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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3423-3430 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.9271 Phase I Trial of Oral Fenretinide in Children With High-Risk Solid Tumors: A Report From the Children's Oncology Group (CCG 09709)
From the Children's Hospital Los Angeles and the Department Pediatrics, University of Southern California Keck School of Medicine; Developmental Therapeutics Program, University of Southern California–Children’s Hospital Los Angeles Institute for Pediatric Clinical Research, Los Angeles; Children's Oncology Group, Arcadia, CA; Mayo Clinic, Rochester, MN; and the Children's National Medical Center and Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC Address reprint requests to Judith G. Villablanca, MD, Division of Hematology-Oncology, 4650 Sunset Blvd, MS #54, Los Angeles, CA 90027; e-mail: jvillablanca{at}chla.usc.edu; CC: pubs{at}childrensoncologygroup.org
PURPOSE: To determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors. METHODS: Children 21 years of age or younger received daily doses from 350 mg/m2 to 3,300 mg/m2 (divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose. RESULTS: Fifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m2 with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m2, one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m2, one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m2: grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m2 and 800 mg/m2. There was one complete response and 13 patients with stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 µmol/L at MTD. CONCLUSION: The pediatric MTD of oral capsular fenretinide was 2,475 mg/m2 per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.
Retinoids are vitamin A analogs that modulate growth and differentiation of normal and malignant cells.1 Fenretinide (N-4-hydroxyphenyl retinamide, [4-HPR]), is a synthetic retinoid2 that demonstrates cytotoxicity and/or growth inhibition of cell lines in vitro, including neuroblastoma,3-6 colorectal,7 prostate,8 breast,9-11 and ovarian cancers;12 small-cell lung cancer;13 lymphoid and myeloid leukemia;14,15 Ewing family tumors;17and cell lines resistant to retinoic acid.3,9,11,12,15 Multilog, dose-dependent cytotoxicity for neuroblastoma cell lines occurs at 3 to 10 micromolar 4-HPR, with higher levels active against cell lines resistant to 13-cis-retinoic and/or all-trans-retinoic acid, alkylating agents, and etoposide.3,16 This suggests 4-HPR may be active in high-risk neuroblastoma patients resistant to standard therapy. In contrast to 13-cis- and all-trans-retinoic acids, 4-HPR does not induce tumor maturation, but is cytotoxic via apoptosis and necrosis.4,8,15 4-HPR does not act through retinoid receptors,18,19 although it may selectively activate nuclear retinoid receptors in some cell types.18,20 Specific mechanisms include de novo ceramide synthesis induction,16,21-23 generation of reactive oxygen species,16,24 angiogenesis inhibition,25-27 and increased natural-killer cell activity.28 4-HPR dietary supplementation inhibits mammary tumor formation29,30 and ras+ myc-induced prostate tumors in rats.31 Increased survival was seen in mice treated with 4-HPR with ovarian carcinoma and lymphoma (in combination with rituximab) xenografts.32,33 Fenretinide was originally utilized as a chemopreventative agent with doses up to 800 mg per day in adults,34-39 usually with once daily administration. A single phase II trial for breast cancer and melanoma showed no activity using 300 to 400 mg per day.40 Toxicity was minimal,35-37,40 limited mainly to nyctalopia correlated with plasma retinol levels below 100 ng/mL,34 and resolving with normalization of retinol levels after stopping fenretinide.41 Other toxicities included skin rash, pruritus, dryness of eyes/lips/skin, hepatic dysfunction, hypertriglyceridemia, hypercholesterolemia, myalgias, arthralgias, arthritis, headache, nausea, vomiting, diarrhea, and abdominal pain.35-37,40 Peak levels of 1 to 3 micromolar 4-HPR occur at approximately 6 hours42 in adults.41,43,44 The half-life (beta) is 13.7 hours.44 Blood levels remain constant over 5 years of administration.41 The main metabolite, N- (4-methoxyphenyl) retinamide (4-MPR), has peak levels at approximately 10 hours42 with a beta half-life of 23 hours.44 High fat meals significantly increase bioavailability.42 We hypothesized that with dose escalation, higher plasma levels comparable with those effective in vitro could be achieved and would have antitumor activity. Because 4-HPR is rapidly cytotoxic, an intermittent schedule (7 days of 4-HPR every 3 weeks) was chosen to minimize adverse effects. This rationale provided the basis for designing a phase I trial for recurrent/resistant pediatric solid tumors. Pharmacokinetic studies were done to determine if levels required for activity in vitro could be obtained.
