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

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Summary

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/m2 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 μM; 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.

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Acknowledgment

We are grateful to Dr. Mary Varterasian for critical review of the manuscript.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, 525 East 68th Street, J-321, New York, NY, 10021, USA

    Bryan J. Schneider

  2. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, C361 Med Inn, P.O. Box 5848, Ann Arbor, MI, 48109, USA

    Francis P. Worden & Collette M. Hodges

  3. Division of Hematology and Oncology, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA

    Shirish M. Gadgeel & Antoinette J. Wozniak

  4. Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA

    Ralph E. Parchment & James Zwiebel

  5. Biostatistics Core Facility, Department of Urology, University of Michigan Cancer Center, 300 N. Ingalls, 8D15, Ann Arbor, MI, 48109-0473, USA

    Rodney L. Dunn

  6. Providence Cancer Institute, 22301 Foster Winter Drive, Southfield, MI, 48075, USA

    Michael J. Kraut

  7. Lab of Human Toxicology Pharmacology, NCI-Frederick, P.O. Box B, Building 431 Room 104, Frederick, MD, 21702-1201, USA

    Ralph E. Parchment

  8. National Cancer Institute, 6130 Executive Blvd, Ste 7131, Bethesda, MD, 20892-7426, USA

    James Zwiebel

  9. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, C350 Med Inn, P.O. Box 5848, Ann Arbor, MI, 48109-5848, USA

    Gregory P. Kalemkerian

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  1. Bryan J. Schneider
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Correspondence to Bryan J. Schneider.

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Schneider, B.J., Worden, F.P., Gadgeel, S.M. et al. Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer. Invest New Drugs 27, 571–578 (2009). https://doi.org/10.1007/s10637-009-9228-6

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  • DOI: https://doi.org/10.1007/s10637-009-9228-6

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