Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 5, pp 875–880 | Cite as

Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer

  • Geoffrey Y. Ku
  • David H. Ilson
  • Lawrence H. Schwartz
  • Marinela Capanu
  • Eileen O’Reilly
  • Manish A. Shah
  • David P. Kelsen
  • Gary K. Schwartz
Original Article



We sought to determine the response rate and toxicity profile of sequential paclitaxel and bryostatin-1, a novel, selective inhibitor of protein kinase C, in patients with advanced esophageal cancer.

Patients and methods

Patients with advanced esophageal and gastroesophageal junction cancer were enrolled. All gave informed consent. They were initially treated with paclitaxel 90 mg/m2 intravenously on Day 1 and bryostatin-1 50 μg/m2 on Day 2 weekly for three consecutive weeks out of four. Because of severe myalgias, dosing was reduced to paclitaxel 80 mg/m2 with bryostatin-1 40 μg/m2 and then to paclitaxel 80 mg/m2 with bryostatin-1 25 μg/m2.


Twenty-four patients were enrolled, with 22 assessable for response. The partial response rate was 27%. 10 patients treated with bryostatin-1 40–50 μg/m2 had a response rate of 40 versus 17% at bryostatin-1 25 μg/m2 (p-value = 0.3). Median time-to-progression was 3.7 months and median survival was 8.3 months. Grade 3/4 myalgias were seen in 50% of patients. Myalgias appeared to be related to bryostatin-1 dose. Because of toxicity, the trial was closed prior to full accrual.


Despite potential anti-tumor activity of this combination in patients with advanced esophageal cancer, further development is not warranted, given the severe toxicity, especially myalgias, that were seen.


Bryostatin-1 Esophageal cancer Gastroesophageal cancer Paclitaxel Protein kinase C 



Supported in part by FDA-R01-001826 from the Food and Drug Administration Orphan Drug Program (to GKS).


