An overview on Vadimezan (DMXAA), the vascular disrupting agent

Amir Daei Farshchi Adli1, Rana Jahanban-Esfahlan1,2, Khaled Seidi1, Sonia Samandari- Rad3,4, Nosratollah Zarghami1,5,6*

1Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. [email protected], [email protected], [email protected].

2Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.

3Physiology Research Center, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

4Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. [email protected].

5Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

6Iranian National Science Foundation, Tehran, Iran. [email protected]

Correspondence should be addressed to:

Nosratollah Zarghami: Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. Mobile: +989143043710, Email: [email protected].

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cbdd.13166
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Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA(ASA404) or Vadimezan, a flavone-acetic acid-based drug is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however proposed direct and indirect mechanisms of action for DMXAA comprises: i) inducing apoptosis in endothelial cells; ii) hemorrhagic necrosis and ischemia in tumor; iii) release of serotonin (5-HT); vi) stimulation of innate immune system; v) production of inflammatory cytokines e.g. TNF, IL- 6, GCSF, KC, IP-10, and MCP-1; vi) activation of NFκB and p38 (MAPK); vii) production of nitric oxide and viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and Phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed.

Keywords: Vascular disrupting agents (VDAs), DMXAA, ASA404, Vadimezan, cancer combination therapy.


Cancer is a public health issue and one of the chief causes of death in the world with about 8.2 million deaths in 2012[1, 2]. The rate of cancer is expected to increase. So finding a new effective remedy is a necessity. In recent years, targeting of tumor vessels has been one of the main strategies for cancer treatment, due to its unmatched characteristics[3, 4]. Solid tumors require new blood vessels to deliver nutrients and oxygen to the cancer cells to grow and survive[5]. As angiogenesis inhibitors interfere with the formation of new blood vessels in solid tumors, anti-vascular agents target the established vessels in the tumor tissue exclusively[6]. There are two main categories of anti-vascular agents: ligand-dependent agents and small anti-vascular agents[7]. Small anti-vascular agents also include tubulin binding agents—for example, combretastatin-A4 phosphate[8], OXi4503[9], and flavonoid derivatives[10]. DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) is a flavonoid derivative that is considered one of the most promising anti-vascular agents[11]. Currently, DMXAA has undergone several clinical trials. In this review, development, and mechanism of DMXAA action, the clinical trials, the combination therapy, and the forthcoming of this drug will be discussed.

DMXAA development

The production of DMXAA drug was based on the discovery that Flavone-8-Acetic Acid (FAA) can cause tumor necrosis (Figure1). The FAA, a flavonoid group—which was initially synthesized as a nonsteroidal anti-inflammatory drug—surprisingly, demonstrated anti-tumor properties, as well[12-14]. However, the FAA was unsuccessful in clinical trials[15]. Therefore, the researchers at the Auckland Cancer Society Research Center (ACSRC) began testing for a more active form of the FAA and were able to synthesize DMXAA, a derivative of xanthone

and FAA analog. DMXAA has 10 to 15 times more activity than FAA. The other names of this drug are ASA404 and Vadimezan[16].

Proposed mechanism of action of DMXAA

The structure of tumor vascularization is different from normal tissues of the body[17]. Tumor vessels are immature because their hierarchical network build up is unlike normal vascular tissues, in fact, they are unevenly distributed and chaotic[5]. Tumor endothelial cells are structurally and physiologically abnormal, and more permeable to macromolecules compared to normal tissues, and also their blood flow rate is far less than normal tissues[18]. These features are considered to be the major weaknesses of tumor vessels and, therefore, can be utilized as points of a target for eliminating tumors[19].

Two types of mechanisms of action have been proposed for DMXAA: Direct and Indirect. DMXAA direct effect (DMXAA direct mechanism of action) include specific and irreversible destruction of established tumor vasculatures and the complete blockade of tumor blood flow[14, 20]. This effect is due to the induction of apoptosis in tumor endothelial cells, which, in turn, causes hemorrhagic necrosis and ischemia in tumor tissues[20-22]. The destruction of tumor vessels can be considered as the first impact of DMXAA that appears about 30 minutes after injection[23, 24]. The destruction of tumor vessel through aggregation of platelets stimulates and increases the release of serotonin (5-HT) in the plasma[23, 24]. Thus, we can consider the stable form of serum serotonin (5HIAA) as an anti-vascular marker[25]. The activation of the innate immune system is an indirect effect of DMXAA, a feature which is considered to be absent in other anti-vascular agents[26]. The induction of innate immune system stimulates inflammatory cytokine production which is responsible for tumor-specific inflammatory responses[11, 27]. Approximately, four hours after injection of DMXAA, the

amount of interleukin 6 (IL-6), tumor necrosis factor (TNF), granulocyte colony stimulating factor(GCSF), and several chemokines—such as macrophage inflammatory protein 1α (MIP-
1α), IP-10 and, KC— increases[28-30]. The rate of cytokine rising caused by DMXAA is greater in tumor tissues compared to plasma[29]. Although the molecular target of DMXAA is yet unknown, it seems that, unlike the human stimulator of Interferon gene (STING) that is not induced by DMXAA [31], the induction of the innate immune system in mice occurs by STING. DMXAA stimulates pathways that have been observed in NFκB activation in monocytes[30], vascular endothelial cells[20], and various tumor cells[32]. NFκB also promotes the production of TNF and other inflammatory cytokines[33]—which change the organization of the cytoskeleton in the tumor endothelial cells, thus, alerting their structure and shape[34]. DMXAA also escalates the levels of nitric oxide[35]. Both TNF and nitric oxide elicit vascular disrupting properties[11]. The production of TNF and nitric oxide along with other cytokines is the reason of tumor necrosis[12]. Three functions of increased permeability increased apoptosis, and decreased blood flow is mediated by TNF because in mice lacking the TNF gene[36] or TNF receptor gene[28] these three functions cannot be seen. The presence of TNF, however, reduces the maximum tolerated dose of DMXAA. Consequently, TNF is an important factor affecting the performance and toxicity of DMXAA[28].

The other effects of DMXAA include activation of p38 (MAPK) and TBK1-IRF3 pathways[37], and reduction of tumor energetics and membrane turnover[38]. Studies have, also, shown that DMXAA inhibits the activation of platelet and induces thrombosis through inhibition of phosphodiesterase and thromboxane A2 signaling [39]. Table 1 summarizes the proposed mechanisms for DMXAA.

Clinical efficacy

The DMXAA drug can be utilized alone or in combination with other anti-cancer agents to treat cancer. A web search with the terms DMXAA, Vadimezan and ASA404 in the database of clinical studies ( culminated in 18 results. These clinical trials are summarized in Tables 2 and 3. Our main focus in this paper is on presenting the newer information, including clinical trials, that, to the best of our knowledge, have not been discussed in detail earlier, in previous review articles (i.e., [40], [11],[12],[41]). Furthermore, for the completeness purposes, we have also included a brief summary of the clinical trials that have already been discussed in detail in previous review articles to help refer the interested readers to the relevant sources.

Phase I clinical trials of ASA404: Single-agent

So far, the data for four single-agent ASA404 Phase I clinical trials have been published. The first three clinical trials have been well reviewed by Baguley and McKeage in 2010[40]. Here we will just summarize them. In the first study, forty-six cancer patients participated in a dose-escalation (Phase I study) sponsored by UK cancer research. A partial response in a locally recurrent melanoma patient in the dose of 1300 mg/m2 was observed[42].

In a parallel study sponsored by UK cancer research, sixty-three cancer patients once every three weeks received 6 to 4900 mg/m2 DMXAA injections in 20 minutes. Similar to the aforementioned study, in this study, partial response with the dose of 1100 mg/m2 in a squamous cell carcinoma patients was also observed [43].