Patients who were 21 years of age or younger when diagnosed with a malignant solid tumor with either recurrent or refractory disease or recurrent neuroblastoma treated with myeloablative therapy and autologous stem-cell transplantation with any disease status were eligible. Informed consent approved by a local human investigations committee was obtained. Specific disease sites were reviewed only in patients reporting a response or stable disease for eight courses or more. Normal organ function, absolute neutrophil count 750/µL or greater, and platelets 50,000/µL or higher were required. Hematologic criteria were waived for patients with marrow metastases. Postmenarchal females were required to have a negative serum beta-human chorionic gonadotropin and to utilize contraception. Fenretinide was provided by Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute as 100 mg gelatin capsules given orally as intact capsules for up to 30 courses in doses from 350 mg/m2 to 3,300 mg/m2 per day (Table 1). Neuroblastoma patients entering with no measurable/assessable tumor received a maximum of eight courses. Total daily dose was divided into two doses for levels one to four, and into three doses for levels five to nine due to the number of capsules. Softening capsules by soaking briefly in water was allowed. High-fat food was recommended with each dose to promote absorption.
Dose-limiting toxicity (DLT) was defined as grade 3 or 4 toxicity (National Cancer Institute Common Toxicity Criteria, version 2) excluding grade 3 nausea/vomiting, grade 3 hepatic toxicity resolving before next course, grade 3 fever, and nyctalopia. Dose escalation was performed using a standard 3 + 3 design.45 The maximum-tolerated dose (MTD) was defined as the maximum dose where at least five of six patients did not demonstrate DLT. During the first 3 years of accrual, a fourth patient was entered at a dose level if, when the fourth patient presented, evaluation of the first three patients was not complete but showed no DLT. Dose escalation proceeded if no more than one of these four patients had DLT. An ophthalmologic examination with visual acuity assessment was required at entry, then after every three courses. Disease evaluations were done at entry and after courses 2, 5, 8, 12, 16, 20, 24, and 30. Neuroblastoma responses were graded using the International Neuroblastoma Response Criteria.46 Radiographic scans and bone marrow slides were centrally reviewed for patients with improving or stable disease for eight or more courses, with documentation on two evaluations 4 or more weeks apart. Progression-free survival (PFS) was defined as time from enrollment to progression. Steady-state levels were obtained at course one (before the first dose on day 4, before morning dose, and 6 hours postdose on day 7); before morning dose on day one of courses 2, 5, and 9; and before morning dose on day 7 of courses four and eight. Fenretinide, 4-MPR, and retinol were measured using a modification of the assay of Formelli et al.43 Plasma proteins were precipitated by adding 900 µL ice-cold acetonitrile and 100 µL ice-cold saturated potassium phosphate to each 500 µL plasma sample. Retinol standard curve samples were prepared by adding known amounts of authentic compound to 500 µL of 5% serum albumin. The high-performance liquid chromatography separations were performed on a Phenomenex Luna C182 (100 mm x 4.6 mm internal diameter, 3 µ; Phenomenex, Torrance, CA) fitted with a Brownlee RP-18 precolumn (15 mm x 3.2 mm internal diameter, 7 µ; Perkin-Elmer, Wellesley, MA) eluted with a mobile phase composed of acetonitrile:water:glacial acetic acid (80:18:2). The flow rate, injection volume, and ultraviolet absorption wavelength were 0.9 mL/min, 50 µL, and 340 nm, respectively. Data current to April 2004 were used for this report.
Patient Characteristics Fifty-four patients were enrolled from April 1998 to January 2002 (Table 2).
Toxicity. Table 3 summarizes toxicities. Patients completed a median of five courses (range, 1 to 30). Fifty patients were assessable for dose-escalation purposes. Four patients were unassessable due to intracranial hemorrhage from tumor after single dose (600 mg/m2 per day); disease progression before completion of toxicity evaluation period (1,860 mg/m2 per day); drug administered dissolved in liquid (3,300 mg/m2 per day); or inability to swallow the prescribed capsules (3,300 mg/m2 per day).
DLTs are summarized in Table 1. The patient with DLT at 1,395 mg/m2 per day had a prior liver transplant, but entered with normal liver function. The patient with DLT at 1,860 mg/m2 per day had pre-existing hypoalbuminemia and hypophosphatemia. Alkaline phosphatase elevation on day 21/course two in one patient required dose reduction (after alkaline phosphatase normalized 20 days later), and did not recur during six additional courses. Fractionation of alkaline phosphatase revealed 58% bone/42% liver isoenzymes. In addition to DLT, one patient at 3,300 mg/m2 per day was unable to swallow the prescribed capsules. The MTD was 2,475 mg/m2 per day divided tid. Three patients with neuroblastoma (age 7 years, 8 years, and 11 years) had pseudotumor cerebri during course two (600 mg/m2 per day), course three (800 mg/m2 per day), and course one (3,300 mg/m2 per day). Fenretinide was restarted with dose reduction in one patient, with recurrence of pseudotumor, and the drug was stopped. All patients had elevated CSF opening pressure without papilledema. Head computed tomography or magnetic resonance imaging showed small epidural tumor masses, diffuse small low-density metastatic lesions throughout the skull, or several dural-based enhancing masses over the cerebral convexities respectively in the three patients. These lesions were not felt to cause elevated CSF pressure. Responses. At study entry, 35 of 39 neuroblastoma patients had either measurable or assessable tumor. Five of these 35 patients were unassessable for response. One patient was taken off study by parent choice before progression after one course; one patient received radiotherapy course seven to the single tumor site. The other three unassessable patients were taken off study for clinical progression after courses three, eight, and 11, but did not have consistent disease evaluations to document all tumor sites, and therefore the duration of tumor stabilization could not be confirmed. Four of 39 neuroblastoma patients had no measurable/assessable tumor, and received eight courses of fenretinide per protocol. All four patients relapsed (at 1 month, 2 months, 3 months, and 23 months off therapy). Overall, 30 neuroblastoma patients were considered assessable for response. Fourteen (47%) of 30 assessable neuroblastoma patients had a response or stable disease for 8 or more courses (Table 4). Sixteen patients progressed after a median of two courses (range, 1 to 4). Table 5 lists nonneuroblastoma responses.
The median PFS for the 35 patients with neuroblastoma who entered study with measurable or assessable tumor was 6 months (95% CI of true median PFS, 1.5 months to 12 months). No patients died before progression. The relative risk for progression in this same group for patients with bone marrow tumor at entry was 1.4 (95% CI, 0.68 to 4.4).
Pharmacokinetics
Steady-state peak and trough 4-MPR plasma concentrations paralleled those of 4-HPR. Substantial variability occurred in 6-hour concentration values at each dose level (Fig 1B; Table 6); peak and trough plasma concentrations correlated with dose. Increasing dose frequency from two to three times each day, with dose increase from 1,050 mg/m2 to only 1,395 mg/m2, resulted in two-fold increases in steady-state peak and trough 4-HPR and 4-MPR concentrations (Figs 1A and 1B; Table 6), suggesting increased drug bioavailability and/or drug accumulation at higher rates of administration. Mean retinol plasma concentrations before treatment with fenretinide were 3.05 µmol/L (range, 0.15 µmol/L to 9.07 µmol/L), and fell by a mean decrease of 95.5% (range, 83.8% to 100%) after 7 days of treatment (Fig 2). Retinol plasma concentrations increased to 69% (range, 0% to 147%) of initial values before course two, and 59% (range, 0% to 92%) of the initial value before course five (Fig 2).