  1. 1.
    Ajani JA, Jiang Y, Faust J, Chang BB, Ho L, Yao JC, Rousey S, Dakhil S, Cherny RC, Craig C, Bleyer A (2006) A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest New Drugs 24:353–357PubMedCrossRefGoogle Scholar
  2. 2.
    Asiedu C, Biggs J, Lilly M, Kraft AS (1995) Inhibition of leukemic cell growth by the protein kinase C activator bryostatin 1 correlates with the dephosphorylation of cyclin-dependent kinase 2. Cancer Res 55:3716–3720PubMedGoogle Scholar
  3. 3.
    Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:2241–2252PubMedCrossRefGoogle Scholar
  4. 4.
    Evans DL, Dive C (1993) Effects of cisplatin on the induction of apoptosis in proliferating hepatoma cells and nonproliferating immature thymocytes. Cancer Res 53:2133–2139PubMedGoogle Scholar
  5. 5.
    Grant S, Jarvis WD, Swerdlow PS, Turner AJ, Traylor RS, Wallace HJ, Lin PS, Pettit GR, Gewirtz DA (1992) Potentiation of the activity of 1–beta-D-arabinofuranosylcytosine by the protein kinase C activator bryostatin 1 in HL–60 cells: association with enhanced fragmentation of mature DNA. Cancer Res 52:6270–6278PubMedGoogle Scholar
  6. 6.
    Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, Kolesnick RN (1994) Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 180:525–535PubMedCrossRefGoogle Scholar
  7. 7.
    Hennings H, Blumberg PM, Pettit GR, Herald CL, Shores R, Yuspa SH (1987) Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 8:1343–1346PubMedCrossRefGoogle Scholar
  8. 8.
    Hickman PF, Kemp GJ, Thompson CH, Salisbury AJ, Wade K, Harris AL, Radda GK (1995) Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study. Br J Cancer 72:998-1003PubMedGoogle Scholar
  9. 9.
    Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP (2007) Paclitaxel given by a weekly 1–h infusion in advanced esophageal cancer. Ann Oncol 18:898–902PubMedCrossRefGoogle Scholar
  10. 10.
    Jarvis WD, Fornari FA Jr., Browning JL, Gewirtz DA, Kolesnick RN, Grant S (1994) Attenuation of ceramide-induced apoptosis by diglyceride in human myeloid leukemia cells. J Biol Chem 269:31685–31692PubMedGoogle Scholar
  11. 11.
    Jarvis WD, Kolesnick RN, Fornari FA, Traylor RS, Gewirtz DA, Grant S (1994) Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci USA 91:73–77PubMedCrossRefGoogle Scholar
  12. 12.
    Kaubisch A, Kelsen D, Saltz L, Kemeny N, O’Reilly E, Ilson D, Endres S, Barazzuol J, Schwartz G (1999) A pase I trial of weekly sequential bryostatin-1 (BRYO) and paclitaxel in patients with advanced solid tumors. Proc Amer Soc Clin Onc 18:166a (Abstract 639)Google Scholar
  13. 13.
    Koutcher JA, Motwani M, Zakian KL, Li XK, Matei C, Dyke JP, Ballon D, Yoo HH, Schwartz GK (2000) The in vivo effect of bryostatin-1 on paclitaxel-induced tumor growth, mitotic entry, and blood flow. Clin Cancer Res 6:1498–1507PubMedGoogle Scholar
  14. 14.
    Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207-214PubMedCrossRefGoogle Scholar
  15. 15.
    Mohammad RM, al-Katib A, Pettit GR, Sensenbrenner LL (1994) Successful treatment of human Waldenstrom’s macroglobulinemia with combination biological and chemotherapy agents. Cancer Res 54:165–168PubMedGoogle Scholar
  16. 16.
    National Cancer Institute (1999) NCI, Common Toxicity Criteria, version 2.0,. BethesdaGoogle Scholar
  17. 17.
    Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1671PubMedCrossRefGoogle Scholar
  18. 18.
    Philip PA, Harris AL (1995) Potential for protein kinase C inhibitors in cancer therapy. Cancer Treat Res 78:3–27PubMedGoogle Scholar
  19. 19.
    Philip PA, Rea D, Thavasu P, Carmichael J, Stuart NS, Rockett H, Talbot DC, Ganesan T, Pettit GR, Balkwill F, et al. (1993) Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor alpha induction in vivo. The Cancer Research Campaign Phase I Committee. J Natl Cancer Inst 85:1812–1818PubMedCrossRefGoogle Scholar
  20. 20.
    Schwartz GK, Shah MA (2005) Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 23:9408–9421PubMedCrossRefGoogle Scholar
  21. 21.
    Schwartz LH, Colville JA, Ginsberg MS, Wang L, Mazumdar M, Kalaigian J, Hricak H, Ilson D, Schwartz GK (2006) Measuring tumor response and shape change on CT: esophageal cancer as a paradigm. Ann Oncol 17:1018–1023PubMedCrossRefGoogle Scholar
  22. 22.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10PubMedCrossRefGoogle Scholar
  23. 23.
    Thompson CH, Macaulay VM, O’Byrne KJ, Kemp GJ, Wilner SM, Talbot DC, Harris AL, Radda GK (1996) Modulation of bryostatin 1 muscle toxicity by nifedipine: effects on muscle metabolism and oxygen supply. Br J Cancer 73:1161–1165PubMedGoogle Scholar
  24. 24.
    Wender PA, Clarke MO, Horan JC (2005) Role of the A-ring of bryostatin analogues in PKC binding: synthesis and initial biological evaluation of new A-ring-modified bryologs. Org Lett 7:1995–1998PubMedCrossRefGoogle Scholar
  25. 25.
    Wender PA, Horan JC (2006) Synthesis and PKC binding of a new class of a-ring diversifiable bryostatin analogues utilizing a double asymmetric hydrogenation and cross-coupling strategy. Org Lett 8:4581–4584PubMedCrossRefGoogle Scholar
  26. 26.
    Wender PA, Horan JC, Verma VA (2006) Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs. Org Lett 8:5299–5302PubMedCrossRefGoogle Scholar
  27. 27.
    Wender PA, Verma VA (2006) Design, synthesis, and biological evaluation of a potent, PKC selective, B-ring analog of bryostatin. Org Lett 8:1893–1896PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Geoffrey Y. Ku
    • 1
  • David H. Ilson
    • 1
  • Lawrence H. Schwartz
    • 2
  • Marinela Capanu
    • 3
  • Eileen O’Reilly
    • 1
  • Manish A. Shah
    • 1
  • David P. Kelsen
    • 1
  • Gary K. Schwartz
    • 1
  1. 1.Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of Biostatistics and EpidemiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations