Vadimezan – Oh Fmk Caspase Inhibitorvi

Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800 mg/m2 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer
Mark J. McKeagea,∗ , Martin Reckb, Michael B. Jamesonc, Mark A. Rosenthald, David Gibbse,
Paul N. Mainwaring f, Lutz Freitag g, Richard Sullivanh, Joachim Von Paweli
a Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Rd, Grafton, Private Bag 92019, Auckland 1142, New Zealand
b Krankenhaus Grosshansdorf, Woehrendamm 80, D-22927 Grosshansdorf, Germany
c Waikato Hospital, Private Bag 3200, Hamilton, New Zealand
d Royal Melbourne Hospital, Melbourne 3050, Australia
e Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand
f Mater Health Services, Brisbane, QLD 4101, Australia
g Lungenklinik Hemer, Theo-Funccius-Str. 1, D-58675 Hemer, Germany
h Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand
i Asklepios Fachkliniken, Robert-Koch-Allee 2, D-82131 Gauting, Germany

A R T I C L E I N F O A B S T R A C T

Article history:
Received 15 January 2009
Received in revised form 26 March 2009 Accepted 28 March 2009

Keywords:
ASA404 AS1404 DMXAA
Vadimezan
Non-small cell lung carcinoma Clinical trial
Phase II

This single-arm phase II study evaluated the tumor-vascular disrupting agent ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800 mg/m2 plus standard therapy of carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). This ASA404 dose is 50% higher than that used in previous phase II studies. Thirty patients with histologically conﬁrmed stage IIIb or IV NSCLC previously untreated with chemotherapy received carboplatin AUC 6 mg/ml min plus pacli- taxel 175 mg/m2 plus ASA404 1800 mg/m2 every 21 days for up to six cycles. The addition of ASA404 1800 mg/m2 to standard therapy produced little change in the systemic exposure of either total or free carboplatin or paclitaxel, and was generally well-tolerated, with no cardiac serious adverse events or clin- ically relevant ophthalmic abnormalities. The best overall tumor response was partial response, which was seen in 37.9% of patients by independent assessment and in 46.7% by investigator assessment. Stable disease was seen in 48.3% of patients by independent assessment and in 43.3% by investigator assessment. Median time to tumor progression was 5.5 months by investigator assessment and median survival was
14.9 months. The data from this trial corroborate ﬁndings from a recent randomized phase II trial, which suggested improvements in efﬁcacy variables, including survival, when ASA404 1200 mg/m2 was added to standard therapy for advanced NSCLC. The manageable safety proﬁle, lack of adverse pharmacokinetic interactions and efﬁcacy outcomes seen in this single-arm study suggest that ASA404 1800 mg/m2 is a viable dose for future combination studies.

1. Introduction

Tumor vasculature, with its distinct features compared to nor- mal vasculature, represents an attractive target for cancer therapy [1]. The recent introduction of anti-angiogenic agents, such as the vascular endothelial growth factor-binding monoclonal anti- body bevacizumab [2,3] and the anti-angiogenic multiple kinase inhibitor sorafenib [4], has established vascular targeting as a viable treatment approach for various solid tumors.

∗ Corresponding author. Tel.: +64 9 3737 599×87322; fax: +64 9 3737 556.
E-mail address: [email protected] (M.J. McKeage).

Small molecule vascular disrupting agents (VDAs) include the tubulin-depolymerizing combrestatin A-4-phosphate [5–7] and ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA). ASA404 is a Tumor-VDA that has a distinct mode of action, which is microtubule-independent and has been shown in animal models to culminate in hemorrhagic necrosis of the hypoxic central tumor region [1,8–13].
ASA404 was generally well-tolerated in two phase I trials in which 109 patients received ASA404 monotherapy [14,15]. Tran- sient prolongation of the heart rate-corrected cardiac QT (QTc) interval was seen at high doses ( 2000 mg/m2) and transient, dose- dependent visual disturbances were also observed. A third phase I study investigated the potential for cardiac and ophthalmic toxicity

and found ASA404 doses of 1200 mg/m2 and 1800 mg/m2 to be well-tolerated, with no signiﬁcant effect on QTc interval or dete- rioration in ophthalmic variables [16]. Near maximal levels of the tumor-vascular damage biomarker 5-hydroxyindoleacetic acid (5-HIAA) were seen at these doses [17] and ASA404 plasma con- centrations were within the preclinical therapeutic range [18].
ASA404 has been found to have additive or supra-additive effects when combined with chemotherapy in animal models [19–21]; the therapeutic gain was most striking with taxanes, but was also apparent for agents such as platinum compounds [19,21]. These observations led to the safety and efﬁcacy of ASA404 being investigated in combination with taxanes and plat- inum chemotherapy regimens in advanced non-small cell lung cancer (NSCLC), recurrent platinum-sensitive ovarian cancer and metastatic hormone-refractory prostate cancer [22–24].
In a recent phase II randomized trial, we tested ASA404 1200 mg/m2 in the ﬁrst-line treatment of advanced NSCLC. We found that the addition of ASA404 1200 mg/m2 to standard doses of carboplatin and paclitaxel was well-tolerated, produced no sub- stantial additional toxicity and appeared to improve a range of efﬁcacy endpoints compared with carboplatin and paclitaxel alone, including response rate (31% versus 22%), median time to tumor progression (TTP; 5.4 months versus 4.4 months) and median sur- vival (14.0 months versus 8.8 months) [24].
We conducted this additional single-arm study to evaluate the efﬁcacy, safety and tolerability of ASA404 at the higher dose of 1800 mg/m2 combined with standard carboplatin and paclitaxel chemotherapy. The study was performed immediately after the phase II randomized study at a number of the same centers.

2. Patients and methods

2.1. Patient population

Men and women aged 18 years with histologically conﬁrmed, locally advanced or metastatic NSCLC (stage IIIb/IV, not curable by surgery or radiotherapy), 1 unidimensionally measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) [25] and no previous chemotherapy were eligible for inclu- sion. Other requirements included Karnofsky performance status 70%, life expectancy 3 months and adequate hematological, renal and hepatic functions. There were no restrictions relating speciﬁcally to prior history of hemoptysis, anticoagulant therapy, tumor cavitation or proximity to major blood vessels. Eligible patients could have either squamous and non-squamous histol-
ogy.
Speciﬁc criteria for exclusion were major surgery, chemotherapy or radiotherapy (unless palliative) within 4 weeks of enrollment; CNS metastases; small cell or mixed lung cancer; clinically sig- niﬁcant cardiac arrhythmia or QTc interval prolongation; severe or uncontrolled systemic disease; pregnancy; use of medication known to affect systemic serotonin levels or QTc interval within
2 weeks, or an expected need for such treatment during the study.
Patients were recruited from eight centers in Australia, New Zealand and Germany. The study was conducted according to the Declaration of Helsinki. Ethics committee approval and informed patient consent were obtained before the start of the trial.

2.2. Study design

This was a multicenter, single-arm study in which patients received ASA404 1800 mg/m2 and standard therapy of paclitaxel 175 mg/m2 plus carboplatin dosed to AUC 6 mg/ml min [26]. Treat- ment was given every 21 days for up to six cycles, or until patient

withdrawal. On day 1 of each treatment cycle, patients received paclitaxel as a 3-h i.v. infusion, then carboplatin as a 30-min i.v. infusion, then ASA404 as a 20-min i.v. infusion. Dose modiﬁcation of ASA404 was not permitted. The dose of paclitaxel was not altered unless dose reduction was required due to toxicity attributed to this agent.
The ﬁrst six patients were recruited according to early stopping rules to monitor safety. A detailed pharmacokinetic (PK) evalua- tion was undertaken to assess the potential for drug interaction between ASA404 and paclitaxel and carboplatin in combination. To facilitate this, the ASA404 regimen was modiﬁed for these ﬁrst six patients, with the ﬁrst cycle of treatment comprising paclitaxel and carboplatin, then up to ﬁve cycles of the ASA404-chemotherapy combination, and ﬁnally a single cycle of ASA404 alone. Further patients were then enrolled to provide a total of approximately 30 eligible patients.

2.3. Assessments

Patients attended a screening visit for standard screening assess- ment no more than 28 days before treatment, a study visit every week and a follow-up visit 4 weeks after study completion or with- drawal.
Tumor response was evaluated using RECIST. An independent outcomes committee undertake a blinded radiological review of all tumor assessments at the end of the study. Tumors were measured every 6 weeks until disease progression, then survival was assessed every 3 months.
Safety assessments included a symptom-directed clinical exam- ination before drug administration at all treatment cycles, and at a safety follow-up visit. Laboratory tests were performed by a cen- tral laboratory; whole blood samples were collected before drug administration for all treatment cycles, on days 8 and 15 after drug administration and at the safety follow-up visit. A urine sample was collected for urinalysis before the start of drug administration at cycles 1, 3 and 6 and at follow-up.
Intensive electrocardiographic assessments were conducted throughout the study. Three standard 12-lead ECGs were acquired during the 30-min before paclitaxel administration in order to determine baseline variability of ECG parameters (at cycles 1, 2 and 6 for the ﬁrst 6 patients; at cycles 1 and 6 for all other patients) and then at the end of carboplatin infusion (at cycle 1 for the ﬁrst 6 patients). Single ECGs were collected immediately before adminis- tration of ASA404 and then 10 min, 20 min, 1 h, 2 h and 4 h after the start of the ASA404 infusion (at cycles 2 and 6 for the ﬁrst 6 patients; at cycles 1 and 6 for all other patients). ECGs were also collected immediately before paclitaxel infusion and ASA404 infusion, and 1 h from the start of ASA404 infusion (at cycles 3–5 for the ﬁrst 6 patients; at cycles 2–5 for all other patients). If a patient developed a QTc interval (Bazett’s correction) >520 ms (men) or >540 ms (women), further ECGs were acquired until the QTc interval returned to within 30 ms of baseline on two consecu- tive ECGs.
Ophthalmic tests were performed before treatment and at follow-up. These included best corrected visual acuity, ophthalmo- logical examination, contrast sensitivity, color vision/color contrast sensitivity and central visual ﬁeld.
For the ﬁrst six patients recruited according to early stopping rules, serial PK samples were collected and analyzed after carbo- platin and paclitaxel dosing at cycle 1; after ASA404, carboplatin and paclitaxel dosing at cycle 2; and after ASA404 monotherapy 3 weeks after the end of cycle 6. Total and free concentrations for each drug were determined before infusion, at the end of infusion and at various intervals after infusion. In addition, plasma samples were analyzed for 5-HIAA concentration 2 h and 4 h after the start of ASA404 dosing on day 1 of cycles 1 and 2.

2.4. Statistical analysis

A total sample size of 30 patients was planned. Assuming an overall response rate of 27% or above, then the lower limit of the 95% conﬁdence interval would be at least 12%.
Eligible patients were deﬁned as those who met the criteria for inclusion and received at least one dose of study treatment. Efﬁcacy analyses were performed on all eligible patients who received ASA404 1800 mg/m2. Safety analyses were performed on all enrolled patients who received at least one dose of study treat- ment.
Primary safety outcomes were treatment-emergent adverse events (AEs), laboratory abnormalities, effect on QTc interval, and ophthalmic toxicity. A treatment-emergent AE was deﬁned as any unfavorable and unintended sign (including an abnormal labora- tory ﬁnding), symptom or disease associated temporally with the use of a medicinal product, whether or not considered to be related to the product. Pre-existing conditions that worsened during the study were reported as AEs. AEs occurring from the time of con- sent until 30 days after the last day of ASA404 administration were recorded. AEs were listed using MedDRA coding for System Organ Class and Preferred Term and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, or as mild, moderate or severe if NCI- CTCAE were not applicable. The relationship of the AE to treatment was assessed as deﬁnite, probable, possible or unrelated.
Plasma concentrations of ASA404, carboplatin and paclitaxel were summarized at each sampling time point. Mean maxi- mum observed concentration (Cmax) and area under the plasma concentration–time curve from time of dosing with extrapolation to inﬁnity (AUC(0–∞)) were calculated and expressed as a ratio (co-administration/alone). A ratio was regarded as statistically sig- niﬁcant at the 5% level if its 95% conﬁdence interval did not include unity.
Efﬁcacy endpoints were objective response rates, TTP and sur- vival. Kaplan–Meier survival curves were ﬁtted for TTP and survival and were used to estimate median values.
Summary statistics are reported as number and percentage of patients for categorical measures, and mean, standard deviation (SD), median and 95% conﬁdence intervals (CI) for continuous mea- sures.

3. Results

3.1. Accrual and patient characteristics

A total of 32 patients were recruited to receive ASA404 1800 mg/m2, including the ﬁrst six patients recruited according to early stopping rules. One patient withdrew consent before treat- ment and another patient experienced a serious adverse event (SAE) during the ﬁrst paclitaxel infusion and was therefore not included in the eligible population. In summary, 32 patients were recruited, of whom 31 were included in the safety population and 30 were considered eligible for efﬁcacy evaluation. One patient could not be evaluated for tumor response by independent assessment.
Pre-treatment patient characteristics are shown in Table 1. Approximately two-thirds of the patients were men. A majority of the patients had adenocarcinoma (58%), a majority had stage IV dis- ease (61%) and most had a Karnofsky performance status 90 (77%). Approximately one-third of patients had squamous cell carcinoma.

3.2. Treatment

The mean number of chemotherapy cycles given was 5.0 cycles/patient. Dose modiﬁcation of carboplatin and ASA404 was

NSCLC: non-small cell lung cancer; SD: standard deviation.

not permitted according to the protocol. Nine patients required a dose reduction of paclitaxel to alleviate neuropathy, neutropenia or thrombocytopenia. Overall, 14.2% of all treatment cycles were delayed; 58.1% patients received six treatment cycles.

3.3. Pharmacokinetics

PK evaluation was carried out for the ﬁrst six patients to assess the potential for drug interaction between ASA404 and carboplatin and paclitaxel. At cycle 1, these six patients received the carboplatin and paclitaxel combination alone and PK parameters were found to be consistent with published values [27]. At cycle 2, carboplatin and paclitaxel were co-administered with ASA404 and the PK param- eters were compared with those observed with carboplatin and paclitaxel alone. Mean PK parameters for carboplatin and paclitaxel from cycle 2, expressed as ratios to those from cycle 1, are shown in Table 2. Co-administration of ASA404 did not signiﬁcantly alter the PK parameters of either carboplatin or paclitaxel.
At cycle 7, ASA404 was administered alone and PK parame- ters were consistent with those reported previously with ASA404 monotherapy in phase I studies [16]. Mean PK parameters for ASA404 from cycle 2 expressed as ratios to those from cycle 7, are shown in Table 2. Co-administration with carboplatin and paclitaxel did not alter the mean systemic exposure to total ASA404, although there was an approximately 9-fold increase in both the AUC and Cmax values for free ASA404.

3.4. Pharmacodynamics

Peak levels of 5-HIAA occurred 4 h after ASA404 dosing. Mean concentrations (n = 6) at this time point were 176.2 91.7 nM, rep- resenting an increase of 117.7 36.6 nM from baseline. This relative increase is similar to that seen with ASA404 1800 mg/m2 in phase I studies [15,16].

3.5. Safety

Overall, the addition of ASA404 1800 mg/m2 to standard doses of carboplatin and paclitaxel was generally well-tolerated. The proportions of patients with treatment-emergent AEs, ASA404- or standard therapy-related AEs, SAEs, and deaths or study dis- continuations due to AEs are summarized in Table 3. Fifteen patients (48%) experienced one or more treatment-emergent SAE. Only one death occurred on study in the safety population, attributed to acute respiratory failure secondary to lung cancer. There were no reported AEs grade 3 associated with vascular effects of bleeding, pulmonary hemorrhage, hemoptysis, hyper-

Table 2
Ratios (co-administration/alone)a of mean pharmacokinetic parameters for paclitaxel and carboplatin (cycle 2/cycle 1) and for ASA404 (cycle 2/cycle 7) (n = 5).

Total carboplatin Free carboplatin Paclitaxel Paclitaxel metabolite Total ASA404 Free ASA404
AUC(0–∞) 0.97 0.87 1.07 0.93 0.91 9.39
95% CI 0.43, 1.51 0.37, 1.37 0.82, 1.32 0.11, 1.76 0.52, 1.30 1.59, 17.19
Cmax 1.03 0.98 1.00 0.95 0.96 9.80
95% CI 0.84, 1.21 0.81, 1.15 0.75, 1.25 0.73, 1.16 0.90, 1.03 4.54, 15.07
a In cycle 1 carboplatin and paclitaxel were given alone; in cycle 2 carboplatin and paclitaxel were co-administered with ASA404; in cycle 7 ASA404 was given alone.

tension or proteinuria. There were no apparent differences in safety between squamous and non-squamous patients receiving ASA404 1800 mg/m2.
AEs leading to withdrawal of patients from the study as deter- mined by the investigator were bone marrow toxicity, infusion site reaction, neutropenic sepsis, peripheral neuropathy and QTc inter- val prolongation (the last was shown by independent assessment to be a misdiagnosis).
Grades 3 and 4 toxicities are shown in Table 4; those that occurred in the largest percentage of patients were neutropenia (81%) and leucopenia (39%); grade 3 infections were documented in 13% of patients. The most frequent non-hematological grades 3 and 4 toxicities were nervous system disorders (19%), with periph- eral neuropathy being the most frequent event (10%). All other non-hematological toxicities of grade 3 or 4 were seen in one or two patients only ( 6.5%). The most frequent AEs considered deﬁ- nitely related to ASA404 were infusion site pain (45%) and dysgeusia (6.5%).

3.6. Efﬁcacy

The best overall tumor response by independent assessment was PR, which was seen in 37.9% (95% CI 20.7, 57.7) of patients, and 48.3% (95% CI 29.5, 67.5) of patients had SD. By investigator assessment, the response rate was 46.7% (95% CI 28.3, 65.7) and 43.3% (95% CI
25.5, 62.6) of patients had SD.
The probability of remaining free of disease progression is shown in Fig. 1; using investigator assessment data, the median TTP

Table 3
Summary of treatment-emergent adverse events (safety population).

No. of patients (%)
≥1 Adverse event Related to ASA404 31 (100)
Deﬁnite 15 (48)
Probable 4 (13)
Possible 10 (32)
Unrelated 2 (7)
Related to standard therapy
Deﬁnite 15 (48)
Probable 12 (39)
Possible 3 (10)
Unrelated 1 (3)
Grade 1a/mildb
2 (6)
Grade 2a/moderateb
11 (36)
Grade 3a/severeb
15 (48)
Grade 4a, b
2 (7)
Grade 5a, b
1 (3)

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading.
b Worst severity grade.

Table 4
Summary of treatment-emergent grade 3 and 4 toxicities (safety population).

Toxicity No. of patients (%)
Grade 3 Grade 4
Non-hematological
Nervous system disorders 6 (19) 0 (0)
Infection and infestations 4 (13) 0 (0)
Psychiatric disorders 2 (7) 0 (0) Respiratory, thoracic and mediastinal disorders 2 (7) 0 (0) Neoplasms (benign, malignant and unspeciﬁed) 2 (7) 0 (0) Fatigue 2 (7) 0 (0)
Alopecia 2 (7) 0 (0)
Pyrexia 1 (3) 0 (0)
Pain in extremity 1 (3) 0 (0)
Hypotension 1 (3) 0 (0)
Hyponatremia 1 (3) 0 (0)
Drug hypersensitivity 1 (3) 0 (0)
Abdominal pain 1 (3) 0 (0)
Hematological (derived from laboratory data)
Neutropenia 8 (26) 17 (55)
Leucopenia 11 (36) 1 (3)
Thrombocytopenia 3 (10) 1 (3)
Anemia 2 (7) 0 (0)

was 5.5 months (95% CI 4.6–7.9). The probability of survival is shown in Fig. 2; median survival was 14.9 months (95% CI 10.2–16.6).

4. Discussion

This single-arm, open-label study evaluated the addition of the Tumor-VDA ASA404 at a dose of 1800 mg/m2 to standard therapy of carboplatin and paclitaxel in patients with locally advanced and metastatic NSCLC.
The ASA404 1800 mg/m2 dose used in this study was 50% higher
than that used in previous phase II studies [22–24], yet its addition to standard therapy produced no prohibitive additional toxicity.

Fig. 1. Kaplan–Meier estimate of the probability of remaining free of disease pro- gression; eligible population (n = 30).

Fig. 2. Kaplan–Meier estimate of the probability of survival; eligible population (n = 30).

The AEs of CTC grade 3 or above reported by most patients were neutropenia, leucopenia and peripheral neuropathy, which are associated with standard therapy [3]. Although the incidence of grade 3 or 4 neutropenia (81%) was higher than that expected for standard therapy alone, its severity was generally manageable and acceptable, and there was no apparent increase in levels of neu- tropenic sepsis or other clinical sequelae of blood cytopenias. Other AEs frequently associated with standard therapy, such as nausea and renal toxicity, did not appear to be exacerbated by the addition of ASA404 at 1800 mg/m2.
The addition of ASA404 1800 mg/m2 to standard therapy did
not produce any clinically signiﬁcant ophthalmic abnormalities despite careful monitoring for such effects with intensive clini- cal, ophthalmic and electro-retinographic assessments. This dose of ASA404 does not seem to be associated therefore with the oph- thalmic AE proﬁle observed at higher monotherapy doses during phase I testing [14–16].
In the phase I studies of ASA404, the predominant cardiac AE was QTc interval prolongation [14,16], although it was only observed at doses higher than 1800 mg/m2. QTc interval prolongation did not occur in this study, despite intensive ECG monitoring. In addition, no cardiac AEs of grade 3 or above were observed. Nonetheless, as cardiac toxicity could result from the mechanism of action of vascular disrupting agents [28] the cardiac safety proﬁle of ASA404 should continue to be monitored in future studies.
As was seen in the previous randomized study of ASA404 at 1200 mg/m2 in NSCLC, co-administration of ASA404 1800 mg/m2 with carboplatin and paclitaxel produced little change in the sys- temic exposure or disposition of either total or free carboplatin or paclitaxel/6-alpha-hydroxy paclitaxel, and did not markedly alter the systemic exposure of total ASA404. Also in-line with previous ﬁndings, the concentration of free ASA404, however, was increased, which is consistent with an effect of the chemotherapy drugs on partitioning of ASA404 within plasma.
The outcomes from our single-arm study of ASA404 1800 mg/m2 added to standard doses of carboplatin and paclitaxel appear to compare favorably with those from the previous randomized phase II study in NSCLC, which included the same centers and com- pared ASA404 1200 mg/m2 plus carboplatin and paclitaxel (ASA404 1200) with carboplatin and paclitaxel alone (standard therapy) [24]. Response rates were 37.9% by independent assessment in the present study, compared with 31.3% in the ASA404 1200 group and 22.2% in the standard therapy group in the randomized study. The response rate in the standard therapy group was similar to that

reported previously for carboplatin plus paclitaxel in patients with advanced NSCLC [29]. Median TTP was 5.5 months by investigator assessment in this study compared with 5.4 months in the ASA404 1200 group and 4.4 months in the standard therapy group in the randomized study, while median survival was 14.9 months in this study compared with 14.0 months in the ASA404 1200 group and
8.8 months in the standard therapy group in the randomized study. The current study included 11 patients with squamous histol- ogy, and the previous randomized study of ASA404 at 1200 mg/m2 included a further 11 patients with squamous histology. Although these numbers are relatively small, it is notable that no evidence was seen for a difference in safety proﬁle between squamous and non-squamous patients receiving ASA404. This contrasts with pre- vious observations with bevacizumab [2] and sorafenib [30], where different safety proﬁles have been apparent in squamous and non-
squamous patients.
In conclusion, data from this single-arm study, in which patients with advanced NSCLC received ASA404 1800 mg/m2 and standard chemotherapy, corroborate ﬁndings from the previous phase II randomized controlled study of ASA404 1200 mg/m2 in the same setting. Apparently favorable efﬁcacy outcomes, lack of adverse pharmacokinetic interactions and an acceptable safety proﬁle with 1800 mg/m2 ASA404 in this study have led to the selection of this dose for use in phase III combination studies in NSCLC, which are currently ongoing.

Conﬂict of interest

There are no conﬂicts of interest.

Acknowledgements

This work was supported by Antisoma Research Limited, Lon- don, UK. We thank the patients, families, study staff and the Antisoma clinical development team.
Funding: Funding to support the study was provided by Anti- soma Research Limited, London, UK.

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