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.

Results: In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m2). At 60 mg/m2, four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m2, two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m2 (HP patients) and 60 mg/m2 (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m2). At 18 mg/m2, two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m2. Voreloxin exhibited low clearance (2 L/h/m2), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria.

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.

Translational Relevance

This original article describes the results of the initial clinical research studies with voreloxin, the first member of a new drug class of anticancer quinolones in clinical testing. Voreloxin, a first-in-class anticancer quinolone derivative, is a replication-dependent DNA-damaging agent that intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin has shown potent antitumor activity in a variety of nonclinical models. In these phase 1 dose-escalation studies in patients with relapsed or refractory solid tumors, the safety profile, pharmacokinetics, and preliminary clinical activity of voreloxin are described for two dosing schedules: every 3 weeks or weekly for 3 weeks. Based on these results, additional phase 1 and phase 2 clinical studies of voreloxin as a single agent were initiated in patients with ovarian cancer, lung cancer, and acute myeloid leukemia; and voreloxin in combination with cytarabine in patients with acute myeloid leukemia.

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 (14). Voreloxin is a replication-dependent DNA-damaging agent that intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks, G2 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 (1012).

We report the results of two phase 1 studies (SPO-0001 and SPO-0002) conducted in patients with a variety of relapsed/refractory solid tumors. The objectives were to determine the safety and tolerability of voreloxin administered by i.v. injection either once every 3 weeks or once weekly for 3 weeks every 28 days (six cycles in total), assess the pharmacokinetic profile after one i.v. dose, define the recommended dosing schedule for phase 2 studies, and obtain preliminary objective tumor response data. The primary end points were determination of dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD).

Study design

SPO-0001 and SPO-0002 were open-label, phase 1, dose-escalation studies conducted in four medical centers in compliance with local institutional review board approval. All patients provided informed consent in accordance with the principles of the Declaration of Helsinki. Eligibility criteria, safety and efficacy assessments, dose-escalation procedures, DLT definitions, pharmacokinetic sampling schedule, and methods were identical for both studies.

Patient selection

Eligible patients were required to be 18 y of age or older with advanced, measurable, histologically or cytologically confirmed, relapsed or refractory solid tumors. Required pretreatment laboratory values included hemoglobin, ≥9.0 g/dL; absolute neutrophil count (ANC), ≥1,500 cells/mm3; platelets, ≥100,000 plt/mm3; serum creatinine, ≤1.5 times the upper limit of normal; total bilirubin, ≤2 mg/dL; prothrombin time and international normalized ratio/activated partial thromboplastin time within the institutional normal limit; and aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels <3 times the upper limit of normal unless malignant hepatic involvement was present. Patients were required to have Eastern Cooperative Oncology Group performance status scores of 0-1, and prior to study initiation, must not have received any chemotherapy or immunotherapy within 4 wk or radiation therapy within 2 wk. Additionally, patients with active comorbid conditions or with a history of prior pelvic radiation or radiation to ≥25% of bone marrow reserve were excluded. Patients with brain metastases were excluded unless they had received adequate treatment for their central nervous system disease and had a minimum of 3 mo with no radiologic evidence of progressive central nervous system disease following treatment completion.

No limit was imposed on the number of therapies that patients could have received before enrollment. To characterize the dose-limiting effects of voreloxin in the context of prior therapy, in SPO-0001, patients were classified as heavily pretreated (HP) if they previously received more than six courses of an alkylator-containing chemotherapy regimen, had more than two courses of carboplatin or mitomycin-C, received any regimen containing a nitrosourea, had radiation to 25% of bone marrow areas, or had widespread bone metastases (13). Patients were classified as minimally pretreated (MP) if their therapeutic history did not meet the HP definition.

Treatment: evaluation of two dosing schedules

Voreloxin was administered on day 1 of a 21-d cycle in SPO-0001 (dose levels 3, 6, 12, 24, 36, 48, 60, and 75 mg/m2) and on days 1, 8, and 15 of a 28-d cycle in SPO-0002 (dose levels 3, 6, 12, 15, 18, and 24 mg/m2), for up to six cycles. The initial dose for cohort 1 in both studies was 3 mg/m2, which was doubled for subsequent cohorts until a protocol-defined DLT occurred. After the first DLT, dose escalation proceeded based on a modified Fibonacci sequence (13).

In both studies, voreloxin was administered undiluted at 10 mg/mL by i.v. injection over 10 min without antiemetic premedication during cycle 1. Prophylactic antiemetic therapy was allowed during subsequent cycles if the patient experienced vomiting. A DLT was defined as any of the following: ANC ≤500 cells/mm3 (grade 4 neutropenia) lasting more than 7 d or ANC ≤1,000 cells/mm3 (grade 3 neutropenia) accompanied by fever ≥38.5°C; platelet count <25,000 plt/mm3 (grade 4 thrombocytopenia) or bleeding requiring transfusion; nonhematologic adverse events grade ≥3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0,9

9National Cancer Institute. Common Terminology Criteria for Adverse Events. Version 3.0. 2006. Version 4 criteria are available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf.

or any adverse event requiring a voreloxin dose delay longer than 14 d. The MTD was defined as the highest dose level that produced no more than a 33% incidence of DLT.

The target enrollment was three patients per dose cohort, with cohort expansion to six patients if a DLT was observed in one of the first three patients. Cohort expansion was discontinued after two patients experienced a DLT in a cohort, and the prior cohort dose was declared the MTD. After the MTD was determined, additional patients were enrolled at MTD to further assess safety and tolerability at the MTD.

Assessment of response

Objective tumor response was measured radiographically according to Response Evaluation Criteria in Solid Tumors (RECIST; ref. 14). In patients with ovarian cancer, response was also measured using the Rustin criteria, which defines response as either a 50% or 75% decrease in serum CA-125 levels (15).

Assessments of safety and follow-up

Patients had a physical examination, laboratory evaluation, vital signs assessment, and ECG at baseline. Laboratory values and vital signs were assessed at every visit for both studies. Adverse events were recorded beginning on the first day of treatment in cycle 1 through 28 d after the last treatment. Serious adverse events (SAE) were defined as events that resulted in death, were immediately life-threatening, resulted in or prolonged hospitalization, or caused significant disability/incapacity. The severity of adverse events was defined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.9 Adverse events assessed by the investigator as having a reasonable possibility of being causally related to voreloxin were followed until the condition returned to baseline grade, stabilized and was considered irreversible, or resulted in death. This assessment included patients who discontinued voreloxin treatment due to adverse events, but who did not withdraw consent for further follow-up. Safety data were collected for 28 d after the final dose of voreloxin was administered.

Pharmacokinetic analysis

The pharmacokinetic profile was determined for the first dose of voreloxin in SPO-0001 and for the first and third weekly doses in SPO-0002. Blood for pharmacokinetic evaluation was collected before the i.v. dose was administered, at the end of the infusion, and then at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 33, and 48 h postdose. Plasma samples were analyzed for voreloxin by Alta Analytical Laboratory, Inc., using a validated liquid chromatography-tandem mass spectrometry method that had a lower limit of quantitation of 1 ng/mL (401.45 ng was equivalent to 1 μmol/L of voreloxin). The analytic method for the determination of voreloxin concentrations in plasma has been described previously (16). Peak concentration (Cmax), area under the concentration-time curve (AUC) from time zero to infinity (AUC0-inf), mean residence time when the drug concentration-time profile was extrapolated to infinity (MRTinf), terminal half-life, total body clearance, and apparent volume of distribution at steady state (Vss) were estimated by noncompartmental analysis assuming bolus administration, using WinNonlin software (version 4.1, Pharsight Corporation).

SPO-0001

Patient characteristics

Forty-three patients were enrolled and 41 were treated between June 2004 and December 2005. Two patients did not receive voreloxin due to active comorbid conditions. The treatment population consisted of 25 males and 16 females with a median age of 59 years (Table 1). The most common tumor type was ovarian (n = 9), followed by non–small cell lung (n = 6) and colon (n = 5) cancer. Seventeen patients (42%) classified as MP received a median of 2 prior anticancer treatments; 24 (59%) classified as HP received a median of 5.5 prior anticancer treatments.

Table 1.

Patient characteristics

CharacteristicSPO-0001SPO-0002
No. of enrolled/treated patients 43/41 21/21 
Sex, n (%) 
    Male 25 (61) 9 (43) 
    Female 16 (39) 12 (57) 
Age (y) 
    Median (range) 59 (33-79) 61 (19-81) 
ECOG score, n (%) 
    0 13 (32) 9 (43) 
    1 27 (66) 12 (57) 
    2 1 (2) 
No. of prior regimens, median (range) 
    MP 2 (0-5) NA 
    HP 5.5 (1-14) NA 
Tumor types 
    Ovarian 
    Lung 
    Colon 
    Renal/renal pelvis 
    Other* 
    Melanoma 
    Sarcomas 
    Unknown primary 
    Pancreatic 
    Rectal/small bowel 
    Breast 
    Nasopharyngeal/salivary gland 
CharacteristicSPO-0001SPO-0002
No. of enrolled/treated patients 43/41 21/21 
Sex, n (%) 
    Male 25 (61) 9 (43) 
    Female 16 (39) 12 (57) 
Age (y) 
    Median (range) 59 (33-79) 61 (19-81) 
ECOG score, n (%) 
    0 13 (32) 9 (43) 
    1 27 (66) 12 (57) 
    2 1 (2) 
No. of prior regimens, median (range) 
    MP 2 (0-5) NA 
    HP 5.5 (1-14) NA 
Tumor types 
    Ovarian 
    Lung 
    Colon 
    Renal/renal pelvis 
    Other* 
    Melanoma 
    Sarcomas 
    Unknown primary 
    Pancreatic 
    Rectal/small bowel 
    Breast 
    Nasopharyngeal/salivary gland 

NOTE: Voreloxin dosing was every 3 wk (SPO-0001) or weekly for 3 wk every 28 d (SPO-0002).

Abbreviations: ECOG, Eastern Cooperative Oncology Group; NA, not applicable.

*SPO-0001 includes one each of cholangiocarcinoma, neuroendocrine, uterine, and esophageal cancer. SPO-0002 includes one each of cholangiocarcinoma and neuroendocrine cancer.

Determination of MTD

No patients enrolled in the 3, 6, 12, 24, or 36 mg/m2 groups experienced a DLT. At 48 mg/m2, one of three patients developed DLTs (grade 4 neutropenia); therefore, the cohort was expanded to six patients and no further events occurred. Eight patients were treated at the next cohort dose at 60 mg/m2 (five HP, three MP). Although none of the MP patients experienced DLTs, four of the HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever), and grade 3 febrile neutropenia with pneumonia (n = 1). Thereafter, dose escalation proceeded separately for HP and MP patients. For the HP group, 5 additional patients were treated at the previous dose level (48 mg/m2) for a total of 11 patients; 2 patients experienced DLTs with grade 4 neutropenia (1 with concomitant grade 4 thrombocytopenia and grade 3 nausea/vomiting), and this dose was considered the MTD. For the MP group, dose escalation continued as planned to the next dose level of 75 mg/m2, the level at which two patients experienced DLTs (one patient with grade 4 neutropenia and grade 4 thrombocytopenia, and one patient with grade 2 oral thrush lasting 29 days and grade 3 neutropenia), and further dose escalation was stopped. Thus, according to the predefined DLT criteria, MTDs were determined to be 48 mg/m2 for HP patients and 60 mg/m2 for MP patients. A summary of protocol-defined DLTs is presented in Table 2.

Table 2.

DLTs of voreloxin

SPO-0001 (n = 41)SPO-0002 (n = 21)
Voreloxin dose (mg/m23, 6, 12, 24, 36 48 60 75 3, 6, 12, 15 18 24 
No. of patients with DLTs 
Pretreatment status (HP/MP)  HP HP MP  NE NE 
Protocol-defined DLT 
    ANC ≤500/μL lasting >7 d 
    ANC ≤1,000/μL with fever >38.5°C 
    Platelets <25,000/μL 
    Bleeding requiring transfusion 
    Nonhematologic AE grade ≥3 
    Any AE grade requiring dose delay >14 d 
    Inability to receive all three doses in cycle 1 due to any AEs related to voreloxin 
SPO-0001 (n = 41)SPO-0002 (n = 21)
Voreloxin dose (mg/m23, 6, 12, 24, 36 48 60 75 3, 6, 12, 15 18 24 
No. of patients with DLTs 
Pretreatment status (HP/MP)  HP HP MP  NE NE 
Protocol-defined DLT 
    ANC ≤500/μL lasting >7 d 
    ANC ≤1,000/μL with fever >38.5°C 
    Platelets <25,000/μL 
    Bleeding requiring transfusion 
    Nonhematologic AE grade ≥3 
    Any AE grade requiring dose delay >14 d 
    Inability to receive all three doses in cycle 1 due to any AEs related to voreloxin 

NOTE: Dose group (number of patients) in SPO-0001: 3, 6, 12, and 24 mg/m2 (3 each), 36 mg/m2 (6), 48 mg/m2 (11), 60 mg/m2 (8), and 75 mg/m2 (4); SPO-0002: 3 mg/m2 (4), 6 mg/m2 (3) 12 mg/m2 (3), 15 mg/m2 (6), 18 mg/m2 (4), and 24 mg/m2 (1). Voreloxin dosing was every 3 wk (SPO-0001) or weekly for 3 wk every 28 d (SPO-0002).

Abbreviations: NE, not evaluated; AE, adverse event.

Safety profile

The median number of completed cycles was three (range, one to six). Eleven (27%) patients (five HP and six MP) completed all six cycles.

Overall, nausea was the most frequent adverse event of any relationship or grade (25 of 41 patients, 61%), followed by vomiting (42%), neutropenia (37%), fatigue (32%), and constipation (29%). Nonhematologic toxicity was mild, grades 1 to 2 in severity, and transient in most patients. Grades 3 or 4 nonhematologic toxicity was reported in 18 patients, all at voreloxin doses of ≥48 mg/m2 as shown in Table 3.

Table 3.

All grade 3/4 adverse events in SPO-0001 (n = 41)

Adverse eventGradeVoreloxin dose (mg/m2)
36122436486075
Hematologic 
    Anemia 
    Neutropenia 
 
    Febrile neutropenia 
    Thrombocytopenia 
    Pancytopenia 1* 
Nonhematologic 
    Gastrointestinal 
        Constipation 
        Nausea 
        Small intestinal obstruction 1 
        Vomiting 1* 
    General disorders 
        Fatigue 
    Hepatobiliary 
        Hypoalbuminemia 
    Infections 
        Pyelonephritis 1 
        Sepsis 1* 
        Staphylococcal infection 1 
    Respiratory 
        Dyspnea 
        Influenza 
        Pharyngolaryngeal pain 
        Pleural effusion 1 
        Pneumonia 1* 
        Pulmonary embolism 1 
Adverse eventGradeVoreloxin dose (mg/m2)
36122436486075
Hematologic 
    Anemia 
    Neutropenia 
 
    Febrile neutropenia 
    Thrombocytopenia 
    Pancytopenia 1* 
Nonhematologic 
    Gastrointestinal 
        Constipation 
        Nausea 
        Small intestinal obstruction 1 
        Vomiting 1* 
    General disorders 
        Fatigue 
    Hepatobiliary 
        Hypoalbuminemia 
    Infections 
        Pyelonephritis 1 
        Sepsis 1* 
        Staphylococcal infection 1 
    Respiratory 
        Dyspnea 
        Influenza 
        Pharyngolaryngeal pain 
        Pleural effusion 1 
        Pneumonia 1* 
        Pulmonary embolism 1 

NOTE: Additional SAEs included grade 2 right leg thrombosis (related), febrile neutropenia (related), and pancreatitis (not related), and grade 5 left hemiplegia/pleural effusion in the same patient (both not related). Dose group (number of patients): 3, 6, 12, and 24 mg/m2 (3 each), 36 mg/m2 (6), 48 mg/m2 (11), 60 mg/m2 (8), 75 mg/m2 (4). Voreloxin dosing was every 3 wk (SPO-0001) or weekly for 3 wk every 28 d (SPO-0002).

*Related SAE.

Unrelated SAE.

Neutropenia was the most commonly reported grade 3 to 4 hematologic event in patients treated with 48 mg/m2 or higher: grade 4 neutropenia (n = 12) and grade 3 neutropenia (n = 3, one with fever). The ANC nadir occurred between days 7 and 14 of cycle 1, and recovery was within 14 to 21 days for most patients. Other hematologic toxicities reported were grade 3 anemia (n = 4) and grade 4 thrombocytopenia (n = 2). No patient required a voreloxin dose delay longer than 14 days after cycle 1, or had bleeding requiring transfusion.

In 10 patients, toxicities were considered to be SAEs, and six of the events experienced by 5 patients were assessed as related to voreloxin as shown in Table 3. Six patients died during the study; all deaths were secondary to disease progression.

SPO-0002

Patient characteristics

Between October 2004 and August 2006, 21 patients (median age, 61 years) with diverse histologies were enrolled and treated: lung, colon, pancreatic, or sarcoma (n = 3 each); breast or nasopharyngeal/salivary gland (n = 2 each); and ovarian or other cancer (n = 1 each; Table 1).

Determination of MTD

Six voreloxin cohort dose levels were evaluated: 3 mg/m2 (n = 4), 6 mg/m2 (n = 3), 12 mg/m2 (n = 3), 24 mg/m2 (n = 1), 18 mg/m2 (n = 4), and 15 mg/m2 (n = 6). The cohort dose was doubled in sequence from 3 mg/m2 until the first patient treated at 24 mg/m2 experienced a DLT (grade 3 neutropenia causing inability to receive all three voreloxin doses in cycle 1). Therefore, for the next cohort, the dose was reduced to 18 mg/m2. At this dose level, two of four patients experienced DLTs (two with grade 3 neutropenia, one with a pleural effusion requiring voreloxin dose delay for recovery and causing inability to receive all three doses in cycle 1). Per study design, the next cohort dose was reduced further to 15 mg/m2, and at this level, none of the six patients experienced a DLT. Therefore, the MTD for the weekly dosing schedule was determined to be 15 mg/m2.

Safety profile

Two of the 21 patients completed all six cycles of treatment with a follow-up assessment at 28 days. For the remaining 19 patients, study discontinuation was due to disease progression (n = 13); adverse event (grade 3 neutropenia, hepatic steatosis), withdrawal of consent, or physician discretion (n = 2 each). Adverse events of any relationship or grade included nausea and constipation (n = 8), abdominal pain (n = 6), diarrhea, vomiting, pyrexia, and pain in extremity (n = 5 each). No grade 4 hematologic or nonhematologic events were reported. Four patients experienced grade 3 neutropenia: 15 mg/m2 (n = 1), 18 mg/m2 (n = 2), and 24 mg/m2 (n = 1). All grade 3 nonhematologic adverse events at 18 mg/m2 occurred in a single patient, and all but one event at 6 mg/m2 occurred in a single patient. Five patients experienced six SAEs, including one each of gastrointestinal obstruction, bile duct obstruction, recurrent malignant pleural effusion, increased abdominal pain, pneumonia (exacerbation of), and congestive heart failure. None of the SAEs was assessed by the investigators as related to voreloxin.

One patient with a history of hypertension, hyperlipidemia, myocardial infarction, coronary artery disease, and congestive heart failure died on study due to congestive heart failure and pneumonia considered unrelated to voreloxin.

Pharmacokinetics

Pharmacokinetic evaluation of the first dose of voreloxin on cycle 1 day 1 (both studies) and the third dose on day 15 (SPO-0002) showed that plasma voreloxin concentrations were highest immediately postdose, ranged from 0.07 to 14.4 μg/mL, and declined in a biphasic fashion consisting of a short initial phase followed by a longer terminal phase (Fig. 1). Pharmacokinetic variables were similar for the two dosing schedules. As shown in Table 4, voreloxin exhibited low clearance (2 L/h/m2) and a long terminal half-life (22 hours), and notably, clearance, Vss, and terminal half-life were unaffected by dose. Systemic exposure (AUC) increased linearly with dose (17). Differences in infusion times (1-11 minutes, median 5 minutes) precluded the assessment of proportionality based on Cmax. No change in pharmacokinetic variables was observed for the third weekly dose of voreloxin compared with the first dose on day 1.

Fig. 1.

Mean voreloxin concentration-time data by cohort. Voreloxin pharmacokinetic profiles were evaluated in SPO-0001 patients administered a first dose of 3 to 75 mg/m2 (A), SPO-0002 patients administered a first dose of 3 to 24 mg/m2 (B), and SPO-0002 patients administered a third weekly dose of 3 to 18 mg/m2 (C). Voreloxin was administered as an i.v. injection within 1 to 10 min.

Fig. 1.

Mean voreloxin concentration-time data by cohort. Voreloxin pharmacokinetic profiles were evaluated in SPO-0001 patients administered a first dose of 3 to 75 mg/m2 (A), SPO-0002 patients administered a first dose of 3 to 24 mg/m2 (B), and SPO-0002 patients administered a third weekly dose of 3 to 18 mg/m2 (C). Voreloxin was administered as an i.v. injection within 1 to 10 min.

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Table 4.

Pharmacokinetic variables for voreloxin

SPO-0001, Dose 1SPO-0002, Dose 1Dose 3
No. of patients 40 21 17 
Dose range (mg/m23-75 3-24 3-18 
Half-life (h) 22 ± 11 19 ± 5 16 ± 4 
Clearance (L/h/m22.0 ± 0.7 2.0 ± 0.7 2.3 ± 0.7 
Vss (L/m253 ± 11 47 ± 13 48 ± 7 
Mean residence time (h) 30 ± 15 25 ± 8 22 ± 5 
Cmax range (μg/mL) 0.07-14.4 0.07-7.3 0.21 ± 3.1 
AUC0-inf, range (μg·h/mL) 0.92-91 1.5-15 1.4 ± 8.4 
    3 mg/m2 1.1 (n = 3) 1.8 (n = 4) NA 
    6 mg/m2 3.0 (n = 2) 2.1 (n = 3) NA 
    12 mg/m2 6.3 (n = 3) 6.9 (n = 3) NA 
    15 mg/m2 NA 8.5 (n = 6) NA 
    18 mg/m2 NA 9.3 (n = 4) NA 
    24 mg/m2 12.8 (n = 3) 15.2 (n = 1) NA 
    36 mg/m2 17.0 (n = 6) NA NA 
    48 mg/m2 29.2 (n = 11) NA NA 
    60 mg/m2 40.8 (n = 8) NA NA 
    75 mg/m2 46.6 (n = 4) NA NA 
SPO-0001, Dose 1SPO-0002, Dose 1Dose 3
No. of patients 40 21 17 
Dose range (mg/m23-75 3-24 3-18 
Half-life (h) 22 ± 11 19 ± 5 16 ± 4 
Clearance (L/h/m22.0 ± 0.7 2.0 ± 0.7 2.3 ± 0.7 
Vss (L/m253 ± 11 47 ± 13 48 ± 7 
Mean residence time (h) 30 ± 15 25 ± 8 22 ± 5 
Cmax range (μg/mL) 0.07-14.4 0.07-7.3 0.21 ± 3.1 
AUC0-inf, range (μg·h/mL) 0.92-91 1.5-15 1.4 ± 8.4 
    3 mg/m2 1.1 (n = 3) 1.8 (n = 4) NA 
    6 mg/m2 3.0 (n = 2) 2.1 (n = 3) NA 
    12 mg/m2 6.3 (n = 3) 6.9 (n = 3) NA 
    15 mg/m2 NA 8.5 (n = 6) NA 
    18 mg/m2 NA 9.3 (n = 4) NA 
    24 mg/m2 12.8 (n = 3) 15.2 (n = 1) NA 
    36 mg/m2 17.0 (n = 6) NA NA 
    48 mg/m2 29.2 (n = 11) NA NA 
    60 mg/m2 40.8 (n = 8) NA NA 
    75 mg/m2 46.6 (n = 4) NA NA 

NOTE: Data are mean ± SD, unless otherwise noted. Voreloxin dosing was every 3 wk (SPO-0001) or weekly for 3 wk every 28 d (SPO-0002).

Abbreviations: Vss, volume of distribution at steady state; Cmax, maximum concentration; AUC0-inf, area under the concentration-time curve from time zero to infinity; NA, not applicable.