PK studies on seven of eight patients with DLT, including three patients with pseudotumor cerebri, were not predictive of toxicity. Peak 4-HPR levels on day 1 in four patients with DLT were 1.72 to 10.84. Steady-state levels on day 7 in six patients with DLT were 2.15 to 8.91.
A phase I trial of fenretinide for recurrent solid tumors in adults utilizing the same schedule as our pediatric study47 at doses of 500 mg/m2 to 4,800 mg/m2 per day, reported toxicities including grade 1 to 2 abdominal cramping, dry skin, visual changes, nyctalopia, nausea, vomiting, diarrhea, and one instance of grade 3 hepatic dysfunction at 4,800 mg/m2 per day. No MTD was reached, however PKs data suggested an oral absorption plateau at 900 mg/m2 per dose, with similar systemic exposures after bid or tid dosing. Peak plasma levels on day 7 of therapy were 3 µmol/L to 5 µmol/L. The recommended phase II dose was 900 mg/m2 per day BID. Two minimal responses occurred in breast cancer (duration, 12 courses) and renal cell carcinoma (duration, nine courses). In contrast, clinical toxicity determined the MTD in our trial. However, overall toxicities were mild and rapidly reversible. The incidence of nyctalopia was lower than in adults, likely due to under-reporting by young children. Reversible retinol depletion was similar, with no other ophthalmologic toxicity. Gastrointestinal adverse effects were more prominent in patients consuming higher numbers of capsules. PKs were not predictive of toxicities. Only three children younger 4 years of age were entered, due to difficulty swallowing the capsules. Different formulations are needed to make this agent feasible for young children. Pseudotumor cerebri occurred in three (6%) of 54 patients at three different dose levels, suggesting it may not be dose related. This toxicity was not observed in the phase I and III studies of 13-cis-retinoic acid in children,48,49 but was reported in pediatric studies of all-trans-retinoic acid50 and 9-cis-retinoic acid.51 The etiology of pseudotumor cerebri related to retinoids is unknown. Vitamin A deficiency can be associated with structural changes in arachnoid villi in calves,52 but retinoid effects have not been described. Pseudotumor cerebri is more common in patients younger than 9 years to 12 years of age for trans- and 9-cis-retinoic acid.50,51 Our patients were 7 years, 8 years, and 11 years of age. No cases occurred in adult trials with fenretinide47 or other retinoids.35-37,40,53 The low incidence and reversible nature suggest that pseudotumor cerebri should not limit 4-HPR use in children. A phase I study of fenretinide administered once daily for 28 days using 100 to 4,000 mg/m2 per day, followed by a 7-day rest for up to six courses in children with neuroblastoma has been reported.54 Toxicity was not dose limiting, and included cutaneous adverse effects, nyctalopia, and one patient who had abnormal transaminases (at 4,000 mg/m2 per day). There were no cases of pseudotumor cerebri. Dose escalation was stopped because of poor compliance with the number of capsules. This schedule achieved peak levels of 10 µmol/L. In contrast to our trial, toxicities were associated with higher peak 4-HPR plasma levels, suggesting the increased toxicity in our trial may be due to higher levels of 4-HPR systemic exposure with multiple daily doses. In this study, 10 µmol/L 4-HPR plasma levels were achieved without significant toxicity. Ten micromolar levels of 4-HPR have activity in vitro against neuroblastoma cell lines in 20% oxygen, however, significant activity in 2% to 4% oxygen (levels in tumor tissue and bone marrow) requires higher 4-HPR concentrations, and/or addition of a ceramide modulator.3,16,21 The significant variation in steady-state levels and area under the time-concentration curve may be due to variable dietary fat consumption affecting fenretinide absorption.42 The gelatin capsule formulation may contribute to poorer absorption, especially with larger numbers of capsules. PKs data suggests a drug absorption plateau above 1,860 mg/m2 per day, similar to adult data.47 Steady-state trough concentrations of fenretinide and 4-MPR were achieved by day 4 and maintained through day 7. Increasing dose frequency from two to three times daily had a greater effect on steady-state plasma concentration than increasing dose, consistent with increased drug accumulation and/or bioavailability with more frequent administration. Retinoids are primarily delivered to tissues via retinol binding protein (RBP),55 which