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Phase I study of intravenous ASA404 (vadimezan) administered in combination with paclitaxel and carboplatin in Japanese patients with non-small cell lung cancer

Authors


To whom correspondence should be addressed. E-mail: 107974@aichi-cc.jp

Abstract

ASA404 (5,6-dimethylxanthenone-4-acetic acid, vadimezan), a flavone-8-acetic acid analogue, is a novel tumor-vascular disrupting agent. In this study, the safety and tolerability, pharmacokinetics and pharmacodynamics of ASA404 in combination with standard therapy of paclitaxel and carboplatin (P/C) were assessed. A total of 15 Japanese patients with stage IV advanced non-small cell lung cancer were enrolled and P/C plus ASA404 at three dose levels (600–1800 mg/m2) was administered every 3 weeks. Dose limiting toxicities were observed in two patients during Cycle 1 of ASA404 treatment (Grade 3 febrile neutropenia at ASA404 1200 mg/m2 and Grade 3 QT prolongation at ASA404 1800 mg/m2) and the incidence of dose limiting toxicity was ≤1/3. The most frequently reported adverse events were injection site pain, peripheral sensory neuropathy, alopecia, neutropenia, nausea, anorexia and arthralgia, which were similar to those seen in previous Phase I/II studies. Pharmacokinetic analysis revealed the plasma area under the curve (AUC) of total ASA404 increased in a mostly dose-proportional manner within the dose range investigated. Administration of ASA404 raised plasma 5-hydroxyindole-3-acetic acid level dose-dependently by 116 and 204% after 1200 and 1800 mg/m2 doses, respectively. Partial response was observed in four patients (27%), and seven patients (47%) exhibited stable disease. Overall, the safety and preliminary efficacy profiles were comparable to those seen in non-Japanese patients in previous Phase I and Phase II studies, and support the further evaluation of ASA404 (1800 mg/m2) in Phase III studies in combination with P/C in Japanese patients with advanced non-small cell lung cancer. (Cancer Sci 2011; 102: 845–851)

Worldwide, over 1.3 million people are diagnosed each year with lung cancer, with over 1.1 million deaths.(1,2) Non-small cell lung cancer (NSCLC) accounts for 87% of all lung cancers, with most patients diagnosed at advanced stages for which the 5-year survival rate is poor (<5%).(3,4) Lung cancer is also a disease that predominantly affects the elderly, with most cases (85%) occurring in patients over 60 years of age.(5) In Japan alone, the number of newly diagnosed patients with NSCLC reached 85 000 by 2005, and 45 927 Japanese men and 17 307 women died from the disease in 2006.(6,7) Current standard treatments are usually platinum-based combination therapies, and platinum-taxane regimens predominate in Japan (>55%).(8) These treatment regimens extend survival but are rarely curative,(9,10) and there remains a need for more effective and better tolerated therapies.

Like all solid tumors, lung tumors depend upon a functional vascular supply to meet demand for oxygen and nutrients required for growth and development.(11) Furthermore, a high level of vascularity in peripheral lung tumor tissue has been shown to correlate with lung cancer progression.(12) Microvessel density in lung cancers is also a prognostic indicator of metastasis and poor survival.(13–15) The vasculature of solid tumors is typified by aberrant vessels, the unique characteristics of which present an opportunity for selective therapeutic intervention.(16,17) ASA404 (vadimezan), a flavone-8-acetic acid analogue, is a tumor-vascular disrupting agent (tumor-VDA) that selectively targets the immature and rapidly proliferating endothelial cells of established tumor vasculature.(18) ASA404 induces rapid tumor endothelial cell apoptosis and a cascade of events that induces a sustained effect on tumor blood flow, causing hypoxia, vascular failure, and inflammatory responses.(18–22) These effects lead to extensive tumor necrosis,(23) although a viable rim of surviving cells remains at the tumor periphery when the agent is used alone.(24) The activity of ASA404, which causes necrosis at the tumor core, may thus be maximized by combining it with chemotherapeutic agents, which often have greatest effect at the tumor periphery. Preclinical studies on ASA404 combined with various chemotherapeutic agents have demonstrated enhanced anti-tumor activity compared with chemotherapy alone. This synergy is most notable with taxanes,(25–27) and studies in combination with paclitaxel in human NSCLC xenografts have produced tumor cures.(25,28)

Three Phase I clinical studies with ASA404 established a maximum tolerated dose of 3700 mg/m2, with dose-limiting toxicities (DLTs) occurring at doses of 4900 mg/m2.(29–31) Side effects were relatively mild, and only transient, with moderate cardiac changes occurring at higher doses.(29,30) Visual disturbances were also reported in these studies but only at the highest doses (≥2400 mg/m2).(29–31) A dose of 1200 mg/m2 was selected for a randomized Phase II study to determine the feasibility of combining ASA404 with paclitaxel and carboplatin (P/C). The study (= 37) examined the potential for pharmacokinetic (PK) interactions between components of this regimen and evaluated its safety and efficacy in patients with previously untreated advanced NSCLC.(32) The ASA404 combination improved a range of efficacy endpoints compared with P/C alone—most notably overall survival (14.0 months in the P/C + ASA404 [1200 mg/m2] group vs 8.8 months for P/C alone). The risk of death was reduced by 27% (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.39, 1.38) with a response rate of 31 vs 22% for P/C alone.(32) A single-arm extension of this study (n = 29) subsequently elevated the ASA404 dose to 1800 mg/m2, which was well tolerated, and a median survival of 14.9 months was demonstrated.(33) Safety and efficacy endpoints were also similar in both squamous and non-squamous patients.(34) Phase II evaluations have shown that ASA404 is a promising addition to standard NSCLC chemotherapy but this must be confirmed in a larger prospective study. The Phase III study of ASA404 as a first-line treatment for NSCLC in combination with P/C (ATTRACT-1) was halted following interim data analysis showing futility. However, no safety concerns were identified.(35)

The primary objective of this open-label, non-randomized, sequential dose escalation Phase I study was to assess the safety profile and tolerability of ASA404 when administered in combination with fixed doses of P/C in Japanese patients with previously untreated, stage IIIb/IV advanced NSCLC. Secondary objectives were to characterize the PK profile in Japanese patients, to assess pharmacodynamic (PD) effects and evaluate preliminary anti-tumor activity.

Materials and Methods

Patient population.  Japanese patients ≥20 years of age with newly diagnosed, histologically or cytologically confirmed, stage IIIb/IV NSCLC were eligible for inclusion. Other requirements were that patients had no prior treatment for stage IIIb/IV disease (prior neoadjuvant or adjuvant chemotherapy within 6 months was allowed), World Health Organization (WHO) performance status (PS) of 0–1 and life expectancy ≥12 weeks. Eligible patients could have either squamous or non-squamous histology.

Specific criteria for exclusion were: symptomatic central nervous system (CNS) metastases requiring treatment; second primary cancer with the exception of non-melanoma skin cancer or cervical cancer in situ; radiotherapy (unless palliative) within 4 weeks; major surgery within 4 weeks; prior exposure to tumor-VDAs or other vascular targeting agents; pleural effusion requiring drainage; hemoptysis associated with NSCLC; long QT syndrome; myocardial infarction within 12 months; poorly controlled angina pectoris; ventricular tachycardia; history of ventricular fibrillation or torsades de pointes and use of medication known to prolong the QT interval.

Dosing and administration.  The dose of ASA404 was selected based on the current data from clinical studies held in western countries. ASA404 was administered at doses of 600, 1200 and 1800 mg/m2 as a 20 min intravenous (IV) infusion following infusion of paclitaxel (200 mg/m2 IV over 3 h) and carboplatin (IV over 30 mins at a plasma AUC of 6 mg/ml × min) on day 1 of every cycle. Each treatment cycle span was 21 days and study treatment was administered for six cycles, although responding patients could proceed beyond six cycles. The initial dose of ASA404 was 600 mg/m2, followed by dose escalation to 1200 mg/m2, and then to 1800 mg/m2. Evaluation at each dose level was performed based on data from at least three patients during cycle 1. If a DLT was confirmed during cycle 1 in one of the first three patients, the dose cohort was expanded by three additional patients for evaluation. Intra-patient dose escalation was not permitted for any patient. If the probability of DLT incidence was ≤1/3, escalation to the next dose level was performed. The recommended dose for the next phase was set as the highest achievable dose with a DLT incidence ≤1/3.

Safety assessments.  The safety population comprised all patients who had received at least one dose of ASA404 and had at least one post-baseline safety assessment after drug administration. The dose-determining population included all patients from the safety population who either completed minimum safety evaluation requirements or discontinued due to DLT in cycle 1. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0 (Japanese version). A DLT was defined as a study drug-related adverse event (AE) including cardiac toxicity, QT prolongation, Grade 4 neutropenia (for >7 days), Grade 4 thrombocytopenia and persistent CNS toxicity, including ophthalmic toxicity, or abnormal laboratory value, occurring during cycle 1. Resumption of drug administration followed if dose modification criteria were met. No study drug dose reduction was permitted.

All patients were followed for AEs and serious AEs (SAEs) for 4 weeks following the last dose of ASA404. Patients whose treatment was permanently discontinued due to an AE or abnormal laboratory value were followed at least once a week for 4 weeks. SAEs or events that had a suspect relationship to study drug, were followed at 4 week intervals, until resolution or stabilization of the event, whichever came first. Visual disturbances were assessed in all patients at baseline and end of treatment.

Pharmacokinetic and pharmacodynamic analyses.  To characterize the PK profile of ASA404, plasma concentrations of total (sum of plasma protein bound and unbound) ASA404 were measured during cycle 1 (immediately prior to infusion, <1 min before the end of infusion, and at 0.5, 1, 2, 4, 6, 24 and 48 h time points after infusion) and cycles 2–6 (immediately prior to infusion, <1 min before the end, and 1 and 4 h after infusion). Free (protein unbound) plasma ASA404 concentrations were also measured in cycle 1 only. Previous studies have shown that co-administration of ASA404 does not fundamentally alter the PK parameters of either paclitaxel or carboplatin.(32)

Urinary excretion was determined at cycle 1 day 1 (prior to infusion, start of infusion to 6 h post-infusion, and 6–24 h post-infusion) and cycle 1 day 2 (24–48 h post-infusion). Concentrations of ASA404 in plasma and urine were determined by liquid chromatography/tandem mass spectroscopy. Pharmacokinetic parameters were calculated by a non-compartmental method using WinNonlin Professional Edition (Pharsight, St. Louise, MO, USA) by lead PK analyst.

Plasma was also collected to evaluate the PD of ASA404 and determine whether markers predictive of activity could be defined. The ASA404-induced vascular damage biomarker, 5-hydroxyindole-3-acetic acid (5-HIAA) was determined, together with the angiogenesis markers, vascular endothelial growth factor (VEGF), placental growth factor, soluble VEGF receptors-1 and -2 (sVEGFR-1 and -2) and basic fibroblast growth factor. These samples were taken on cycle 1 day 1 at pre-study treatment, post-P/C dosing but pre-study drug infusion, 4 h post-study drug infusion and 24 h post-study drug infusion; and on cycle 2 day 1, cycle 4 day 1 and cycle 6 day 1 at pre-study treatment, post-carboplatin but pre-study drug infusion, and 1 h post-study drug infusion. In addition, a single blood collection was taken at the end of treatment visit.

Efficacy assessments.  Efficacy was determined using the full analysis population of all patients who had received at least one dose of ASA404 according to the intention to treat principle. Tumor response was assessed in patients with measurable disease at baseline according to response evaluation criteria in solid tumors (RECIST) criteria, performed within 28 days before start of treatment. Tumor assessment was every 6 weeks and at the end of study. Best overall response in each patient was evaluated as complete response, partial response, progressive disease or stable disease. The objective response rate in this study was evaluated as the number of patients with complete response or partial response.

Results

Accrual and patient characteristics.  A total of 15 patients with NSCLC were recruited and baseline characteristics are shown in Table 1. The majority of patients (60%) had adenocarcinoma, 13% had squamous cell carcinoma, and all patients had stage IV disease. WHO performance status (PS) was predominantly PS = 1 (73%). Approximately 70% of patients received a third course of ASA404 treatment.

Table 1.   Patient baseline characteristics
 P/C + ASA404
600 mg/m2
= 3
P/C + ASA404
1200 mg/m2
n = 6
P/C + ASA404
1800 mg/m2
n = 6
All subjects
n = 15
  1. P/C, paclitaxel and carboplatin; SD, standard deviation; WHO PS, World Health Organization Performance Status.

Sex n (%)
 Female1 (33)5 (83)2 (33)8 (53)
 Male2 (67)1 (17)4 (67)7 (47)
Age (years)
 Mean ± SD57.3 ± 12.6662.8 ± 6.2760.2 ± 2.5660.7 ± 6.62
WHO PS n (%)
 01 (33)0 (0)3 (50)4 (27)
 12 (67)6 (100)3 (50)11 (73)
Histology/cytology n (%)
 Adenocarcinoma1 (33)4 (67)4 (67)9 (60)
 Squamous cell carcinoma0 (0)1 (17)1 (17)2 (13)
 Other2 (67)1 (17)1 (17)4 (27)
Stage n (%)
 Stage III0 (0)0 (0)0 (0)0 (0)
 Stage IV3 (100)6 (100)6 (100)15 (100)
 Prior antineoplastic therapy1 (33)2 (33)0 (0)3 (20)

Safety.  Two patients exhibited DLT during cycle 1 of ASA404 treatment: one of six patients at a dose of 1200 mg/m2 had Grade 3 febrile neutropenia and one of six patients at a dose of 1800 mg/m2 had Grade 3 QT prolongation (the event resolved by day 6 of cycle 1; patient was discontinued).

The AEs observed were as expected for this population and for this class of drug,(29–33) and were experienced by all patients. The most frequently reported AEs by system organ class (SOC) were blood and lymphatic disorders, general disorders and administration site conditions, and nervous system disorders (= 15, all 100% incidence). Blood and lymphatic disorders (n = 15, 100%) consisted of neutropenia including one neutrophil count decreased (n = 13, 87%), anemia (n = 9, 60%), thrombocytopenia (n = 4, 27%), and lymphopenia (n = 3, 20%). The most frequently reported Grade 3 or 4 hematological abnormality as a laboratory parameter was reduction in absolute neutrophils. The most common AEs of any grade were injection site pain, peripheral sensory neuropathy and alopecia, each occurring in 14 (93%) patients across all doses (Table 2). These events were mostly Grade 1 or 2, and resolved without treatment or concomitant medications. Other frequently occurring AEs were neutropenia, including one neutrophil count decreased (n = 13), anorexia (n = 12), arthralgia (n = 12), and nausea (n = 12). Grade 3 febrile neutropenia was reported as DLT in one patient, but Grade 3 or 4 AEs occurred with low frequency (<15%) with the exception of neutropenia (87% over all doses, including reduced neutrophil count and febrile neutropenia) and are presented in Table 3.

Table 2.   Frequently occurring (≥33% in all patients) adverse events of any grade, regardless of study drug relationship by preferred term
Adverse eventsP/C + ASA404
600 mg/m2
n = 3 (n, %)
P/C + ASA404
1200 mg/m2
n = 6 (n, %)
P/C + ASA404
1800 mg/m2
n = 6 (n, %)
All patients
n = 15 (n, %)
  1. *Including decreased neutrophil count. P/C, paclitaxel and carboplatin.

Alopecia2 (67)6 (100)6 (100)14 (93)
Injection site pain2 (67)6 (100)6 (100)14 (93)
Peripheral sensory neuropathy3 (100)5 (83)6 (100)14 (93)
Neutropenia3 (100)6 (100)*4 (67)13 (87)
Anorexia3 (100)5 (83)4 (67)12 (80)
Arthralgia3 (100)5 (83)4 (67)12 (80)
Nausea3 (100)5 (83)4 (67)12 (80)
Fatigue2 (67)4 (67)4 (67)10 (67)
Anemia2 (67)4 (67)3 (50)9 (60)
Constipation2 (67)2 (33)4 (67)8 (53)
Myalgia2 (67)2 (33)4 (67)8 (53)
Diarrhea2 (67)2 (33)1 (17)5 (33)
Table 3.   Grade 3 or 4 adverse events, regardless of study drug relationship by preferred term
Adverse eventsP/C + ASA404
600 mg/m2
n = 3 (n, %)
P/C + ASA404
1200 mg/m2
n = 6 (n, %)
P/C + ASA404
1800 mg/m2
n = 6 (n, %)
All patients
n = 15 (n, %)
  1. *Including decreased neutrophil count. P/C, paclitaxel and carboplatin.

Neutropenia3 (100)6 (100)*4 (67)13 (87)
Anemia0 (0)1 (17)1 (17)2 (13)
Anorexia0 (0)1 (17)1 (17)2 (13)
QT Prolongation0 (0)0 (0)1 (17)1 (7)
Enterocolitis hemorrhagic0 (0)1 (17)0 (0)1 (7)
Febrile neutropenia0 (0)1 (17)0 (0)1 (7)
Femoral neck fracture0 (0)1 (17)0 (0)1 (7)
Hyponatremia0 (0)1 (17)0 (0)1 (7)
Lymphopenia0 (0)1 (17)0 (0)1 (7)
Peripheral sensory neuropathy0 (0)0 (0)1 (17)1 (7)
Pneumonia0 (0)0 (0)1 (17)1 (7)

Serious adverse events occurred in six patients, five of which occurred during the study, with none occurring at the lowest dose level of 600 mg/m2, four at 1200 mg/m2 and two at 1800 mg/m2. All these SAEs occurred in one patient each, were not clustered in any particular primary system organ class and consisted of hemorrhagic enterocolitis, femoral neck fracture, pneumonia, pharyngitis and tumor hemorrhage. Seven patients discontinued the study due to AEs (three at the 1200 mg/m2 dose and four at 1800 mg/m2). No deaths were reported during the study, but one patient died more than 40 days after the last administration of ASA404 1800 mg/m2 due to acute myocardial infarction.

Electrocardiogram (ECG)-evaluated QT prolongation occurred in three patients and T-wave inversion in one patient treated with ASA404. QT prolongation was reported in two patients who received P/C + ASA404 1800 mg/m2, one of which was Grade 3 and judged as a DLT. However, both events were asymptomatic and resolved within a short period (1 and 4 days, respectively) without treatment. There were no other cardiac events in this study.

No ophthalmic abnormalities were reported at ASA404 doses of 600 and 1200 mg/m2; two incidences of dyschromatopsia occurred at the higher dose of 1800 mg/m2. Visual acuity changes were not reported at any of the ASA404 dose levels used in this study.

Efficacy.  The best overall response by investigator assessment was partial response, which was observed in four patients (27%), and seven patients (47%) exhibited stable disease. Response data are presented in Table 4.

Table 4.   Best overall response observed by investigator assessment and RECIST criteria
Best overall responseP/C + ASA404
600 mg/m2
n = 3 (n, %)
P/C + ASA404
1200 mg/m2
n = 6 (n, %)
P/C + ASA404
1800 mg/m2
n = 6 (n, %)
All patients n = 15 (n, %)
  1. P/C, paclitaxel and carboplatin; RECIST, response evaluation criteria in solid tumors.

Complete response0 (0)0 (0)0 (0)0 (0)
Partial response0 (0)3 (50)1 (17)4 (27)
Stable disease3 (100)2 (33)2 (33)7 (47)
Progressive disease0 (0)1 (17)3 (50)4 (27)

