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Investigational New Drugs

, Volume 27, Issue 6, pp 571–578 | Cite as

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

  • Bryan J. SchneiderEmail author
  • Francis P. Worden
  • Shirish M. Gadgeel
  • Ralph E. Parchment
  • Collette M. Hodges
  • James Zwiebel
  • Rodney L. Dunn
  • Antoinette J. Wozniak
  • Michael J. Kraut
  • Gregory P. Kalemkerian
PHASE II STUDIES

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.

Keywords

Fenretinide 4-HPR Small cell lung cancer Relapsed 

Notes

Acknowledgment

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

References

  1. 1.
    Jemal A, Murray T, Siegel R et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96 doi: 10.3322/CA.2007.0010 CrossRefPubMedGoogle Scholar
  2. 2.
    Murray N, Erridge S, Turrisi AT (2005) Multimodality therapy for limited stage small cell lung cancer: combination chemotherapy and thoracic irradiation. In: Pass HI, Carbone DP, Johnson DH, Minna JD, Turrisi AT (eds) Lung cancer: principles and practice. Lippincott Williams & Wilkins, Philadelphia, pp 674–691Google Scholar
  3. 3.
    Spira A, Ettinger DS (2004) Multidisciplinary management of lung cancer. N Engl J Med 350:379–392 doi: 10.1056/NEJMra035536 CrossRefPubMedGoogle Scholar
  4. 4.
    Chute JP, Chen T, Feigal E et al (1999) Twenty years of phase III trial for patients with extensive-stage small cell lung cancer: perceptible progress. J Clin Oncol 17:1794–1801PubMedGoogle Scholar
  5. 5.
    Schneider BJ (2008) Management of recurrent small cell lung cancer. JNCCN 6:323–331PubMedGoogle Scholar
  6. 6.
    Lippman SM, Kessler JF, Meyskens FL (1987) Retinoids as preventive and therapeutic anticancer agents (part I). Cancer Treat Rep 71:391–405PubMedGoogle Scholar
  7. 7.
    Nervi C, Vollberg TM, George MD et al (1991) Expression of nuclear retinoic acid receptors in normal tracheobronchial cells and in lung carcinoma cells. Exp Cell Res 195:163–170 doi: 10.1016/0014-4827(91)90512-S CrossRefPubMedGoogle Scholar
  8. 8.
    Gebert JF, Moghal N, Frangioni JV et al (1991) High frequency of retinoid acid receptor beta abnormalities in human lung cancer. Oncogene 6:1859–1868PubMedGoogle Scholar
  9. 9.
    Geradts J, Chen JY, Russell EK et al (1993) Human lung cancer cell lines exhibit resistance to retinoic acid treatment. Cell Growth Differ 4:799–809PubMedGoogle Scholar
  10. 10.
    Kim YH, Dohi DF, Han GR et al (1995) Retinoid refractoriness occurs during lung carcinogenesis despite functional retinoid receptors. Cancer Res 55:5603–5610PubMedGoogle Scholar
  11. 11.
    Naik HR, Kalemkerian G, Pienta KJ (1995) 4-Hydroxyphenylretinamide in the chemoprevention of cancer. Adv Pharmacol 33:315–347 doi: 10.1016/S1054-3589(08)60673-0 CrossRefPubMedGoogle Scholar
  12. 12.
    Delia D, Aiello A, Lombardi L et al (1993) N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hematopoietic cell lines including those unresponsive to retinoid acid. Cancer Res 53:6063–6041Google Scholar
  13. 13.
    Mariotti A, Marcora E, Bunone G et al (1994) N-(4-hydroxyphenyl)retinamide: a potent inducer of apoptosis in human neuroblastoma cells. J Natl Cancer Inst 86:1245–1247 doi: 10.1093/jnci/86.16.1245 CrossRefPubMedGoogle Scholar
  14. 14.
    Oridate N, Lotan D, Mitchell MF et al (1995) Induction of apoptosis by retinoids in human cervical cell lines. Int J Oncol 7:433–441Google Scholar
  15. 15.
    Hail N, Kim HJ, Lotan R (2006) Mechanisms of fenretinide-induced apoptosis. Apoptosis 11:1677–1694 doi: 10.1007/s10495-006-9289-3 CrossRefPubMedGoogle Scholar
  16. 16.
    Kalemkerian GP, Slucher R, Ramalingam S et al (1995) Growth inhibition and induction of apoptosis by fenretinide in small cell lung cancer cell lines. J Natl Cancer Inst 87:1674–1680 doi: 10.1093/jnci/87.22.1674 CrossRefPubMedGoogle Scholar
  17. 17.
    Zou CP, Kurie JM, Lotan D et al (1998) Higher potency of N-(4-hydroxyphenyl) retinamide than all-trans-retinoic acid in induction of apoptosis in non-small cell lung cancer cell lines. Clin Cancer Res 4:1345–1355PubMedGoogle Scholar
  18. 18.
    Camerini T, Mariani L, De Palo G et al (2001) Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 19:1664–1670PubMedGoogle Scholar
  19. 19.
    Formelli F, Clerici M, Campa T et al (1993) Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations. J Clin Oncol 11:2036–2042PubMedGoogle Scholar
  20. 20.
