Advertisement

Investigational New Drugs

, Volume 25, Issue 3, pp 217–225 | Cite as

A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours

  • Tara BaetzEmail author
  • Elizabeth Eisenhauer
  • Lillian Siu
  • Martha MacLean
  • Karen Doppler
  • Wendy Walsh
  • Bryn Fisher
  • Azhar Z. Khan
  • Dinesh P. de Alwis
  • A. Weitzman
  • Leslie H. Brail
  • Malcolm Moore
Phase I Studies

Summary

Background: LY293111 is an oral agent known to be a leukotriene B4 (LTB4) receptor antagonist and a 5-lipoxygenase inhibitor resulting in selective inhibition of the lipoxygenase pathway. Lipoxygenases metabolize arachidonic acid and have been involved in cancer cell proliferation and survival. In addition, LY293111 has been found to be a peroxisome proliferator activated receptor-gamma (PPAR-γ) agonist. Antineoplastic activity of LY293111 has been identified in preclinical models both alone and in combination with chemotherapy agents including irinotecan. The NCIC Clinical Trials Group studied LY293111 in combination with irinotecan to determine the recommended dose of the combination and to describe its tolerability and pharmacokinetic interaction. In addition the anti-tumour activity of LY293111 in combination with irinotecan was documented.

Patients and methods: Twenty-eight patients with advanced solid tumours were treated on seven dose levels with the combination of irinotecan and LY293111. Irinotecan was administered intravenously every 21-days as a single dose. LY293111 was administered twice daily continuously by mouth.

Results: Dose limiting toxicity (DLT) of grade 3 diarrhea was seen in two patients with doses of irinotecan 300 mg/m2 IV every 21-days in combination with LY293111 300 mg BID. Subsequently the dose of irinotecan was decreased to 250 mg/m2 IV every 21-days with escalating doses of LY293111. A DLT of grade 3 abdominal pain was seen at dose 600 mg BID of LY293111 with irinotecan 250 mg/m2. The pharmacokinetics (PK) indicated that the administration of LY293111 did not have an effect on the PK of irinotecan or its metabolite SN-38. No responses were seen; seven patients had stable disease of a median duration of 4.4 months (range 2.8–13 months).

Conclusion: The recommended phase II dose of LY293111 is 600 mg orally BID in combination with irinotecan 250 mg/m2 IV every 21-days. Gastrointestinal adverse effects were common but could be well managed.

