Phase I Study of ON 01910.Na, a Novel Modulator of the Polo-Like Kinase 1 Pathway, in Adult Patients With Solid Tumors

Abstract

Purpose

We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G₂/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).

Patients and Methods

Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1.

Results

Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months.

Conclusion

ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.

INTRODUCTION

Cell cycle dysregulation is considered among the hallmark characteristics of cancer and thus constitutes a primary target for anticancer drug development. One key mediator in the intricate and overlapping control points into the mitotic phase is the polo-like kinase 1 (Plk1)–centered regulatory loop.^1,2 Plk1 is a key mitotic regulator that modulates the transition through the G₂/M checkpoint by influencing the activation of the phosphatase CDC25C and cyclin B1.³ Plk1 is overexpressed in non–small-cell lung cancer,⁴ head and neck squamous cell cancer,⁵ prostate cancer,⁶ ovarian cancer,⁷ and pancreatic cancer.^8,9 In non–small-cell lung cancer, head and neck squamous cell cancer, and ovarian cancer, high Plk1 expression was an independent prognostic factor of shorter survival. Several modalities targeting Plk1 have explored its role in cancer, including deletion mutants inducing apoptosis,¹⁰ antisense oligonucleotides with antiproliferative effect in lung¹¹ and pancreatic cancer,⁸ and interference RNAs on cervical and lung cancer.¹² This validated Plk1 as an anticancer target,¹³ but these approaches are difficult to translate to the clinic.

ON 01910.Na is a small-molecule drug that disrupts Plk1-mediated G₂/M cell cycle transition and induces mitotic arrest and apoptosis.¹⁴ Structurally, it is not an adenosine triphosphate mimetic and is believed, to compete for the substrate-binding site of the enzyme. ON 01910.Na decreases the activation/phosphorylation state of cell cycle effectors downstream of Plk1 such as CDC25C.^14,15 ON 01910.Na showed efficacy against breast and pancreatic cancer xenografts.^14,15

In an analysis of 33 investigational agents tested in phase I trials from 1991 through 2001, body-surface area (BSA)–based dosing only significantly reduced interpatient variability in drug clearance in five of the 33 agents, all five of them being conventional cytotoxics.¹⁶ On the basis of these results, the authors suggested that BSA need not be used to determine the doses of investigational agents in phase I studies. Therefore, we chose flat dosing versus a BSA-based dose calculation.

The present phase I study represents the first-in-man (to our knowledge) experience with ON 01910.Na. The primary objective was to determine the maximum-tolerated dose (MTD) of ON 01910.Na administered by 2-hour infusion on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. The secondary objectives included determining the qualitative and quantitative toxicity of ON 01910.Na and its reversibility; investigating the clinical pharmacology of ON 01910.Na, including plasma pharmacokinetics; and documenting any antitumor activity.

PATIENTS AND METHODS

Patient Eligibility

Patients had histologically confirmed malignancy for which standard curative or palliative measures did not exist; age ≥ 18 years; Eastern Cooperative Oncology Group performance status ≤ 2; life expectancy ≥ 12 weeks; and adequate bone marrow, hepatic, and renal function (absolute neutrophil count ≥ 1,500/μL, platelets ≥ 100,000/μL, bilirubin < 1.5× the upper limit of normal [ULN], AST or ALT < 2.5× ULN, and creatinine < 1.5× ULN). Patients could have received any prior therapy ending ≥ 28 days before study without residual toxicity. Measurable disease was not a requirement for study entry. Patients with radiated, clinically stable brain metastases were allowed. Patients with severe, clinically significant, and/or uncontrolled medical conditions were excluded. Our institutional review board granted approval, and written informed consent was mandatory.

Treatment Plan

ON 01910.Na was supplied by Onconova Therapeutics Inc (Newton, PA). The drug was formulated in polyethylene glycol 400 and diluted with saline for administration. Treatment consisted of ON 01910.Na administered intravenously as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle in an outpatient setting. This is based on similar divided dose schedules that showed higher efficacy in animal tumor models compared with shorter duration of administration. The starting dose of ON 01910.Na was 80 mg, which was approximately 10% of the lethal dose in 10% of treated rats for daily administration. No prophylactic antiemetics were administered. In the absence of treatment delays as a result of adverse events, treatment was administered until disease progression, intercurrent illness, unacceptable adverse event(s), or withdrawal of consent. Re-treatment required adequate laboratory parameters on every evaluation and resolution of all nonhematologic toxicities (except alopecia and fatigue) to baseline or less than grade 1. In case of a delay of more than 14 days, the patient was removed from the study.

Assessments, Follow-Up, and Monitoring

Toxic events were observed until resolution to baseline or less than grade 1. Before study entry, patients underwent a clinical history and physical examination, performance status assessment, CBC, platelet count, chemistries, urinalysis, stool for occult blood, pregnancy test (if applicable), chest x-ray, ECG, and disease assessment by computed tomography (CT) scan. Hematology was repeated before every infusion during the first cycle and then weekly; chemistries were performed weekly (or when indicated). CT scan of disease sites was repeated every two cycles. Adverse events were classified/graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events (version 3). Response was evaluated by Response Evaluation Criteria in Solid Tumors.¹⁷ Patients were considered assessable for toxicity once therapy started and assessable for efficacy if at least one cycle was administered.

Definition of Dose-Limiting Toxicity, MTD, and Dose-Escalation Plan

Dose-limiting toxicity (DLT) was defined as any drug-related grade 4 hematologic toxicity (grade 4 neutropenia ≥ 5 days), other toxicities ≥ grade 3, and grade 2 hemorrhage or neurologic toxicities. An accelerated titration design was used for dose escalation, where one patient was treated at each dose level until occurrence of ≥ grade 2 toxicity, after which three patients were treated per dose level. If no DLTs were encountered in any of the three patients in cycle 1, dose escalation was allowed. If one of the three patients experienced a DLT, three more patients were to be enrolled at the same dose level, and if none of these three additional patients experienced a DLT, dose escalation was allowed. The MTD was defined as the highest feasible dose tested in which fewer than 33% of patients experienced DLT attributable to the study drug, when at least six patients were treated at that dose and were assessable for toxicity.

Pharmacokinetic Sampling and Analytic Assay

Blood samples were collected in a tube with heparin anticoagulant at the following time points on days 1 and 15 during the first cycle: before treatment; during infusion at 15, 30, and 60 minutes and 1 hour and 59 minutes; and after the infusion at 10, 20, and 30 minutes and 1, 2, 4, 8, 24, and 48 hours. Additionally, a pretreatment trough level was obtained on days 4, 8, 11, 18, and 28. Samples were centrifuged at 1,000× g at 4°C for 10 minutes, and plasma was stored at −80°C until analysis. ON 01910.Na plasma concentrations were determined using validated liquid chromatography/mass spectrometry/mass spectometry, as described previously.¹⁸ The low and high calibration curves were established at ON 01910.Na plasma concentrations of 10 to 2,000 ng/mL and 100 to 20,000 ng/mL, respectively. The low and high curves were cross validated, and a 1:100 dilution schema was also validated.¹⁸

Pharmacokinetic Data Analysis

ON 01910.Na pharmacokinetic parameters for individual patients were estimated using compartmental analysis with WINNonlin version 5.2 (Pharsight Corporation, Cary, NC). Individual patient ON 01910.Na plasma concentration-time data were fitted with two-compartment modeling with a first-order elimination process from the central compartment. A t test was used for the comparison of parameters on days 1 and 15. The a priori level of significance was P < .05. Statistical analyses were performed with SPSS version 10.0 (SPSS Inc, Chicago, IL).

RESULTS

Patient Characteristics

Between August 2004 and March 2007, 20 patients with advanced solid tumors were enrolled onto the study. Nineteen patients were assessable for toxicity, and response could be evaluated in 16 patients. One patient in the 3,120-mg cohort developed rapid disease progression before completing her first cycle, was considered not assessable, and was replaced. Response could not be assessed in three additional patients (one was taken off study as a result of an unrelated event, one died, and a third withdrew consent). Demographic and clinical characteristics of the patients are listed in Table 1. A total of 33 cycles of the study drug was delivered (median, two cycles; range, one to four cycles).

Table 1.

Patient Characteristics

Characteristic	No. of Patients (N = 20)
Sex
Male	9
Female	11
Age, years
Median	63
Range	46-73
Eastern Cooperative Oncology Group performance status
0	8
1	11
2	1
Primary tumor site
Colorectal	7
Pancreas (adenocarcinoma)	3
Ovary	3
Biliary	2
Hepatocellular	2
Carcinoid	1
Duodenal	1
Endometrial	1

Dose-Escalation Process

The starting dose of ON 01910.Na was 80 mg (Table 2). Eight dose levels (80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg) were explored with one-patient cohorts, and no grade 2 or greater toxicities were documented. At the 4,370-mg dose level, the first patient experienced two grade 2 toxicities, and the cohort was expanded to three patients. No DLTs were seen, but as a result of multiple grade 2 events in these three patients, the cohort was expanded to six total patients to further characterize the toxicity profile and test the safety/feasibility of this dose level. The fifth patient, a woman with rapidly progressing colorectal cancer, died 12 hours after receiving her fifth infusion on cycle 1. Other patients at this dose level had experienced repeated grade 2 abdominal pain and fatigue. Of the remaining patients, two were decreased by one dose level and continued therapy, and one withdrew consent. As a result of these circumstances, this dose level was considered not feasible, and the next lower dose level (3,120 mg) was expanded to six assessable patients. One patient developed rapid progression before finalizing the first cycle and was replaced, and the third patient developed grade 3 abdominal pain that was considered a DLT. Altogether, seven patients were treated at the 3,120-mg dose level, with one DLT, one patient withdrawing consent as a result of persistent grade 2 fatigue despite having stable disease after two cycles, and seven grade 2 pain events. This dose level was felt to be tolerable and safe, but further escalation was not warranted. Therefore, the recommended dose for further study of ON 01910.Na as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle is 3,120 mg, despite the fact an MTD as originally defined was not reached.

Table 2.

Dose-Escalation Scheme and DLT

ON 01910.Na Dose (mg)	No. of Patients
		Total	DLT in First Cycle
80	1	0
160	1	0
320	1	0
480	1	0
800	1	0
1,280	1	0
2,080	1	0
3,120*	6 + 1	1†
4,370	6	1‡

Abbreviation: DLT, dose-limiting toxicity.

^*Selected dose for phase II studies.

^†The DLT was abdominal pain.

^‡Grade 5 DLT occurred. Dose level did not meet criteria for nontolerable dose level, but after one DLT and several grade 2 toxicities, the dose level was not felt to be feasible.

Toxicity

Treatment was generally well tolerated. The toxic events experienced during cycle 1 and during all cycles of therapy and thought to be possibly, probably, or certainly related to ON 01910.Na are listed in Table 3 and Appendix Table A1 (online only), respectively. The most common adverse events were fatigue, pain, nausea, vomiting, an acute urge to defecate, and abdominal complaints best described as flatulence. Fatigue was mild during the first cycle but reached grade 3 in two patients on cycle 2. Nausea/vomiting, pain, and urge to defecate were infusion related and typically occurred during the second hour of the infusion and the first 2 hours of the postinfusion period. Standard antiemetics both controlled and prevented subsequent occurrences of nausea/vomiting. Pain was categorized as skeletal (typically in the shoulders), abdominal (localized in the right upper quadrant), and related to tumor sites (in an ovarian cancer patient with skin metastasis and a colorectal cancer patient with known bone metastases). Tumor pain did not increase in intensity but remained stable with repeated infusions. Nonsteroidal anti-inflammatory and opioid drugs only partially decreased established pain or prevented it in further infusions. As described earlier, these toxicities clustered at the 3,120- and 4,370-mg dose levels, where most patients had at least one event during the first cycle. Grade 2 elevations in ALT/AST were documented in three patients, with no concomitant alterations in functional liver tests. Hematologic toxicity was mild.

Table 3.

Worst Nonhematologic and Hematologic Toxicities per Patient on Cycle 1

Toxicity	No. of Patients						Toxicity Events by Dose Level (No. of events)
				Grade (No. of events)									1,280 mg (n = 1)			2,080 mg (n = 1)			3,120 mg (n = 7)			4,370 mg (n = 6)
				1	2	3	4	5	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-5
Nonhematologic
Fatigue	11	8	3				1		1		5		4
Pain
Skeletal	8	4	4				1		1		2		4
Abdominal	3		2	1							2	1
Tumor	1		1										1
Nausea	6	6									3		3
Vomiting	5	5									3		2
Urge to defecate	5	5									3		2
Flatulence	4	4									1		3
Elevated AST	3	2	1								2		1
Elevated ALT	2	1	1								1		1
Death	1					1								1
Hematologic
Anemia	2		2								2
Lymphopenia	2		2								2

NOTE. The patients in the first five dose levels (80, 160, 320, 480, and 800 mg; n = 1 each) did not have any drug-related toxicity and are not shown.

A death occurred in a patient while on the study. A patient with rapidly progressing colorectal cancer died approximately 12 hours after receiving the fifth infusion on cycle 1. The administration had been otherwise uneventful, but that day in the morning and prompted by the development of increased symptoms, the possibility of clinical progression had been discussed. An agreement to finalize the first cycle and re-evaluate the status of her disease had been reached. That night, the family reported that the patient vomited and became unresponsive. No resuscitation was attempted, necropsy was not performed, and therefore, the cause of death remains uncertain.

Efficacy

Sixteen patients were assessable for response. In 14 patients, the best response was progression of disease. One patient each had stable disease and a partial response. The first patient had a previously progressing hepatocellular cancer and withdrew consent after two cycles as a result of fatigue despite disease stabilization. The second patient was an ovarian cancer patient diagnosed in October of 2004, with a CA-125 of 66,000 U/mL preoperatively. She underwent surgery followed by eight cycles of carboplatin and paclitaxel, with a CA-125 nadir of 24 U/mL. During her eighth cycle, she developed disease progression (CA-125 went up to 45 U/mL, and new lesions appeared in the pelvis) and started second-line topotecan. After two cycles, progressive disease was documented, with CA-125 increasing to 395 U/mL plus increased tumor volume. She received four cycles of ON 01910.Na at the 4,370-mg dose level. A minor response by CT and a significant decrease in CA-125 (from 385 to 190 U/mL while on therapy) were documented (Fig 1). The degree of the response increased in the observation period, meeting Response Evaluation Criteria in Solid Tumors for a partial response. The patient opted to stop therapy, has been observed since then, and remained progression free for 24 months.

Fig 1.

Clinical course of a 73-year-old woman with relapsed, poor prognosis ovarian cancer. After initial diagnosis in October of 2004 (CA-125 of 66,000 U/mL), she underwent surgery followed by eight cycles of carboplatin and paclitaxel. She developed disease progression during the eighth cycle (CA-125 went up to 45 U/mL from a nadir of 24 U/mL, and new lesions appeared in the pelvis) and started second-line topotecan. After two cycles, progressive disease was again documented, with CA-125 increasing up to 200 U/mL while on treatment and peaking at 395 U/mL, together with increased tumor volume. She received four cycles of ON 01910.Na, evidencing a partial response by computed tomography (CT) and a significant decrease in CA-125. The lower panel shows the evolution of the CA-125, and the upper panel depicts images from CT scan imaging before protocol therapy, at the completion of treatment, and in her 18-month follow-up.

Pharmacokinetics

ON 01,910.Na pharmacokinetic profile was characterized by a rapid distribution phase, with a distribution half-life of 1.0 ± 0.6 hours on both days 1 and 15, and a relatively slow elimination phase, with an elimination half-life of 25.6 ± 27.5 hours and 28.1 ± 16.8 hours on days 1 and 15, respectively (Table 4; Fig 2A). Systemic clearance ranged from 1.6 to 21.4 L/h and 1.9 to 22.8 L/h on days 1 and 15, respectively, and showed distribution in excess of blood volume with a steady-state volume of distribution ranging from 6.2 to 137.5 L and 6.8 to 195.9 L on days 1 and 15, respectively. There were no significant differences in pharmacokinetic parameters between days 1 and 15 (P > .05). Increasing drug exposure was achieved with increasing ON 01910.Na dose (Fig 2B). In patients treated at doses of 3,120 mg (n = 6) and 4,370 mg (n = 7), the interindividual variability in ON 01910.Na clearance assessed as the coefficient of variation were 34.4% and 82.9%, respectively. For all 20 patients, the interindividual variability in ON 01910.Na clearance was 77%.

Table 4.

Summary of Pharmacokinetic Parameters^* of ON 01910.Na After 2-Hour Intravenous Infusion

Dose (mg)	No. of Patients	Cmax (μg/mL)	AUC0-∞(h·μg/mL)	CL (L/h)	CL (L/h/m2)	T1/2,α(h)	T1/2,β(h)	Vss(L)
Day 1
80	1	4.2	8.9	9.0	6.3	0.5	2.6	10.8
160	1	6.1	20.5	7.8	4.1	0.9	19.2	70.9
320	1	6.2	15.0	21.4	11.5	0.2	4.2	48.3
480	1	12.1	24.5	19.6	10.1	0.1	1.5	11.5
800	1	14.7	42.5	18.8	9.5	0.7	24.0	137.5
1,280	1	36.4	95.0	13.5	6.5	0.7	18.0	52.2
2,080	1	91.2	228.9	9.1	4.7	0.7	13.8	29.6
3,120	7	243.1	755.2	4.8	2.5	1.1	37.3	14.3
CV, %		25.3	42.4	34.4	28.4	52.6	104.4	34.6
4,370	6	411.0	1,489.1	4.1	2.3	1.5	27.8	13.2
CV, %		37.0	50.8	82.9	71.8	46.6	49.3	77.4
All				7.9	4.2	1.0	25.6	27.0
CV, %				77.1	74.4	63.8	107.6	116.1
Day 15
80	1	6.4	15.3	5.2	3.7	0.5	4.5	11.3
160	1	5.8	20.2	7.9	4.2	0.6	45.0	195.9
320	1	6.9	16.9	18.9	10.2	0.6	21.3	132.9
480	1	6.2	21.1	22.8	11.7	0.2	20.4	94.8
800†	—	—	—	—	—	—	—	—
1,280	1	46.2	147.4	8.7	4.2	1.1	37.6	67.2
2,080	1	95.2	250.0	8.3	4.3	0.8	18.5	41.0
3,120	5	326.8	972.6	4.2	2.1	1.3	27.7	11.7
CV, %		51.8	49.0	64.0	40.5	33.8	76.6	50.9
4,370	3	371.1	1,331.8	6.1	3.2	1.3	35.5	19.9
CV, %		56.9	72.3	102.9	92.9	53.9	47.5	100.6
All				7.9	4.1	1.0	28.0	47.2
CV, %				80.8	78.4	53.9	59.9	121.7

Abbreviations: C_max, maximum plasma concentration; AUC_0-∞, area under the concentration-time curve from time zero to infinity; CL, clearance; T_1/2,α, distribution half-life; T_1/2,β, elimination half-life; V_ss, steady-state volume of distribution; CV, coefficient of variation.

^*Pharmacokinetic parameters were estimated by fitting individual ON 01910.Na plasma concentration-time curves with two-compartment model. Values are reported as means, except for CV.

^†Pharmacokinetic studies were not performed.

Fig 2.

(A) Representative ON 01910.Na plasma concentration-time profiles after 2-hour intravenous infusion at the dose of 4,370 mg in one patient. The symbols represent the observed concentration data, and the solid and dashed lines represent the predicted concentration-time curve by fitting the observed data with two-compartment model. (B) ON 01910.Na maximum plasma concentration (C_max) and (C) area under the concentration-time curve (AUC_0-∞) as a function of ON 01910.Na dose.

DISCUSSION

ON 01910.Na is a small molecule that disrupts the G₂/M cell cycle transition and induces mitotic arrest and apoptosis and has shown significant antitumor activity in vivo.^14,15 This report summarizes the investigations of the first-in-man (to our knowledge) clinical and pharmacologic experience with this agent. Given the absence of hematologic toxicity in preclinical models and the existing rationale suggesting a benefit with repeated exposure to the drug, a schedule with multiple administrations of short infusions was selected. The accelerated titration escalation design proved to be a valuable strategy in defining a clinically relevant and safe ON 01910.Na dose. This dose-escalation approach allowed a 54-fold dose escalation from the initial dose of 80 mg until grade 2 toxicity occurred at 4,370 mg, a dose level that was ultimately not considered feasible despite the fact that criteria to declare it a nontolerable level were not met. Dose level 8, consisting of 3,120 mg of ON 01910.Na as a 2-hour infusion twice weekly for 3 weeks in 4-week cycles, was defined as the MTD. At this dose level, one DLT (abdominal pain) occurred in six assessable patients, but virtually all patients reported grade 2 clinically significant toxicities during cycle 1. This dose level was considered feasible and the toxicity profile was considered acceptable for phase II development.

The most distinctive toxicities were urge to defecate and pain. There was not an evident sequence relationship between abdominal pain and urge to defecate. Pain was categorized most frequently as skeletal, abdominal, or related to tumor sites. Because most patients had abdominal malignancies, it is difficult to establish the precise origin of the pain, but in two cases, it was unequivocally pinpointed to tumor locations (skin and known bone metastases sites). Tumor pain is a defining toxicity of the cyclin-dependent kinase inhibitor flavopiridol,¹⁹ for which a pro-inflammatory syndrome also consisting of fatigue and fever has been consistently described.^20,21 This phenomenon has been associated with changes in interleukin-6, but its mechanism remains undetermined.²²

ON 01910.Na has been shown to induce a G₂/M arrest and to modulate effectors downstream of Plk1 such as CDC25C, and mechanistic data using Plk1-directed short interfering RNA downregulation indicate that its antitumor effect is at least partially explained by the inhibition of the Plk1 pathway.²³ However, the possibility of additional targets being modulated by ON 01910.Na is suggested by the low hematologic toxicity profile, in contrast to the striking hematologic toxicity reported in patients treated with BI-2536, a highly selective Plk1 inhibitor.²⁴

Antitumor activity was seen in a patient with advanced epithelial ovarian cancer. Plk1 expression is low in normal ovarian surface epithelium and borderline tumors, is high in 26% of ovarian carcinomas, and is associated with shortened survival time in multivariate analysis.⁷ A correlation was found between Plk expression and histologic grade of ovarian cancer, but Ki-67 expression was independent of Plk expression, suggesting that Plk expression reflects the degree of malignancy rather than the proliferation rate.²⁵ Indeed, the patient who had a partial response and was rendered progression free for 2 years after ON 01910.Na therapy had a poor prognosis, having shown disease progression while on primary platinum-based therapy and while on second-line topotecan. However, the activity of ON 01910.Na in this disease does not seem universal. Two other ovarian cancer patients received ON 01910.Na; one patient at the 3,120-mg dose level experienced progressive disease after two cycles, and another patient at the 4,370-mg dose level received only two infusions and opted to come off study after the clinical hold after the grade 5 event. Once additional ovarian carcinoma patients are evaluated in future studies, the determinants of any antitumor activity can be fully elucidated.

In summary, ON 01910.Na showed a distinct and manageable toxicity pattern. The recommended single-agent dose of ON 01910.Na administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle is 3,120 mg. ON 01910.Na pharmacokinetics are characterized by a rapid distribution phase and a relatively slow elimination phase. Single-agent activity was documented in a refractory ovarian cancer patient, warranting further evaluation of ON 01910.Na in this disease.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Manoj Maniar, Onconova Therapeutics Inc (C) Consultant or Advisory Role: None Stock Ownership: Manoj Maniar, Onconova Therapeutics Inc Honoraria: None Research Funding: Antonio Jimeno, Onconova Therapeutics Inc; Michelle A. Rudek, Onconova Therapeutics Inc; Sharyn D. Baker, Onconova Therapeutics Inc; Ross C. Donehower, Onconova Therapeutics Inc Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Antonio Jimeno, Jing Li, Sharyn D. Baker, Ross C. Donehower

Administrative support: Ross C. Donehower

Provision of study materials or patients: Antonio Jimeno, Jing Li, Wells A. Messersmith, Daniel Laheru, Michelle A. Rudek, Manuel Hidalgo, Sharyn D. Baker, Ross C. Donehower

Collection and assembly of data: Antonio Jimeno, Jing Li, Wells A. Messersmith, Daniel Laheru, Michelle A. Rudek, Manuel Hidalgo, Sharyn D. Baker, Ross C. Donehower

Data analysis and interpretation: Antonio Jimeno, Jing Li, Wells A. Messersmith, Daniel Laheru, Michelle A. Rudek, Manoj Maniar, Manuel Hidalgo, Sharyn D. Baker, Ross C. Donehower

Manuscript writing: Antonio Jimeno, Jing Li, Michelle A. Rudek, Sharyn D. Baker, Ross C. Donehower

Final approval of manuscript: Antonio Jimeno, Jing Li, Michelle A. Rudek, Sharyn D. Baker, Ross C. Donehower

Appendix

Table A1.

Worst Nonhematologic and Hematologic Toxicities per Patient on Any Cycle

Toxicity	No. of Patients	Grade (No. of events)									Toxicity Events by Dose Level (No. of events)
				1	2	3	4	5	320 mg (n = 1)			1,280 mg (n = 1)			2,080 mg (n = 1)			3,120 mg (n = 7)			4,370 mg (n = 6)
									Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-5
Nonhematologic
Fatigue	12	7	3	2					1		1		4	2	4
Pain
Skeletal	8	4	4						1		1		2		4
Abdominal	3		2	1									2	1
Tumor	2		2										1		1
Nausea	7	7											3		4
Urge to defecate	6	6					1						3		2
Elevated AST	5	3	2										3		2
Vomiting	5	5											3		2
Flatulence	4	4											1		3
Elevated ALT	2	1	1										1		1
Death	1					1										1
Hematologic
Anemia	2		2										2
Lymphopenia	2		2										2

NOTE. The patients at the 80-, 160-, 480-, and 800-mg dose levels (n = 1 each) did not have any drug-related toxicity and are not shown.