretinide (4-HPR) and its derivatives, particularly those with charged groups, can inhibit cell growth and induce differentiation in cancer cells, suggesting their potential as chemopreventive agents.

The study found that while some phenylretinamides act through retinoid receptors to promote differentiation, 4-MPR, a metabolite of 4-HPR, inhibits cell growth independently of these receptors, highlighting its importance in the therapeutic effects of 4-HPR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites. Sabichi, AL., Xu, H., Fischer, S., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Fenretinide and its relation to cancer. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Fenretinide-associated multilayered retinal hemorrhage in a patient with hairy cell leukemia. [2013]

7. Greece pubmed.ncbi.nlm.nih.gov

N-(4-hydroxyphenyl)retinamide prevents development of T-lymphomas in AKR/J mice. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide. [2016]

9. England pubmed.ncbi.nlm.nih.gov

Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Potent effect of 5-HPBR, a butanoate derivative of 4-HPR, on cell growth and apoptosis in cancer cells. [2016]

11. United States pubmed.ncbi.nlm.nih.gov

Improved oral delivery of N-(4-hydroxyphenyl)retinamide with a novel LYM-X-SORB organized lipid complex. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Clinical development of fenretinide as an antineoplastic drug: Pharmacology perspectives. [2018]

13. Germany pubmed.ncbi.nlm.nih.gov

Activity of fenretinide plus chemotherapeutic agents in small-cell lung cancer cell lines. [2015]

14. United States pubmed.ncbi.nlm.nih.gov

Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites. [2023]