Journal Article

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

Hicks, William J., Wei, Lai, Bekaii-Saab, Tanios, Mortazavi, Amir, Zhou, Bing-Sen, Wu, Xin, Martin, Ludmila Katherine, Yen, Yun, Ling, Yonghua, Liu, Zhongfa, Monk, J. Paul, Deam, Deidre, Otterson, Gregory A., Phelps, Mitch A., Ivy, S. Percy, Grever, Michael R., Harper, Erica J., Liu, Xiyong

2013

Overview

Summary 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.

• Publisher: Springer US,Springer,Springer Nature B.V
• Subject: Adult / Aged / Aged, 80 and over / Anemia - chemically induced / Antineoplastic agents / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacokinetics / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics / Biological and medical sciences / Cancer / Cancer therapies / Chemotherapy / Deoxycytidine - administration & dosage / Deoxycytidine - adverse effects / Deoxycytidine - analogs & derivatives / Deoxyribonucleic acid / DNA / Drug dosages / Drug therapy / Enzymes / Female / General aspects / Humans / Internal medicine / Kinases / Leukopenia - chemically induced / Male / Maximum Tolerated Dose / Medical research / Medical sciences / Medicine / Medicine & Public Health / Middle Aged / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Neoplasms - blood / Neoplasms - drug therapy / Oncology / Pharmacokinetics / Pharmacology / Pharmacology. Drug treatments / Pharmacology/Toxicology / Phase I Studies / Prescription drugs / Pyridines - administration & dosage / Pyridines - adverse effects / Pyridines - pharmacokinetics / R&D / Research & development / Ribonucleoside Diphosphate Reductase - blood / Ribonucleotide reductase / Studies / Thiosemicarbazones - administration & dosage / Thiosemicarbazones - adverse effects / Thiosemicarbazones - pharmacokinetics / Thrombocytopenia - chemically induced / Tumors