Pharmacokinetics.  Mean plasma concentration–time profiles of total and free ASA404 in cycle 1 are shown in Fig. 1, and a summary of PK parameters is given in Table 5. After reaching Cmax at the end of infusion, plasma total ASA404 concentrations decreased biphasically over time at a dose of 600 mg/m2, becoming more monophasic at higher doses, probably due to saturation of plasma protein binding. Cmax increased dose proportionally from 600 to 1200 mg/m2 but less than dose proportionally from 1200 to 1800 mg/m2 (Fig. 2). The plasma AUC of total ASA404 was essentially dose-proportional over the range investigated (Fig. 2). Systemic clearance of total ASA404 decreased slightly with increasing dose from 3.88 L/h at 600 mg/m2 to 2.87 and 2.78 L/h at doses of 1200 and 1800 mg/m2, respectively (Table 5). Systemic clearance of free ASA404 was 20- to 50-fold higher than that of total ASA404 and the distribution volume of free ASA404 was 20- to 40-fold greater than that of total ASA404. Plasma protein binding of ASA404 was >93% and the free fraction in plasma decreased at lower total drug concentrations, indicating that protein binding is saturable. Mean urinary excretion of unchanged ASA404 was 6, 2 and 3% of the administered dose for 600, 1200 and 1800 mg/m2, respectively, and mean renal clearance was 0.2, 0.07 and 0.08 L/h, respectively. Plasma concentrations of ASA404 did not alter at each cycle, indicating that there was no accumulation of ASA404 over repeated 3-weekly dosing, consistent with its observed short elimination half-life of 4.61–7.04 h.

Figure 1.

 Mean plasma concentration–time profiles of total and free ASA404 in cycle 1 of treatment; log-linear plot. SD, standard deviation.

Table 5.   Pharmacokinetic parameters
PK parameterP/C + ASA404
600 mg/m2
n = 3 (mean ± SD)
P/C + ASA404
1200 mg/m2
n = 6 (mean ± SD)
P/C + ASA404
1800 mg/m2
n = 6 (mean ± SD)
  1. †, median (range). AUC, area under the curve; CL, clearance; Cmax, maximum plasma concentration; P/C, paclitaxel and carboplatin; PK, pharmacokinetic; SD, standard deviation; Tmax, time to maximum plasma concentration; Vss, distribution volume at steady state.

TotalTmax (h)0.32 (0.28–0.33)†0.31 (0.28–0.37)†0.33 (0.30–0.35)†
ASA404Cmax (μg/mL)137 ± 9.5224 ± 33.8247 ± 34.1
AUC0-inf (μg*h/L)260 ± 25.9650 ± 97.21040 ± 137
t1/2 (h)7.04 ± 1.065.86 ± 2.594.61 ± 1.07
CL (L/h)3.88 ± 0.772.87 ± 0.572.78 ± 0.55
Vss (L)14.4 ± 3.1211.7 ± 3.4212.9 ± 4.93
FreeTmax (h)0.32 (0.28–0.33)†0.31 (0.28–0.37)†0.33 (0.30–0.35)†
ASA404Cmax (μg/mL)3.69 ± 0.7411.0 ± 4.1720.2 ± 6.03
AUC0-inf (μg*h/L)5.87 ± 0.9718.7 ± 3.2537.6 ± 9.46
t1/2 (h)5.83 ± 0.135.68 ± 2.775.24 ± 1.92
CL (L/h)176 ± 53.7101 ± 24.680.4 ± 28.2
Vss (L)517 ± 171318 ± 81.2292 ± 227
Figure 2.

 Non-linear dose-exposure relationships for ASA404 at each dose level for (a) Cmax and (b) area under the curve (AUC).

Biomarker changes.

Effect of ASA404 on plasma 5-HIAA levels.  Plasma levels of the vascular damage PD biomarker 5-HIAA after infusion of P/C  +  ASA404 were evaluated on day 1 of cycle 1, 2, 4 and 6. Levels of 5-HIAA did not change after paclitaxel or carboplatin infusion, but were elevated 4 h after infusion of ASA404 at 1200 and 1800 mg/m2, and were still higher than baseline at 24 h post-infusion despite a post-4 h decline. Induction of 5-HIAA was dose-dependent, with increases of 116 and 204% over pre-infusion levels for 1200 and 1800 mg/m2 dosing, respectively (Fig. 3). Induction of 5-HIAA was also observed 1 h after ASA404 infusion at all doses in cycles 2, 4 and 6. These results were in agreement with previous studies in which ASA404 caused dose-dependent acute vascular disruption and induction of plasma 5-HIAA.