Keywords

Clinical trial LY293111 Irinotecan Phase I 

References

  1. 1.
    Tang DG, Chen YQ, Honn KV (1996) Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc Natl Acad Sci USA 93:5241–5246PubMedCrossRefGoogle Scholar
  2. 2.
    Crooks SW, Stockley RA (1998) Leukotriene B4. Int J Biochem Cell Biol 30(2):173–178PubMedCrossRefGoogle Scholar
  3. 3.
    Hagmann W (1997) Lipoxygenase in human tumor cells. Pathol Oncol Res 3(2):83–88PubMedGoogle Scholar
  4. 4.
    Reich R, Martin GR (1996) Identification of arachidonic acid pathways required for the invasive and metastatic activity of malignant tumor cells. Prostaglandins 51(1):1–17PubMedCrossRefGoogle Scholar
  5. 5.
    Bortuzzo C, Hanif R, Kashfi K, Staiano-Coico L, Shiff SJ, Rigas B (1996) The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. Biochim Biophys Acta 1300(3):240–246PubMedGoogle Scholar
  6. 6.
    Mann EL, Spiro JD, Chen LL, Kreutzer DL (1994) Phospholipid metabolite expression by head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 120(7):763–769PubMedGoogle Scholar
  7. 7.
    Jackson, WT, Froelich LL, Boyd RJ, Schrementi JP, Saussy DL, Schultz RM, Sawyer JS, Sofia MJ, Herron DK, Goodson T, Snyder DW, Pechous PA, Spaethe SM, Roman CR, Fleisch JH (1999) Pharmacologic actions of the second-generation Leukotriene B4 Receptor Antagonist LY293111: in vitro studies. J Pharmacol Exp Ther 288(1):286–294PubMedGoogle Scholar
  8. 8.
    Mommers JM, Van Tossum MM, Kooijmans-Otero ME, Parker FL, van de Kerkhof PC (2000) VML 295(LY-293111), a novel LTB4 antagonist, is not effective in the prevention of relapse in psoriasis. Br J Dermatol 142(2):259–266PubMedCrossRefGoogle Scholar
  9. 9.
    Evans DJ, Barnes PJ, Spaethe SM, van Alstyne EL, Mitchell MI, O’Connor BJ (1996) Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax 51(12):1178–1173PubMedCrossRefGoogle Scholar
  10. 10.
    Marshall M, Diaz HB, Brozinick J et al (2002) LY293111 inhibits tumor cell growth in vitro through an apparent PPARγ agonist activity. Proc Amer Assoc Cancer Res 43:957 (abstract 4741)Google Scholar
  11. 11.
    Vamecq J, Latruffe N (1999) Medical significance of peroxisome proliferator-activated receptors. Lancet 354:141–148PubMedCrossRefGoogle Scholar
  12. 12.
    Koeffler HP (2003) Peroxisome proliferators-activated receptor γ and cancers. Clin Can Res 9:1–9Google Scholar
  13. 13.
    Hennig R, Ding X, Tong W, Witt RC, Jovanovic BD, Adrian TE (2004) Effect of LY293111 in combination with gemcitabine in colonic cancer. Cancer Letters 210:41–46PubMedCrossRefGoogle Scholar
  14. 14.
    Ding X, Talamonti M, Bell R Jr, Adrian TE (2005) A novel anti-pancreatic cancer agent, LY293111. Anticancer Drugs 16(5):467–473PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang W, McQueen T, Schober W, Rassidakis G, Andreeff, M, Konopleva M (2005) Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation. Leukemia 19:1977–1984PubMedCrossRefGoogle Scholar
  16. 16.
    Tong W-G, Ding X-Z, Hennig R, Witt RC, Standop J, Pour PM, Adrian TE (2002) Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cell. Clin Cancer Res 8:3232–3242PubMedGoogle Scholar
  17. 17.
    Schwartz GK, Weitzman A, O’Reilly E, Brail L, de Alwis DP, Cleverly A, Barile-Thiem B, Vinciguerra V, Budman DR (2005) Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors. J Clin Oncol 23(23):5365–5373PubMedCrossRefGoogle Scholar
  18. 18.
    Rosen LS (1998) Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Oncology suppl 6:103–109Google Scholar
  19. 19.
    Budman DR, Calabro A (2004) Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eicosanoid pathway modulator LY 293111. Anti-Cancer Drugs 15(9):877–881PubMedCrossRefGoogle Scholar
  20. 20.
    Armand JP, Extra YM, Catimel G, Abigerges D, Marty M, Clavel M (1996) Rationale for the dosage and schedule of CPT-11(irinotecan) selected for phase II studies, as determined by European phase I studies. Ann Oncol 7(8):837–842PubMedGoogle Scholar
  21. 21.
    Therasse P, Arbuck SG, Eisenhauer EA, Wander J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors (RECIST guidelines). J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  22. 22.
    Abigerges D, Chabot GG, Armand J-P, Herait P, Gouyette A, Gandia D (1995) Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13(1):210–221.PubMedGoogle Scholar
  23. 23.
    Pitot HC, Goldberg RM, Reid JM, Sloan JA, Skaff PA, Erlichman C, Rubin J, Burch PA, Adjei AA, Albers SA, Schaaf LJ, Elfring G, Miller LL (2000) Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy. Clin Cancer Res 6(6):2236–2244PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Tara Baetz
    • 1
    Email author
  • Elizabeth Eisenhauer
    • 2
  • Lillian Siu
    • 3
  • Martha MacLean
    • 3
  • Karen Doppler
    • 1
  • Wendy Walsh
    • 2
  • Bryn Fisher
    • 2
  • Azhar Z. Khan
    • 4
  • Dinesh P. de Alwis
    • 4
  • A. Weitzman
    • 5
  • Leslie H. Brail
    • 5
  • Malcolm Moore
    • 3
  1. 1.Cancer Centre of Southeastern OntarioKingstonCanada
  2. 2.National Cancer Institute of CanadaClinical Trials GroupKingstonCanada
  3. 3.Princess Margaret Hospital610 University Ave.TorontoCanada
  4. 4.Eli Lilly & Company LimitedSurreyUK
  5. 5.Lilly Research LaboratoriesIndianapolisUSA

Personalised recommendations