Final results of a phase II study of voreloxin in women with platinum-resistant ovarian cancer.

Hirte, Hal W.; McGuire, W. P.; Edwards, Robert P.; Husain, Amreen; Hoskins, Paul; Michels, Jorg; Matulonis, U.; Sexton, C.; Fox, Judith A.; Michelson, Glenn

doi:10.1200/jco.2010.28.15_suppl.5002

Cited by 5 publications

(11 citation statements)

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“…10 Additionally, vosaroxin is not a substrate for the P glycoprotein efflux pump, and its activity is independent of p53 family members; [11][12][13] it may, therefore, bypass some mechanisms of chemotherapy resistance. Consistent with this, single-agent activity has been noted in anthracycline-resistant populations, 13 including women whose ovarian cancer progressed on liposomal doxorubicin 14 and AML patients with refractory/relapsed disease. 15 Overall, the characteristics of vosaroxin suggest that it might have a more favorable risk-benefit profile than that of other commonly used agents, such as anthracyclines.…”

Section: Introductionmentioning

confidence: 61%

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

et al. 2014

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Section: Introductionmentioning

confidence: 61%

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

et al. 2014

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“…These drugs are broadly used in the treatment of both solid and hematologic malignancies [6][7][8]. Objective responses and complete remissions in phase 2 studies of acute myeloid leukemia and platinum-resistant ovarian cancer were observed with vosaroxin (formerly voreloxin), a firstin-class anticancer quinolone derivative [9][10][11]. In both settings, responses were seen in patients whose cancers were resistant to anthracyclines.…”

Section: Introductionmentioning

confidence: 94%

Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks

et al. 2010

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AbstrAct:Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality.

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“…In conclusion, voreloxin is a novel agent with evidence of tolerability and antitumor activity in patients with (23,24). Voreloxin is also being evaluated in a phase 2 clinical study (REVEAL-1) in patients ≥60 years of age with newly diagnosed acute myeloid leukemia (25), and in a phase 1b/2 clinical study in combination with cytarabine for the treatment of patients with relapsed/refractory acute myeloid leukemia (26).…”

Section: Discussionmentioning

confidence: 99%

Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules

Advani

Hurwitz

Gordon

et al. 2010

Clinical Cancer Research

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Purpose: Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity.Experimental Design: Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history. Conclusions: Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia. Clin Cancer Res; 16(7); 2167-75. ©2010 AACR.Voreloxin, a novel naphthyridine analogue, is structurally related to the quinolone class of compounds and is the first member of a new drug class of anticancer quinolone derivatives. Quinolone derivatives have been shown to mediate antitumor activity by targeting mammalian topoisomerases and have shown promising preclinical antitumor activity (1-4). Voreloxin is a replication-dependent DNA-damaging agent that intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks, G 2 arrest, and apoptosis (5).Preclinical data have shown that voreloxin has potent, dose-dependent cytotoxic activity in multiple tumor models, including human xenografts and several multidrug-resistant and aggressive murine syngeneic tumor models (6). Studies with voreloxin in rodents and nonhuman primates have shown that the compound has favorable pharmacokinetic properties: dose-proportional exposure, low interindividual and intraindividual variability, and moderate clearance (7,8). Voreloxin is not a substrate for the P-glycoprotein efflux pump and is not dependent on p53 family members for its activity (9), unlike other DNA intercalators and topoisomerase II inhibitors that are susceptible to these common drug resistance mechanisms (10-12).

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Final results of a phase II study of voreloxin in women with platinum-resistant ovarian cancer.

Cited by 5 publications

References 0 publications

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks

Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules

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