Figure 3.

 Rapid dose-dependent induction of plasma 5-hydroxyindole-3-acetic acid levels after ASA404 infusion at cycle 1 day 1.

Effect of ASA404 on plasma angiogenesis marker levels.  No obvious changes in plasma basic fibroblast growth factor, VEGF, placental growth factor or sVEGFR-2 were observed, and sVEGFR-1 levels were highly variable.

Effect of ASA404 on plasma inflammatory cytokine and von Willebrand factor levels.  On cycle 1 day1, increased plasma levels of the inflammatory cytokines interleukin-8 and monocyte chemotactic protein-1 were observed 4 and 24 h after ASA404 infusion (Fig. 4). Levels of von Willebrand factor increased 4 and 24 h after ASA404 infusion at the 1800 mg/m2 dose, and 24 h after ASA404 infusion at the1200 mg/m2 dose (Fig. 5).

Figure 4.

 Effect of ASA404 on levels of plasma inflammatory cytokines, (a) interleukin-8 and (b) monocyte chemotactic protein-1.

Figure 5.

 Effect of ASA404 on plasma von Willebrand factor levels.

Discussion

This single-arm, open-label study evaluated the addition of the flavonoid tumor-VDA ASA404 at three doses (600, 1200 and 1800 mg/m2) to standard P/C therapy in 15 Japanese patients with stage IV advanced NSCLC. A total of 15 patients were treated with ASA404, and three patients (two patients at 600 mg/m2 and one patient at 1200 mg/m2) completed six cycles of treatment. Approximately 70% of patients received cycle three of ASA404 treatment and the median cumulative dose was similar within each dose level (6100–7600 mg). A total of 12 patients (80%) were discontinued from the study due to AEs (= 7) or progressive disease (= 5). All dose levels were well tolerated when administered every 3 weeks, and the incidence of DLTs was ≤1/3. This safety profile was comparable to that seen in non-Japanese patients in previous Phase I and Phase II studies.(29–33) The most frequently occurring AEs regardless of causality were injection site pain, peripheral sensory neuropathy, alopecia and neutropenia. Cardiac events were not evident in this study with the exception of QT prolongation, which, although reported in three patients, did not require therapeutic intervention and could be managed through study drug discontinuation alone. No new ophthalmological abnormalities were observed in the Japanese patients in this study, suggesting that ASA404 at dose levels up to 1800 mg/m2 can be combined with P/C in this population without the ophthalmic AEs seen at higher doses in previous studies in non-Japanese patients.

PK data indicated saturation of systemic clearance as well as protein binding over the dose range investigated and was consistent with observations in non-Japanese patients.(30) Plasma half-life was consistent with previous studies and confirmed the observed non-accumulation following repeated dosing schedules. PD studies revealed that the pattern of changes seen in plasma angiogenesis markers after ASA404 infusion were markedly different from that seen with anti-angiogenic compounds, for which the typical response is an acute plasma VEGF and placental growth factor increase and sVEGFR-2 decrease.(36,37) The current study indicates that ASA404 has a distinctly different mechanism of action from anti-angiogenic agents with regard to these growth factors. In addition, acute induction of the inflammatory cytokines interleukin-8 and monocyte chemotactic protein-1 was observed after ASA404 infusion. This is in agreement with previous findings that ASA404 may indirectly lead to induction of inflammatory cytokines, vascular damage, and the release of von Willebrand factor.

Although the study was limited to 15 patients, tumor responses were noted, and combined with the observed safety profile, the results support the further evaluation of ASA404 at a dose of 1800 mg/m2 in Phase III studies in combination with P/C in Japanese patients with advanced NSCLC.

Acknowledgment

Writing assistance was provided by Articulate Science, London, UK, supported by Novartis Pharmaceutical Corporation.

Disclosure Statement

Hiromi Tanii is an employee of Novartis. Michael M. Shi is an employee of Novartis, holds stocks in Novartis and receives Research funding. Ken Kobayashi is an employee of Novartis and holds stocks in Novartis.

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