Tumor response

Overall, half of patients (31 of 62) across both studies had the best overall response of stable disease (SD) as determined radiographically by RECIST guidelines. Of 10 patients with ovarian cancer, five also had a best overall response of SD and all completed at least four cycles of treatment with voreloxin.

In SPO-0001, 21 of 41 patients (51%) were considered to have SD as the best overall response. Of 11 patients treated at 48 mg/m2, five (four HP and one MP) had SD: ovarian cancer (n = 2) and colon, unknown primary adenocarcinoma, and non–small cell lung cancer (n = 1 each). Of eight patients treated at 60 mg/m2, six (three HP and three MP) had SD: ovarian cancer (n = 2) and melanoma, pancreatic cancer, neuroendocrine tumor, and metastatic myxoid liposarcoma (n = 1 each).

Of the nine patients with ovarian cancer in SPO-0001, six had CA-125 samples at both baseline and postbaseline. According to Rustin criteria, four of the six patients had a ≥50% decrease in CA-125, including a 75% decrease in one patient. Three of these four patients had SD and completed all six treatment cycles, and then subsequently continued voreloxin treatment in an extension study (SPO-0003). A summary of response data for patients with ovarian cancer is shown in Table 5.

Table 5.

Response in patients with ovarian cancer in SPO-0001 and SPO-0002

Study dose (mg/m2)Patient no.No. of CA-125 samples at baseline/postbaselineBest overall response (RECIST)*CA-125 response (Rustin)
SPO-0001 
    6 04 0/0 PD NE 
    36 33 1/1 PD Increase 
    36 40 0/2 SD NE 
    48 18 1/4 SD ≥50% decrease 
    48 30 1/0 PD NE 
    48 31 1/3 SD 75% decrease 
    48 32 1/1  ≥50% decrease 
    60 24 1/2 SD No change 
    60 25 1/3 SD ≥50% decrease 
SPO-0002 
    18 13 1/0  NE 
Study dose (mg/m2)Patient no.No. of CA-125 samples at baseline/postbaselineBest overall response (RECIST)*CA-125 response (Rustin)
SPO-0001 
    6 04 0/0 PD NE 
    36 33 1/1 PD Increase 
    36 40 0/2 SD NE 
    48 18 1/4 SD ≥50% decrease 
    48 30 1/0 PD NE 
    48 31 1/3 SD 75% decrease 
    48 32 1/1  ≥50% decrease 
    60 24 1/2 SD No change 
    60 25 1/3 SD ≥50% decrease 
SPO-0002 
    18 13 1/0  NE 

NOTE: All patients were classified as HP. Voreloxin dosing was every 3 wk (SPO-0001) or weekly for 3 wk every 28 d (SPO-0002).

Abbreviations: PD, progressive disease; NE, no evaluation due to missing sample(s).

*Assessed radiographically on day 21 of cycles 2, 4, and 6.

Not assessable; patient discontinued due to adverse event (grade 4 neutropenia).

Not assessable; patient withdrew consent after one cycle.

In SPO-0002, 10 of 21 patients (48%) had the best overall response of SD across a wide range of histologies. Ten patients who completed the SPO-0001 or SPO-0002 studies continued to receive voreloxin treatment in SPO-0003, and eight (80%) completed at least four additional cycles (range, 2-29 months). The three patients with ovarian cancer entering from SPO-0001 completed an additional two, three, and four cycles in SPO-0003 before disease progressed.

Our studies, evaluating two dosing schedules, reveal that voreloxin is well tolerated and shows clinical activity in patients with a variety of advanced solid tumors. The primary DLT was neutropenia, which was noncumulative. Other toxicities were infrequent, and mild nausea was the main nonhematologic adverse event. In the SPO-0001 study, as anticipated, MP patients tolerated treatment better than HP patients, as shown by the higher MTD (60 versus 48 mg/m2). Based on these findings, the initial recommended phase 2 single-agent dose of voreloxin is 48 mg/m2 administered every 3 weeks in all patients with advanced solid tumors. In SPO-0002 (weekly administration), the MTD was defined as 15 mg/m2.

No differences were observed in the pharmacokinetic profiles for the two dosing schedules tested (once every 3 weeks or weekly for 3 weeks every 28 days). Voreloxin exhibited low clearance (2 L/h/m2) and a long terminal half-life (22 hours). Exposure to voreloxin increased linearly with dose, with no changes across doses in clearance, Vss, and terminal half-life. No drug accumulation or change in pharmacokinetic variables was seen after repeated weekly dosing. In SPO-0001, average plasma voreloxin concentrations of ≥1 μmol/L were maintained for up to 25 hours in patients treated with voreloxin doses of 48 mg/m2 and higher. Voreloxin levels ≥1 μmol/L have been reported to correlate in vitro with IC90 in multiple hematologic cancer cell lines (18, 19) and >80% inhibition of proliferation of breast (17 of 20) and ovarian (11 of 20) cancer biopsies (20). Our data suggest that clinically active plasma voreloxin concentrations of ≥1 μmol/L are achieved at tolerable doses (48 mg/m2 and higher) in patients with relapsed/refractory solid tumors.

