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
- 449 Downloads
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).
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.
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.
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.
KeywordsPX-12 Thioredoxin Pancreatic cancer Phase II Second-line therapy
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.
- 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
- 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
- 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
- 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
- 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
- 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.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