A phase I study of intravenous fenretinide (4-HPR) for patients with malignant solid tumors.

BACKGROUND: Fenretinide is a synthetic retinoid that can induce cytotoxicity by several mechanisms. Achieving effective systemic exposure with oral formulations has been challenging. An intravenous lipid emulsion fenretinide formulation was developed to overcome this barrier. We conducted a study to establish the maximum tolerated dose (MTD), preliminary efficacy, and pharmacokinetics of intravenous lipid emulsion fenretinide in patients with advanced solid tumors. METHODS: Twenty-three patients with advanced solid tumors refractory to standard treatments received fenretinide as a continuous infusion for five consecutive days in 21-day cycles. Five different dose cohorts were evaluated between doses of 905 mg/m2 and 1414 mg/m2 per day using a 3 + 3 dose escalation design. A priming dose of 600 mg/m2 on day 1 was introduced in an attempt to address the asymptomatic serum triglyceride elevations related to the lipid emulsion. RESULTS: The treatment-related adverse events occurring in ≥ 20% of patients were anemia, hypertriglyceridemia, fatigue, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase, thrombocytopenia, bilirubin increase, and dry skin. Five evaluable patients had stable disease as best response, and no patients had objective responses. Plasma steady-state concentrations of the active metabolite were significantly higher than with previous capsule formulations. CONCLUSION: Fenretinide emulsion intravenous infusion had a manageable safety profile and achieved higher plasma steady-state concentrations of the active metabolite compared to previous capsule formulations. Single-agent activity was minimal but combinatorial approaches are under evaluation.

Quality of Life in a Randomized Breast Cancer Prevention Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women.

Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.

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

Fenretinide (4-HPR) is a synthetic retinoid that has cytotoxic activity against cancer cells. Despite substantial in vitro cytotoxicity, response rates in early clinical trials with 4-HPR have been less than anticipated, likely due to the low bioavailability of the initial oral capsule formulation. Several clinical studies have shown that the oral capsule formulation at maximum tolerated dose (MTD) achieved <10 µmol/L concentrations in patients. To improve bioavailability of 4-HPR, new oral powder (LYM-X-SORB®, LXS) and intravenous lipid emulsion (ILE) formulations are being tested in early-phase clinical trials. ILE 4-HPR administered as five-day continuous infusion achieved over 50 µmol/L at MTD with minimal systemic toxicities; multiple complete and partial responses were observed in peripheral T cell lymphomas. The LXS oral powder 4-HPR formulation increased plasma levels approximately two-fold at MTD in children without dose-limiting toxicities and demonstrated multiple complete responses in recurrent neuroblastoma. The clinical activity observed with new 4-HPR formulations is attributed to increased bioavailability. Phase I and II clinical trials of both LXS 4-HPR and ILE 4-HPR are in progress as a single agent or in combination with other drugs. Impact statement One of the critical components in drug development is understanding pharmacology (especially pharmacokinetics) of the drugs being developed. Often the pharmacokinetic properties, such as poor solubility leading to poor bioavailability, of the drug can limit further development of the drug. The development of numerous drugs has often halted at clinical testing stages, and several of them were due to the pharmacological properties of the agents, resulting in increased drug development cost. The current review provides an example of how improved clinical activity can be achieved by changing the formulations of a drug with poor bioavailability. Thus, it emphasizes the importance of understanding pharmacologic characteristics of the drug in drug development.

Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype.

Over one third of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long-term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives, that is, the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins, and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic), and the humanized mAb to the IL6R receptor tocilizumab (TOC, reduces IL6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high-affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally delivered TOC, TOC+4-HPR, and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents use diverse mechanisms to disrupt tumorigenesis at multiple venues, that is, intracellular, tumor cell-ECM, and tumor microenvironment; beneficial qualities for secondary chemopreventives. Cancer Prev Res; 10(1); 76-88. ©2016 AACR.

Premature physeal closure following 13-cis-retinoic acid and prolonged fenretinide administration in neuroblastoma.

Retinoid therapy has contributed to improved outcomes in neuroblastoma. Clinical trials of fenretinide report favorable toxicity and disease stabilization in patients with high risk (HR) neuroblastoma. Skeletal effects have been described with other retinoids, but not with fenretinide to date. Two patients with HR, metastatic, refractory neuroblastoma received protracted courses of oral fenretinide for more than 5 years' duration. Both developed premature long bone physeal closure, causing limb length discrepancies; their neuroblastoma remains in remission. The radiographic and clinical findings reported suggest these skeletal abnormalities may be a consequence of treatment with 13-cis-retinoic acid (13cisRA) followed by prolonged oral fenretinide exposure.

Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study.

BACKGROUND: Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study. CASE PRESENTATION: On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 µM. Over the next three days, although blood cultures remained negative, the patient's condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity. CONCLUSIONS: After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.

Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.

BACKGROUND: A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. PROCEDURE: 4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design. RESULTS: Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10-46 courses). 4-HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 µM. An MTD was not reached. CONCLUSIONS: 4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course.

Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration.

BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol-binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy. METHODS: The efficacy of fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States. RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of ≤ 1 µM (≤ 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of fenretinide, which have been observed in other disease states. CONCLUSION: The findings of this study and the established safety profile of fenretinide in chronic dosing regimens warrant further study of fenretinide in the treatment of geographic atrophy.

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group.

PURPOSE: To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. EXPERIMENTAL DESIGN: Patients received 7 days of fenretinide: 2,475 mg/m(2)/d divided TID (<18 years) or 1,800 mg/m(2)/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only). RESULTS: Sixty-two eligible patients, median age 5 years (range 0.6-19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17-506) for stratum 1 and 48 days (range 17-892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 µmol/L (coefficient of variation 40-56%) at day 7 course 1. Toxicities were mild and reversible. CONCLUSIONS: Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies.

Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas.

BACKGROUND: The synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR) has shown promising anticancer activity in preclinical studies, but its limited oral bioavailability has hindered clinical assessment. A novel lipid matrix, Lym-X-Sorb (LXS), was evaluated to improve fenretinide bioavailability and attain higher plasma concentrations. PATIENTS AND METHODS: Adults with refractory malignancies were administered fenretinide/LXS oral powder in 2 divided doses over 24 h for 7 consecutive days every 21 days in a standard phase I dose-escalation study with pharmacokinetic analysis. RESULTS: The principal toxicities observed were diarrhea, reversible night blindness, and allergic reaction. The maximum tolerated dose regimens were 1,000 mg/m(2)/day divided into 2 daily doses for 7 days, every 21 days, and 800 mg/m(2)/day divided into 3 daily doses for 7 consecutive days, every 21 days. CONCLUSION: Better fenretinide formulations are needed to improve adult patient acceptability and compliance and to achieve the consistent systemic exposures associated with activity in preclinical models.

Phase III double-blind, placebo-controlled, prospective randomized trial of adjuvant tamoxifen vs. tamoxifen and fenretinide in postmenopausal women with positive receptors (EB193): an intergroup trial coordinated by the Eastern Cooperative Oncology Group.

Fenretinide and tamoxifen have additive antitumor effects preclinically. We performed a randomized, placebo-controlled, double-blind adjuvant trial in breast cancer patients treated for 5 years with tamoxifen, with or without fenretinide. Between October 1995 and October 1999, 426 postmenopausal women with hormone receptor-positive breast cancer were randomized. Patients were monitored for efficacy and toxicity. Four hundred and nineteen patients were evaluable. The study was terminated early due to slow accrual. There were no significant differences between treatment groups in DFS, TTR or survival. More patients stopped treatment early on the fenretinide arm than on placebo (P = 0.02). Grade 3/4 toxicities, including visual problems and musculoskeletal complaints were more common in patients receiving fenretinide (P = 0.007). A Night Blindness Questionnaire was used to monitor nyctalopia, which was slightly, but not significantly, more common on fenretinide. In this underpowered study, no significant difference was observed in efficacy between treatment groups. This trial provides important toxicity information about fenretinide, a retinoid that has been used in the prevention setting, because it is the only placebo-controlled, double-blind randomized study ever performed.

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

Intravenous fenretinide (4-HPR), a cytotoxic retinoid, is being evaluated as part of a phase I clinical trial for patients with hematologic malignancies. In its orally administered form, it is also being evaluated for the treatment of various malignancies and geographic atrophy in subjects with the dry form of age-related macular degeneration. The authors report a case of acute large subretinal and intraretinal hemorrhage noted immediately after initiation of intravenous fenretinide therapy in a patient with hairy cell leukemia. This case highlights the importance of considering multilayered retinal hemorrhage as a possible side effect of fenretinide therapy, especially in patients with underlying hematologic abnormalities.

A phase II study of fenretinide in patients with hormone refractory prostate cancer: a trial of the Cancer Therapeutics Research Group.

PURPOSE: Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer. METHODS: Eligibility criteria included hormone refractory prostate cancer with a rising PSA at least 6 weeks after peripheral anti-androgen withdrawal, ECOG performance status (PS) 0-1, and no prior chemotherapy. Fenretinide was administered orally at 900 mg m(-2) twice daily for 7 of every 21 days. PSA was measured before each cycle. The primary endpoint was a > or =50% reduction in PSA maintained for at least 3 weeks; secondary endpoints included duration of PSA response, time to treatment failure (TTF: treatment stopped for progression or toxicity) and adverse events (AE). RESULTS: Twenty seven pts were recruited from 7 centres over 27 months. Median age was 74 (range 49-86), median baseline PSA was 129 (range 19-1,000), and 70% had a PS of 0. The median number of cycles received was 2 (range 0-11) and 20 pts completed at least 1 cycle. One pt (4%) achieved a 50% reduction in PSA lasting 39 days and 15 pts (56%) had not progressed within 6 weeks of starting fenretinide. The median TTF was 54 days (IQR 19-73): 22 (81%) failed with tumour progression, 3 (11%) failed with toxicity and 2 (7%) never commenced the drug. Grade 3 rash occurred in 1 patient, all other AE were grade 1 or 2. The most common AE were nausea (40%), hot flushes (36%), constipation (32%) and nyctalopia (32%). CONCLUSION: High-dose fenretinide had limited anti-tumour activity in patients with advanced hormone refractory prostate cancer: further evaluation in this setting is not warranted.

Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women.

PURPOSE: Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. PATIENTS AND METHODS: A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. RESULTS: During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. CONCLUSION: Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer.

BACKGROUND: Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. METHODS: Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). RESULTS: Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 µg/ml (7.40 +/- 4.25 muM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 µg/ml and 0.05 +/- 0.07 µg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 µg/ml, with no correlation between salivary and plasma drug levels. CONCLUSIONS: Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.

High-dose fenretinide in oral leukoplakia.

We previously showed that low-dose fenretinide (200 mg/d) had limited activity in retinoid-resistant oral leukoplakia (34% response rate) possibly because serum drug levels were insufficient to induce retinoid receptor-independent apoptosis. Therefore, we designed the single-arm phase II trial reported here to investigate whether higher-dose fenretinide would improve leukoplakia response over that of our previous study. Leukoplakia patients received fenretinide (900 mg/m(2) twice daily) in four 3-week cycles (1 week on drug followed by 2 weeks off). At week 12, clinical responses were determined and blood samples were collected for serum drug level assessments. A planned interim futility analysis led to early trial closure after the initial 15 (of 25 planned) patients because only 3 (20%) had a partial response (stopping rule:

Total rod ERG suppression with high dose compassionate Fenretinide usage.

Fenretinide is a synthetic retinoid that interferes with the attachment of retinol to retinol binding protein. It may inhibit accumulation of A2E and lipofuscin, and is proposed as therapy for Stargardt disease. It is currently used for cancer therapy, and mild depression of rod function and dark adaptation is a side effect at standard dosage. We studied two youngsters (aged between 12 and 13) receiving high doses as compassionate treatment for neuroblastoma: 800 mg daily for 1 out of every 3 weeks, for roughly 2 years. Goldmann-Weekers dark adaptometry, ISCEV standard ERG and mfERG were performed, and blood was analyzed for vitamin A. Neither child complained of night blindness or showed retinal fundus abnormalities. On initial exam, dark adaptation thresholds were elevated by 3 log units, and there were no detectable rod ERG responses. However, cone responses and mfERG were normal. Retesting one subject 3 months after stopping the drug revealed normal rod thresholds (slightly delayed) and low normal rod ERG responses. Serum vitamin A levels were normal from both subjects, but there is no record of whether the samples were drawn during cycles on or off drug. Our study demonstrates that high dose Fenretinide can suppress rod function quite completely, although serum vitamin A and rod function apparently return to normal or near normal levels rapidly once the drug is stopped. It is intriguing that cone function and access to vitamin A seems largely independent of Fenretinide effects on retinol availability.

A phase I-II preoperative biomarker trial of fenretinide in ascitic ovarian cancer.

PURPOSE: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. METHODS: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. RESULTS: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 micromol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 micromol/L 4-HPR. CONCLUSIONS: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention.