Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 3, pp 503–509 | Cite as

A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination

  • Ramesh K. RamanathanEmail author
  • James Abbruzzese
  • Tomislav Dragovich
  • Lynn Kirkpatrick
  • Jose M. Guillen
  • Amanda F. Baker
  • Linda A. Pestano
  • Sylvan Green
  • Daniel D. Von Hoff
Original Article

Abstract

Purpose

This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC).

Methods

PX-12 (54 or 128 mg/m2) was administered by 3-hour IV infusion daily ×5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m2 and then stratified based on CA 19-9 level (≥1,000 vs. <1,000 U/ml) and SUV values on PET scans (≥7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (>18 ng/ml) as an entry criteria after the first 17 patients were accrued.

Results

Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m2 arm. Therapy was well tolerated, and Grade ≥3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5–1.2) and 3.2 months (95% CI 2.4–4.2), respectively.

Conclusions

Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

Keywords

PX-12 Thioredoxin Pancreatic cancer Phase II Second-line therapy 

Notes

Acknowledgments

The authors thank Nina Cantafio for editorial assistance. Dr. Sylvan Green (deceased) for statistical assistance in designing this study. Alton Hiscox, Michael Boice at Prolx Pharmaceuticals for ELISA analysis. Michele Avery for secretarial analysis. Supported in part by grants from NCI: P01 CA109552, R44CA075923 and ProlX Pharmaceuticals. Study identifier: NCT00177242.

References

  1. 1.
    Parkin DM, Bray F, Ferlay J et al (2005) Global Cancer Statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMedGoogle Scholar
  2. 2.
    Rivera F, Lopez-Tarruella S, Vega-Villegas ME et al (2009) Treatment of advanced pancreatic cancer: from gemcitabine single agent to combinations and targeted therapy. Cancer Treat Rev 35:335–339CrossRefPubMedGoogle Scholar
  3. 3.
    Rocha-Lima CM (2008) New directions in the management of advanced pancreatic cancer: a review. Anticancer Drugs 19:435–446CrossRefPubMedGoogle Scholar
  4. 4.
    Hilbig A, Oettle H (2008) Gemcitabine in the treatment of metastatic pancreatic cancer. Expert Rev Anticancer Ther 8:511–523CrossRefPubMedGoogle Scholar
  5. 5.
    Sultana A, Smith CT, Cunningham D et al (2007) Meta-analysis of chemotherapy. J Clin Oncol 25:2607–2615CrossRefPubMedGoogle Scholar
  6. 6.
    Almhanna K, Kim R (2008) Second-line therapy for gemcitabine-refractory pancreatic cancer: is there a standard? Oncology 22:1176–1196PubMedGoogle Scholar
  7. 7.
    Pelzer U, Kubica K, Stieler J et al. (2008) A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. J Clin Oncol 26 (May 20 suppl; abstr 4508)Google Scholar
  8. 8.
    Brell JM, Matin K, Evans T (2009) Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology 76:270–274CrossRefPubMedGoogle Scholar
  9. 9.
    Powis G, Kirkpatrick DL (2007) Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol 7:392–397CrossRefPubMedGoogle Scholar
  10. 10.
    Kontou M, Will RD, Adelfalk C et al (2004) Thioredoxin, a regulator of gene expression. Oncogene 23:2146–2152CrossRefPubMedGoogle Scholar
  11. 11.
    Grogan T, Fenoglio-Priser C, Zaheb R et al (2000) Overexpression of thioredoxin, a putative oncogene, in gastric carcinoma with associated change in proliferation and apoptosis. J Pathol 31:475–481Google Scholar
  12. 12.
    Nakamura H, Bai J, Nishinaka Y et al (2000) Expression of thioredoxin and glutaredoxin, redox-regulating proteins, in pancreatic cancer. Cancer Detect Prev 24:53–60PubMedGoogle Scholar
  13. 13.
    Seo Y, Baba H, Fukuda T et al (2000) High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88:2239–2245CrossRefPubMedGoogle Scholar
  14. 14.
    Raffel J, Bhattacharyya AK, Cui H et al (2003) Increased expression of thioredoxin-1 in human colorectal cancer is associated with decreased patient survival. J Lab Clin Med 142:46–51CrossRefPubMedGoogle Scholar
  15. 15.
    Kirkpatrick DL, Hiscox A, Boice M, et al. (2008) Screening plasma thioredoxin (Trx-1) to potentially guide clinical development of the Trx-1 inhibitor PX-12. EORTC-NCI-AACR symposium on “Molecular targets and cancer therapeutics”, Geneva, Switzerland, Abstract #108Google Scholar
  16. 16.
    Welsh S, Bellamy WT, Briehl MM et al (2002) The recox protein thioredoxin-1 is necessary for the hypoxia dependent increase in HIF-1a and results in increased vascular endothelial growth factor formation by cancer cells and enhanced tumor angiogenesis. Cancer Res 62:5089–5095PubMedGoogle Scholar
  17. 17.
    Semenza Gl (2000) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 35:71–103CrossRefPubMedGoogle Scholar
  18. 18.
    Kirkpatrick D, Kuperus M, Dowdeswell M et al (1998) Mechanism of inhibition of the thioredoxin growth factor system by antitumor 2-imidazolyl disulfides. Biochem Pharmacol 55:987–994CrossRefPubMedGoogle Scholar
  19. 19.
    Ramanathan RK, Kirkpatrick DL, Belani CP et al (2007) A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. Clin Cancer Res 13:2109–2114CrossRefPubMedGoogle Scholar
  20. 20.
    Von Hoff DD, Korn R, Mousses S (2009) Pancreatic cancer—could it be that simple? A different context of vulnerability. Cancer Cell 16:7–8CrossRefGoogle Scholar
  21. 21.
    Komar G, Kauhanen S, Liukko K et al (2009) Decreased blood flow with increased metabolic activity: a novel sign of pancreatic cancer tumor aggressiveness. Clin Cancer Res 15:5511–5517CrossRefPubMedGoogle Scholar
  22. 22.
    Young H, Baum R, Cremerius U et al (1999) Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. EORTC Pet Study Group. Eur J Cancer 35:1773–1782CrossRefPubMedGoogle Scholar
  23. 23.
    Von Hoff DD, Ramanathan RK, Borad M et al (2009) SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: A phase I/II study. J Clin Oncol 27:15s (suppl; abstr 4525)Google Scholar
  24. 24.
    Hess V, Glimelius B, Grawe P et al (2008) CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomized controlled trial. Lancet Oncol 9:132–138CrossRefPubMedGoogle Scholar
  25. 25.
    Nakai Y, Kawabe T, Isayama H et al (2008) CA 19-9 response as an early indicator of the effectiveness of gemcitabine in patients with advanced pancreatic cancer. Oncology 75:120–126CrossRefPubMedGoogle Scholar
  26. 26.
    Ramanathan RK, Dragovich T, Richards D et al (2009) Results from phase Ib studies of PX-12, a thioredoxin inhibitor in patients with advanced solid malignancies. J Clin Oncol 27:15s (suppl; abstr 2571)Google Scholar
  27. 27.
    Callister ME, Burke‐Gaffney A, Quinlan GJ et al (2006) Extracellular thioredoxin levels are increased in patients with acute lung injury. Thorax 61:521–527CrossRefPubMedGoogle Scholar
  28. 28.
    Abdiu A, Nakamura H, Sahaf B et al (2000) Thioreodxoin blood level increases after servere burn injury. Antioxid Redox Signal 2:707–716CrossRefPubMedGoogle Scholar
  29. 29.
    Leaver SK, MacCallum NS, Pingle V et al (2010) Increased plasma thioredoxin levels in patients with sepsis: positive association with macrophage migration inhibitory factor. Instensive Care Med 36:336–341CrossRefGoogle Scholar
  30. 30.
    Jikimoto T, Nishikubo Y, Koshiba M et al (2002) Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis. Mol Immunol 38:765–772CrossRefPubMedGoogle Scholar
  31. 31.
    Jekell A, Hossain A, Alehagen U et al (2004) Elevated circulating levels of thioredoxin and satress in chronic heart failure. Eur J Heart Fail 6:883–890PubMedGoogle Scholar
  32. 32.
    Takahashi K, Chin K, Nakamura H et al (2008) Plasma thioredoxin, a novel oxidative stress marker, in patients with obstructive sleep apnea before and after nasal continuous positive airway pressure. Antioxid Redox Signal 10:715–726CrossRefPubMedGoogle Scholar
  33. 33.
    Marumoto M, Suzuki S, Hosono A et al (2009) Changes in thiordoxin concentrations: an observation in an ultra-marathon race. Environ Heatlth Prev Med. December 2 [Epub ahead of print]Google Scholar
  34. 34.
    Fu JN, Li J, Tan Q et al (2010) Thioredxin reductase inhibitor ethaselen increases the drug sensitivity of the colon cancer cell line LoVo towards cisplatin via regulation of G1 phase and reversal of G2/M phase arrest. Invest New Drugs March 2 [Epub ahead of print]Google Scholar
  35. 35.
    Arnold NB, Ketterer K, Kleeff J et al (2004) Thioredoxin is downstream of smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer. Cancer Res 64:3599–3606CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ramesh K. Ramanathan
    • 1
    • 2
    Email author
  • James Abbruzzese
    • 3
  • Tomislav Dragovich
    • 4
  • Lynn Kirkpatrick
    • 5
  • Jose M. Guillen
    • 4
  • Amanda F. Baker
    • 4
  • Linda A. Pestano
    • 5
  • Sylvan Green
    • 4
  • Daniel D. Von Hoff
    • 1
    • 2
  1. 1.Virgina G Piper Cancer CenterTGenScottsdaleUSA
  2. 2.Translational Genomics Research InstitutePhoenixUSA
  3. 3.The University of Texas M.D. Anderson Cancer CenterHoustonUSA
  4. 4.Arizona Cancer CenterUniversity of ArizonaTucsonUSA
  5. 5.ProlX PharmaceuticalsTucsonUSA

Personalised recommendations