A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors.

Abstract

PURPOSE:

Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G.

EXPERIMENTAL DESIGN:

Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured.

RESULTS:

Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome.

CONCLUSIONS:

This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

• Authors: Amir Mortazavi, Yonghua Ling, Ludmila Katherine Martin, Lai Wei, Mitch A Phelps, Zhongfa Liu, Erica J Harper, S Percy Ivy, Xin Wu, Bing-Sen Zhou, Xiyong Liu, Deidre Deam, J Paul Monk, William J Hicks, Yun Yen, Gregory A Otterson, Michael R Grever, Tanios Bekaii-Saab
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 3 Pg. 685-95 (Jun 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 22847785 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Pyridines
• Thiosemicarbazones
• Deoxycytidine
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• ribonucleotide reductase M2
• Ribonucleoside Diphosphate Reductase
• Gemcitabine

Topics

• Adult
• Aged
• Aged, 80 and over
• Anemia (chemically induced)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives)
• Female
• Humans
• Leukopenia (chemically induced)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (blood, drug therapy)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics)
• Ribonucleoside Diphosphate Reductase (blood)
• Thiosemicarbazones (administration & dosage, adverse effects, pharmacokinetics)
• Thrombocytopenia (chemically induced)
• Gemcitabine