    Marth C, Bock G, Daxenbichler G (1985) Effect of 4-hydroxyphenylretinamide and retinoic acid on proliferation and cell cycle of cultured human breast cancer cells. J Natl Cancer Inst 75:871–875PubMedGoogle Scholar
  21. 21.
    Oridate N, Lotan D, Mitchell MF et al (1995) Inhibition of proliferation and induction of apoptosis in cervical carcinoma cells by retinoids: implications for chemoprevention. J Cell Biochem Suppl 23:80–86 doi: 10.1002/jcb.240590911 CrossRefPubMedGoogle Scholar
  22. 22.
    Mariotti A, Marcora E, Bunone G et al (1994) N-(4-hydroxyphenyl)retinamide: a potent inducer of apoptosis in human neuroblastoma cells. J Natl Cancer Inst 86:1245–1247 doi: 10.1093/jnci/86.16.1245 CrossRefPubMedGoogle Scholar
  23. 23.
    Vaishampayan U, Heilbrun LK, Parchment RE et al (2005) Phase II trial of fenretinide in advanced renal carcinoma. Invest New Drugs 23:179–185 doi: 10.1007/s10637-005-5864-7 CrossRefPubMedGoogle Scholar
  24. 24.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216 doi: 10.1093/jnci/92.3.205 CrossRefPubMedGoogle Scholar
  25. 25.
    Formelli F, Carsana R, Costa A et al (1989) Plasma retinol level reduction by the synthetic retinoid fenretinide: a one year follow-up study of breast cancer patients. Cancer Res 49:6149–6152PubMedGoogle Scholar
  26. 26.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10 doi: 10.1016/0197-2456(89)90015-9 CrossRefPubMedGoogle Scholar
  27. 27.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481 doi: 10.2307/2281868 CrossRefGoogle Scholar
  28. 28.
    von Pawel J, Schiller JH, Shepherd FA et al (1999) Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658–667Google Scholar
  29. 29.
    Dmitrovsky E (2004) Fenretinide activates a distinct apoptotic pathway. J Natl Cancer Inst 96:1264–1265PubMedCrossRefGoogle Scholar
  30. 30.
    O’Donnell PH, Guo WX, Reynolds CP et al (2002) 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 doi: 10.1038/sj.leu.2402485 CrossRefPubMedGoogle Scholar
  31. 31.
    Erdreich-Epstein A, Tran LB, Bowman NN et al (2002) Ceramide signaling in fenretinide-induced endothelial cell apoptosis. J Biol Chem 277:49531–49537 doi: 10.1074/jbc.M209962200 CrossRefPubMedGoogle Scholar
  32. 32.
    Sun SY, Li W, Yue P (1999) Mediation of N-(4-hydroxyphenyl) retinamide-induced apoptosis in human cancer cells by different mechanisms. Cancer Res 59:2493–2498PubMedGoogle Scholar
  33. 33.
    Sabichi AL, Xu H, Fischer S et al (2003) Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites. Clin Cancer Res 9:4606–4613PubMedGoogle Scholar
  34. 34.
    Colombo N, Formelli F, Cantu MG et al (2006) A phase I–II preoperative biomarker trial of fenretinide in ascitic ovarian cancer. Cancer Epidemiol Biomark Prev 15:1914–1919 doi: 10.1158/1055-9965.EPI-06-0183 CrossRefGoogle Scholar
  35. 35.
    Puduvalli VK, Yung WKA, Hess KR et al (2004) Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: a North American Brain Tumor Consortium study. J Clin Oncol 22:4282–4289 doi: 10.1200/JCO.2004.09.096 CrossRefPubMedGoogle Scholar
  36. 36.
    Garaventa A, Luksch R, Lo Piccolo MS et al (2003) Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma. Clin Cancer Res 9:2032–2039PubMedGoogle Scholar
  37. 37.
    Kalemkerian GP, Ou X (1999) Activity of fenretinide plus chemotherapeutic agents in small-cell lung cancer cell lines. Cancer Chemother Pharmacol 43:145–150 doi: 10.1007/s002800050875 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Bryan J. Schneider
    • 1
    Email author
  • Francis P. Worden
    • 2
  • Shirish M. Gadgeel
    • 3
  • Ralph E. Parchment
    • 4
    • 7
  • Collette M. Hodges
    • 2
  • James Zwiebel
    • 4
    • 8
  • Rodney L. Dunn
    • 5
  • Antoinette J. Wozniak
    • 3
  • Michael J. Kraut
    • 6
  • Gregory P. Kalemkerian
    • 9
  1. 1.Division of Hematology/Oncology, Department of Internal MedicineWeill Cornell Medical CollegeNew YorkUSA
  2. 2.Division of Hematology/Oncology, Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  3. 3.Division of Hematology and OncologyKarmanos Cancer InstituteDetroitUSA
  4. 4.Cancer Therapy Evaluation ProgramNational Cancer InstituteRockvilleUSA
  5. 5.Biostatistics Core Facility, Department of UrologyUniversity of Michigan Cancer CenterAnn ArborUSA
  6. 6.Providence Cancer InstituteSouthfieldUSA
  7. 7.Lab of Human Toxicology PharmacologyNCI-FrederickFrederickUSA
  8. 8.National Cancer InstituteBethesdaUSA
  9. 9.Division of Hematology/Oncology, Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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