Patients were considered eligible if they had histologically confirmed advanced solid tumors. The inclusion criteria were as follows: 1) patients for whom no standard therapy exists or who were not amenable to established treatment; 2) between 19 and 70 years of age; 3) Eastern Cooperative Oncology Group performance status of 2 or less; 4) expected life expectancy of at least 12 weeks; 5) adequate hematological, renal, and hepatic function; and 6) no prior chemotherapy, radiation therapy, surgery, and immunotherapy in the previous 4 weeks. Patients with the following conditions were excluded: 1) uncontrolled infectious disease and metastasis to the central nervous system; 2) previous bone marrow transplant; 3) symptomatic atrial or ventricular arrhythmia or congestive heart failure or medical treatment for myocardial infarction within the past 6 months; 4) psychiatric disorders or neurologic problems, including dementia or epilepsy; 5) pregnancy or lactating or with childbearing potential without the use of adequate contraception; and 6) the use of P-gp inhibitors, such as cyclosporine, within 2 weeks prior to study enrollment.

This phase I, open-label, dose-escalating study was conducted at Seoul National University Hospital (Seoul, Korea). This study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB H-0605-025-174). This study was also registered at http://www.clinicaltrial.gov (NCT01491204).

Paclitaxel solution was started with a dose of 60 mg/m² and was increased up to 480 mg/m², in increments of 60 mg/m². A total of 300 mg of paclitaxel, without Cremophor EL (CrEL) and ethanol, is contained in a 10 mL paclitaxel solution. The dose of HM30181A was half that of paclitaxel. HM30181A was administered with 200 mL water, under an overnight fasting condition, 1 hour before paclitaxel treatment. Each cycle was 28 days, and the test drugs were administered on days 1, 8, and 15 within each cycle. No premedication for hypersensitivity was delivered. Toxicity was graded in accordance to the Common Toxicity Criteria for Adverse Events ver. 3.0 [9]. DLT was defined as follows: 1) grade 4 neutropenia that lasted 7 days in duration or with fever (≥ 38.5°C); 2) grade 3/4 thrombocytopenia for ≥ 7 days in duration or with transfusion or bleeding; 3) treatment delay of > 2 weeks due to drug-related toxicities; or 4) grade 3/4 nonhematologic toxicity (excluding nausea, vomiting, alopecia, anorexia, and fever) that occurred during the first cycle of treatment. In case of toxicity corresponding to DLT after the second cycle, the dose of the following cycle was reduced by 25% of the initial dose. If the hematologic and nonhematologic toxicities were not recovered appropriately by the D1 of the following cycle, or it was necessary to delay dosing for patients’ safety, as determined by the principle investigator, administration could be delayed up to 2 weeks. Patients with absolute neutrophil count (ANC) ≥ 1,500/mm³ and platelet count (PLT) ≥ 100,000 /mm³ were permitted for day 1 dosing, and ANC ≥ 1,000/mm³ and PLT ≥ 75,000/mm³ for D8 and D15 dosing. Dose escalation followed the standard 3+3 rule. The MTD was defined as the dose level; at which, two or more patients experienced DLTs.

Tumor responses were evaluated every two cycles according to Response Evaluation Criteria In Solid Tumors (RECIST) ver. 1.0 [10]. Patients were withdrawn from the study when they displayed signs of progressive disease or unacceptable toxicity, or simply when they withdrew consent.

At least two patients at each dose level underwent blood sampling during the first cycle. The blood sampling times for paclitaxel were immediately before administration, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 34, and 48 hours after administration; the blood sampling times for HM30181 were immediately before administration, 0.5, 1, 2, 3, 4, 5, 7, 11, 25, 35, and 49 hours after administration. The plasma concentrations of paclitaxel and HM30181A were measured using a validated liquid chromatography/tandem mass spectrometry method [11]. The actual sample collection time was used for pharmacokinetic analyses. The maximum plasma concentration (C_max) and time required to reach the C_max (T_max) parameter estimates were the actual observed values. The area under the curve (AUC) was calculated by applying a linear-up/logdown trapezoidal method to the observed plasma concentration-time graph. The pharmacokinetic parameters of the test drugs were calculated by using noncompartmental analysis and WinNonlin ver. 5.2 (Pharsight, CA). To evaluate the systemic exposure of paclitaxel according to the dosegroup, we used a noncompartmental analysis because it required little assumption, while providing an exact estimate of pharmacokinetic exposure to individuals. The elimination constant (λz) was determined by a log-linear regression analysis of the terminal phase, and the elimination half-life (T_1/2) was obtained by ln(2)/λz. The AUC from time 0 to infinite time (AUC_inf) was obtained by summing AUC_last (AUC from 0 to the last time to measure the plasma concentration) and AUC_ext (estimated by taking the ratio between the last measurable plasma concentration and λz). Oral clearance (CL/F) was calculated by dividing the total paclitaxel dose by AUC_inf. The volume of distribution (Vd/F) of oral paclitaxel was determined by measuring the ratio of CL/F to λz. The mean residence time was calculated as 1/λz. To evaluate the dose proportionality, the power model (Y=Exp(α) (Dose)^β Exp(ε), If beta=1, dose-proportionality can be declared) was applied to each dose-dependent PK parameter (C_max, AUC_last) [12]. All statistical analys es were performed using SAS ver. 9.1 (SAS Institute Inc., Cary, NC).

A total of twenty-five patients were enrolled in the study. However, one male patient withdrew his consent without any treatment due to an aggravation from an underlying disease. The baseline characteristics of the remaining 24 patients are shown in Table 1. Three patients with history of adenoid cystic carcinoma underwent radiotherapy-only treatment. The remaining 21 patients were treated with systemic chemotherapies.

Distribution of patients across the cohort and dose escalation scheme are described in Table 2. Three patients were selected to receive each dose level, excluding the 240 mg/m² dose level, which induced one case of DLT. All patients adhered to the prescribed medications, and the compliance rate was 100%. A total of 83 cycles of paclitaxel were administrated to 24 patients. The median cycle number for paclitaxel was 2.0 (range, 1 to 16) across the entire study population, and the highest cycle number was observed for the 180 mg/m² dose level (7 cycles; range, 4 to 8).

Regarding the paclitaxel dose level of 240 mg/m², grade 3 neutropenia without fever occurred in a patient with metastatic breast cancer, who was previously treated with four lines of systemic chemotherapies, including paclitaxel. The first cycle could not be completed within 6 weeks in this patient. No other DLT was observed throughout the remaining dose levels; thus, it was not possible to determine MTD.

There were 15 cases of hematologic toxicities and 55 cases of nonhematologic toxicities related to the treatment. Table 3 summarizes the drug-related hematologic toxicities for each dose level. All of the grade 3/4 hematologic toxicities were observed at dose levels of 240 mg/m² or higher. The most frequent drug-related nonhematologic toxicities included diarrhea (16 patients), nausea (8 patients), and alopecia (7 patients). Table 4 summarizes the drug-related nonhematologic toxicities observed during the study. There was no grade 3 or higher nonhematologic toxicity.

One patient with refractory non-small cell lung cancer, who exhibited multiple lung and bone metastases, experienced a serious adverse event (SAE) at a paclitaxel dose of 420 mg/m². SAE was cholangiohepatitis, which was recovered after endoscopic biliary drainage. This event had no causal relationship with the investigational product.

Except the 2 patients who did not consent to collect PK samples and 5 patients whose blood samples were not adequate for analysis, pharmacokinetic evaluations were performed in 17 patients following the first dose over the 60-420 mg/m² dose range of paclitaxel. The pharmacokinetic parameters of paclitaxel are described in Table 5. Fig. 1 depicts the concentration versus time curves of paclitaxel at each dose level. Paclitaxel was rapidly absorbed, and the peak plasma concentration was achieved within 0.5-1 hour of administration. The T_1/2 was 19.9-32.1 hours across all the dose levels (Table 5), which did not show any trend with the dose levels. The mean AUC_last values for the doses of 60, 120, 180, 240, 300, 360, and 420 mg/m² were also shown in Table 5. The maximal C_max value and the maximal AUC_last value were obtained at a dose level of 300 mg/m² and 420 mg/m², respectively. Although the dose proportional tendency in pharmacokinetic property was shown using a power model (95% confidence interval of the slope, 0.414 to 1.305 for C_max and 0.204 to 1.302 for AUC_last) (Fig. 2), C_max and AUC_last of paclitaxel did not exhibit a significant increment in response to paclitaxel dose escalation beyond the dose level of maximal C_max and AUC_last. The plasma concentration of paclitaxel over time revealed that the effective range (0.01-0.1 μM) [13] was achieved with doses of 120 mg/m² or higher for 24 hours.

Twenty-three patients had measurable diseases. Eight (34.8%) of these patients exhibited stable disease (SD), and 15 patients (65.2%) exhibited progressive disease. Tumor shrinkage was not reported in this study. With regard to each dose level, one, one, three, two, and one patient exhibited SD at 60, 120, 180, 240, and 420 mg/m². The median duration of SD was 16.5 weeks (range, 12.5 to 62.3 weeks). Among the eight patients who displayed SD, five had adenoid cystic carcinoma, and the remaining 3 had non-small cell lung cancer, rectal cancer, and gallbladder cancer.