In addition to its favorable pharmacokinetic profile, the DNA damage that results from voreloxin treatment is highly selective (9). The interaction of voreloxin with DNA is saturable, suggesting a specificity of interaction with the DNA and topoisomerase II enzyme analogous to the saturation of bacterial DNA-topoisomerase II by antibacterial quinolones (21). A limitation of the SPO-0001 and SPO-0002 studies is that no provisions were made in the study protocols and patient-informed consent forms to collect patient samples (e.g., tumor biopsies or blood) to perform target-based analysis or investigate the pharmacodynamic profile of voreloxin. However, clinical proof of mechanism has been shown by pharmacodynamic profiling of DNA-damage responses in peripheral blood mononuclear cells from patients with acute myeloid leukemia treated with voreloxin and cytarabine (22).

The combined study population in our studies included 62 patients with a variety of advanced solid tumors that had progressed despite standard chemotherapy or for which no standard effective or curative therapy was available at the time of study. In this group of patients, best overall response of SD was achieved in 50%: 51% (21 of 41) in SPO-0001 and 48% (10 of 21) in SPO-0002.

The largest subgroup of patients in the two studies had platinum-resistant relapsed or refractory ovarian cancer (10 of 62, 16%). Encouraging preliminary clinical activity of voreloxin was observed in this population based on radiographic response (RECIST) and measurement of serum CA-125 (Rustin criteria). Although molecular profiling of patient tumor samples was not included in this study, the activity of voreloxin in ovarian cancer is intriguing because the DNA damage induced can be repaired by homologous recombination repair. Cells deficient in this BRCA-dependent repair mechanism, such as ovarian cancer with BRCA mutations, may have greater sensitivity to voreloxin (20).

In conclusion, voreloxin is a novel agent with evidence of tolerability and antitumor activity in patients with advanced solid tumors. Preliminary objective tumor response data from both dosing schedules warrant the evaluation of voreloxin efficacy in future studies. Two phase 2 studies of voreloxin have recently been completed in non–small cell and small cell lung cancers, and voreloxin is currently under investigation in a phase 2 study in platinum-resistant ovarian cancer. Early results from the ovarian cancer study suggest that doses of voreloxin above 48 mg/m2 are well tolerated, and studies with 60 mg/m2 and 75 mg/m2 are ongoing (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). Results from these ongoing studies will provide additional data regarding the full potential of voreloxin as a new cancer treatment.

R. Allen and J. Fox are current employees of Sunesis; D. Adelman, C. Berman, N. Havrilla, U. Hoch, and J. Silverman are former Sunesis employees.