has a carrying capacity of 3 micromolar to 5 micromolar. The retinol-RBP complex is bound to transthyretin.55 Fenretinide is reported to bind to a 20 kd plasma protein (probably RBP),19 but the fenretinide-RBP complex has poor affinity for transthyretin,56 resulting in lower plasma concentrations of RBP, possibly due to increased renal clearance. Lower plasma RBP has been observed after fenretinide.44 RBP effects on antitumor activity, whether fenretinide can be delivered to tumor cells as free drug, and whether additional protein or lipid binding in plasma occurs with fenretinide are unknown. The Garaventa pediatric phase I trial of 4-HPR54 reported no complete or partial responses; however, stable disease for 6 months or longer was seen in 19 (39%) of 49 neuroblastoma patients, including those in first partial response. The majority of patients entered in our study had neuroblastoma. In contrast to expectations from in vitro data, no mass disease responses occurred. A single complete response was observed in bone scan abnormalities after course eight. Another patient had resolution of iodine 131I metaiodobenzylguamidine scan (MIBG) uptake in bone lesions after course seven with a single focus of tumor in the bone marrow at the same timepoint and marrow progression after 16 courses. Twelve additional patients had prolonged stable disease (median, 18 courses), with one patient remaining stable on compassionate fenretinide 6 years after completing 30 courses on study. Among those patients with stable disease (Table 4), responses were noted at individual disease sites after a median of eight courses (range, 2 to 24), including clearance of bone marrow, improvement or resolution of MIBG uptake, and catecholamine normalization. Two patients with large persistent abdominal masses had stable disease for 30 courses. Insufficient patients were entered with other diagnoses to determine response. However, one of five patients with Ewing sarcoma had stable disease for 30 courses, with gradual resolution of magnetic resonance imaging scan bone abnormalities at the site of a prior pelvic relapse. One patient with melanoma completed 26 courses with stable lung metastases before progression. This response data, within the context of a phase I trial, suggests that the dose and schedule of the capsular fenretinide used in this trial does not have cytotoxic activity. The majority of responses consisted of stabilization of tumor. However, given the minimal toxicity, the disease stabilization observed in these poor prognosis neuroblastoma patients is encouraging. A randomized phase III study would be required to determine if fenretinide affects event-free survival. A novel intravenous formulation57 and a powder formulation delivered in a liquid suspension58 are now beginning pediatric trials in the New Approaches to Neuroblastoma Therapy consortium (www.nant.org) and may achieve higher and more consistent plasma levels by circumventing limitations in gastrointestinal absorption. Antineuroblastoma activity of 4-HPR in hypoxic preclinical models required drug levels tolerated by patients, but higher than levels achieved in the majority of patients in this phase I study.3,16 Formulations feasible in young children are essential to future neuroblastoma trials because the majority of patients are younger than 5 years of age at diagnosis. We conclude that the MTD of oral capsular fenretinide given three times daily is 2,475 mg/m2 per day in children with solid tumors, and achieves plasma levels active in vitro with minimal toxicity. A recently completed, phase II Children's Oncology Group trial for recurrent/resistant high-risk neuroblastoma (ANBL0321) will determine the activity of oral (capsular) 4-HPR in patients with and without mass disease. Additional studies are needed to define fenretinide activity against neuroblastoma and other cancers, utilizing novel fenretinide formulations with increased bioavailability.
The authors indicated no potential conflicts of interest.
Supported by the Neil Bogart Memorial Laboratories of the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research, the Whitier Foundation via the University of Southern California Norris Comprehensive Cancer Center, and National Cancer Institute Grants No. CA81403, U10 CA13539, U01 CA57746, and U01 CA97452. Presented at the 38th Annual Meeting of the American Society of Clinical Oncology in Orlando, FL, May 18-21, 2002. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
INTRODUCTION
) or three (
) doses.
