Phase I Trial of Triapine-Cisplatin-Paclitaxel Chemotherapy for Advanced Stage or Metastatic Solid Tumor Cancers.

Charles A Kunos,Andreas Kaubisch,Mario Sznol,Della Makower,Susan Percy Ivy,Edward Chu

doi:10.3389/fonc.2017.00062

Abstract

Ribonucleotide reductase (RNR) is an enzyme involved in the de novo synthesis of deoxyribonucleotides, which are critical for DNA replication and DNA repair. Triapine is a small-molecule RNR inhibitor. A phase I trial studied the safety of triapine in combination with cisplatin–paclitaxel in patients with advanced stage or metastatic solid tumor cancers in an effort to capitalize on disrupted DNA damage repair. A total of 13 patients with various previously treated cancers were given a 96-h continuous intravenous (i.v.) infusion of triapine (40–120 mg/m2) on day 1, and then 3-h i.v. paclitaxel (80 mg/m2) followed by 1-h i.v. cisplatin (50–75 mg/m2) on day 3. This combination regimen was repeated every 21 days. The maximum tolerated dose (MTD) for each agent was identified to be triapine (80 mg/m2), cisplatin (50 mg/m2), and paclitaxel (80 mg/m2). Common grade 3 or 4 toxicities included reversible anemia, leukopenia, thrombocytopenia, or electrolyte abnormalities. The combination regimen of triapine–cisplatin–paclitaxel resulted in no objective responses; however, five (83%) of six patients treated at the MTD had stable disease between 1 and 8 months duration. This phase I study showed that the combination regimen of triapine–cisplatin–paclitaxel was safe and provides a rational basis for a follow-up phase II trial to evaluate efficacy and progression-free survival in women with metastatic or recurrent uterine cervix cancer.

Highlights

Uterine cervix cancers are aggressive gynecological malignancies marked by abdominopelvic lymph node or visceral organ metastases and by poor metastatic disease-specific survival, and up to 80% have been shown to overexpress ribonucleotide reductase (RNR) [1,2,3,4]
Number. aPatients may have had more than one adverse event. This phase I trial found that triapine–cisplatin–paclitaxel was a safe therapeutic option for patients with previously treated advanced stage or metastatic solid tumor cancers
There was an elevated rate of grade 3 or 4 anemia (77%) after triapine–cisplatin–paclitaxel, possibly as a result of potent iron chelation by triapine [27] without interference in total iron binding capacity [22]

Summary

Introduction

Uterine cervix cancers are aggressive gynecological malignancies marked by abdominopelvic lymph node or visceral organ metastases and by poor metastatic disease-specific survival, and up to 80% have been shown to overexpress ribonucleotide reductase (RNR) [1,2,3,4]. Expansion of nucleotide pools during DNA damage has a clear physiological role, and it has been shown that increased nucleotide concentrations as outputs from RNR help cells survive DNA damage [19]. Such findings provide a strong rationale for clinical development of new agents that exploit RNR repair and DNA damage responses, especially in cancers with unchecked RNR. In preclinical studies of uterine cervix cancer cells, triapine potently blocks deoxynucleotide output by RNR after DNA damage, protracts cell cycle arrest at the G1–S-phase checkpoint, and leads to unresolved γH2AX foci (i.e., phosphorylated histones flanking DNA double-strand breaks) marking DNA damage [13,14,15]—all disruptive to normal RNR functions (Figure 1)

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Conclusion