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. Ramanathan, James Abbruzzese, Tomislav Dragovich, Lynn Kirkpatrick, Jose M. Guillen, Amanda F Baker, Linda A. Pestano, Sylvan Green, Daniel D. Von Hoff

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)503-509
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number3
DOIs
StatePublished - Mar 2011

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gemcitabine
Thioredoxins
Odors
Metabolites
Pancreatic Neoplasms
Plasmas
Molecules
Proto-Oncogenes

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

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. / Ramanathan, Ramesh K.; Abbruzzese, James; Dragovich, Tomislav; Kirkpatrick, Lynn; Guillen, Jose M.; Baker, Amanda F; Pestano, Linda A.; Green, Sylvan; Von Hoff, Daniel D.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 3, 03.2011, p. 503-509.

Research output: Contribution to journalArticle

Ramanathan, Ramesh K. ; Abbruzzese, James ; Dragovich, Tomislav ; Kirkpatrick, Lynn ; Guillen, Jose M. ; Baker, Amanda F ; Pestano, Linda A. ; Green, Sylvan ; Von Hoff, Daniel D. / 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. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 67, No. 3. pp. 503-509.
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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.",
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T1 - 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

AU - Ramanathan, Ramesh K.

AU - Abbruzzese, James

AU - Dragovich, Tomislav

AU - Kirkpatrick, Lynn

AU - Guillen, Jose M.

AU - Baker, Amanda F

AU - Pestano, Linda A.

AU - Green, Sylvan

AU - Von Hoff, Daniel D.

PY - 2011/3

Y1 - 2011/3

N2 - 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.

AB - 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.

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KW - Second-line therapy

KW - Thioredoxin

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