Helix Medical Communications LLC edited early drafts of the manuscript.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1
Sissi
C
,
Palumbo
M
. 
The quinolone family: from antibacterial to anticancer agents
.
Curr Med Chem Anticancer Agents
2003
;
3
:
439
50
.
2
Anderson
VE
,
Osheroff
N
. 
Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde
.
Curr Pharm Des
2001
;
7
:
337
53
.
3
Gatto
B
,
Capranico
G
,
Palumbo
M
. 
Drugs acting on DNA topoisomerases: recent advances and future perspectives
.
Curr Pharm Des
1999
;
5
:
195
215
.
4
Yamashita
Y
,
Ashizawa
T
,
Morimoto
M
,
Hosomi
J
,
Nakano
H
. 
Antitumor quinolones with mammalian topoisomerase II mediated DNA cleavage activity
.
Cancer Res
1992
;
52
:
2818
22
.
5
Stockett
D
,
Byl
JA
,
Hawtin
RE
, et al
. 
SNS-595 is a potent anti-tumor agent that has a dual mechanism of action: DNA intercalation and site-selective topoisomerase II poisoning [abstract]
.
Proc of the 99th Annual Meeting of the Amer Assoc Cancer Res; 2008 Apr 12-16, San Diego, CA
,
Philadelphia (PA) AACR
, 
2008
.
Abstract 1860
.
6
Hoch
U
,
Lynch
J
,
Sato
Y
, et al
. 
Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models
.
Cancer Chemother Pharmacol
2009
;
64
:
53
65
.
7
Silverman
J
,
Hoch
U
,
Evanchik
M
,
Furutani
Y
,
Walker
D
. 
In vitro and in vivo activity of SPC-595, a novel cell cycle inhibitory cytotoxic in murine syngeneic and human xenograft tumor models [abstract]
.
Proc Amer Assoc Cancer Res
2004
;
45
.
Abstract 3840
.
8
Hoch
U
,
Evanchik
M
,
Silverman
J
. 
CYP450 inhibition, induction, metabolism, and routes of elimination of SNS-595, a novel cell cycle inhibitor currently in phase 1 clinical trials [abstract]
.
17th AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther. Nov 14-18, 2005
,
Philadelphia, PA
.
Abstract C221
.
9
Hawtin
RE
,
Stockett
DE
,
Byl
JA
, et al
.
Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II
. 
2009
,
Located at: Public Library of Science [forthcoming]
.
10
Kolitz
JE
,
George
SL
,
Dodge
RK
, et al
. 
Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: Final induction results of Cancer and Leukemia Group B Study 9621
.
J Clin Oncol
2004
;
22
:
4290
301
.
11
Guo
A
,
Marinaro
W
,
Hu
P
,
Sinko
PJ
. 
Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT)
.
Drug Metab Dispos
2002
;
30
:
457
63
.
12
Mechetner
E
,
Kyshtoobayeva
A
,
Zonis
S
, et al
. 
Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin
.
Clin Cancer Res
1998
;
4
:
389
98
.
13
Tolcher
AW
,
Eckhardt
SG
,
Kuhn
J
, et al
. 
Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties
.
J Clin Oncol
2001
;
19
:
2937
47
.
14
Therasse
P
,
Arbuck
SG
,
Eisenhauer
EA
, et al
. 
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada
.
J Natl Cancer Inst
2000
;
92
:
205
16
.
15
Rustin
GJ
. 
Use of CA-125 to assess response to new agents in ovarian cancer trials
.
J Clin Oncol
2003
;
21
:
187s
93s
.
16
Evanchik
MJ
,
Allen
D
,
Yoburn
JC
,
Silverman
JA
,
Hoch
U
. 
Metabolism of (+)-1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595), a novel replication-dependent DNA-damaging agent
.
Drug Metab Dispos
2009
;
37
:
594
601
.
17
Smith
BP
,
Vandenhende
FR
,
DeSante
KA
, et al
. 
Confidence interval criteria for assessment of dose proportionality
.
Pharm Res
2000
;
17
:
1278
83
.
18
Lancet
J
,
Kantarjian
H
,
Ravandi
F
, et al
. 
SNS-595 demonstrates clinical responses in a phase 1 study in acute leukemia. American Society of Hematology Annual Meeting Abstracts
.
Blood
2007
;
110
:
442
.
19
Lawrence
CE
,
Arbitrario
JP
,
Kumer
JL
,
Wright
J
. 
SNS-595, a novel S-phase active cytotoxic, exhibits potent in vitro and in vivo activities, and has the potential for treating advanced hematologic malignancies [abstract]
.
Proc Amer Assoc Cancer Res
2006
;
47
.
Abstract 4726
.
20
Hawtin
RE
,
Mamuszka
H
,
Arkin
MR
,
Fox
JA
. 
Ex vivo activity of SNS-595 against biopsies of acute myeloid leukemia, triple negative breast and ovarian cancers supports ongoing and potential clinical indications [abstract]
.
Proc of the 99th Annual Meeting of the Amer Assoc Cancer Res; 2008 Apr 12-16, San Diego, CA
,
Philadelphia (PA) AACR
, 
2008
.
Abstract 2830
.
21
Kwok
Y
,
Zeng
Q
,
Hurley
LH
. 
Structural insight into a quinolone-topoisomerase II-DNA complex. Further evidence for a 2:2 quinobenzoxazine-Mg2+ self-assembly model formed in the presence of topoisomerase II
.
J Biol Chem
1999
;
274
:
17226
35
.
22
Conroy
A
,
Tan
N
,
Wong
OK
,
Fox
JA
,
Hawtin
RE
. 
Clinical evidence of mechanism-based activity in voreloxin-treated AML patients [abstract]
.
AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther. Nov 15-19, 2009
,
Boston, MA
.
Abstract C226
.
23
McGuire
W
,
Matulonis
U
,
Hirte
H
, et al
. 
A phase 2 trial of SNS-595 in women with platinum resistant epithelial ovarian cancer [abstract]
.
SGO 39th Annual Meeting on Women's Cancer. Mar 10, 2008
,
Tampa, FL
.
Abstract
.
24
Hirte
HW
,
McGuire
W
,
Edwards
R
, et al
. 
A phase II trial of voreloxin in women with platinum-resistant ovarian cancer. 2009 ASCO Annual Meeting Proceedings Part I
.
J Clin Oncol
2009
;
27
:
291s
.
Abstract 5559
.
25
Maris
MB
,
Ravandi
F
,
Stuart
R
, et al
. 
A phase II study of voreloxin as single agent therapy for elderly patients (pts) with newly diagnosed acute myeloid leukemia (AML) [abstract]. 2009 ASCO Annual Meeting Proceedings Part I
.
J Clin Oncol
2009
;
27
:
367s
.
Abstract 7048
.
26
Lancet
JE
,
Karp
J
,
Cripe
L
, et al
. 
Phase Ib/II pharmacokinetic/pharmacodynamic (PK/PD) study of combination voreloxin and cytarabine in relapsed or refractory AML patients [abstract]. 2009 ASCO Annual Meeting Proceedings Part I
.
J Clin Oncol
2009
;
27
:
357s
.
Abstract 7005
.