In conclusion, the application of DMXAA at low doses was well tolerated by the cancer patients in the above studies and the low doses of DMXAA did not cause myelosuppression[42, 43]. Significant clinical changes in vision, retinal and electrophysiological parameters was not seen after six times injections of DMXAA[44]. The investigation on the blood flow parameters made via a dynamic contrast enhanced-MRI method on sixteen Phase I patients before and 6-24 hours after treatment with DMXAA, showed that DMXAA in doses of 500 to 4900 had reduced the tumor blood flow[45].

Following the above studies, an additional but complete double-blinded, randomized, crossover study on new fifteen patients inflicted by refractory tumors was carried out, using weekly sequential doses of 300 to 3000, to closely compare the impact of these sequential doses on the immunity, cardiac, and visual disturbances seen in these new fifteen patients with those seen in the former patients in prior studies. A dose-dependent increase in the plasma 5-HIAA level was detected, which essentially proves that the damage of blood vessels leads to the serotonin release. At high doses of 2400/3000 mg/m2, a transient and moderate increase in QTc was noted. The results showed that the dose of 1200-1800 had the least significant side effect on the QTc interval and had the highest therapeutic effect with blood vessel destruction, which was shown by the HIAA biomarker concentration. [46].

The fourth study was sponsored by Novartis Pharmaceuticals, a Single Center, Open-label study for the characterization of parameters—such as absorption, distribution, metabolism, and excretion (ADME)—with a single dose of 3000 mg/m2 DMXAA [14C] in seven patients with the advanced tumor. In this study, the drug’s mass balance was 86.9% in both urine and feces. The study also discovered two new metabolites of M7 and M10 in the pathway for the metabolism of this drug[47].

Phase I clinical trials of ASA404: combination therapy

The data from Phase I and ex vivo studies suggest that DMXAA may have a better performance in combination with the other anti-cancer drugs. Animal model studies have shown that DMXAA acts as synergistic chemotherapy[48-50]. There are seven records for phase I clinical trials of combination therapy on the website of clinical trials. One study has been withdrawn, and four studies have no reports. Two Phase I study was also conducted by Novartis Pharma in Japan, which has published papers and is briefly discussed here.

The first trial was performed on fifteen Japanese NSCLC patients. Of these fifteen patients, three received 600 mg/m2 doses, six received 1200 mg/m2 and the remaining six received a dose of 1800 mg/m2 DMXAA plus 200 mg/m2 carboplatin and paclitaxel (AUC = 6) at six times in 21 days. In this single-arm, open-label trial, Vadimezan and paclitaxel/carboplatin was used in first treatment line. Vadimezan was well tolerated by the patients under trials, and the side effects were similar to other combination therapy studies —such as peripheral neuropathy, neutropenia, injection site pain, and alopecia. PK parameters were consistent with those seen in non-Japanese patients. Cardiac cases were not observed except in three patients that had QT prolongation. Of all the patients receiving DMXAA, only three patients completed six cycles of treatment. Dose-limiting toxicity (DLT) incidence was less than one third, which was seen in two patients. one patient had neutropenia with doses of 1200 mg/m2, and the other patient had QTc prolongation with doses of 1800 mg/m2. In this study, the level of plasma 5-hydroxyindole-3-acetic acid exhibited an increase in the range of 116% to 204%, as the amount of the applied dose was increased from 1200 to 1800 mg/m2, respectively. Such result clearly implies the dose dependency of 5-hydroxyindole-3-acetic acid increase. In four patients (27%) tumor response was seen, and in seven patients (47%) stable disease was detected[51].

In the second Japanese single-arm, open-label study, nine patients with recurrent solid tumors in advanced level were treated with Vadimezan 1800 mg/m2 and docetaxel 60 mg/m2 (n = 3) or 75 mg/m2 (n = 6). The rate of DLTs was less than one-third patients, one patient had a partial response. Five patients (55.6%) showed having unchanging disease[52].

Phase II clinical trials of ASA404: combination therapy

Randomized, Open-Label, Phase I/II study of DMXAA was conducted on locally advanced and metastatic NSCLC patients. This study, sponsored by Antisoma Research, used DMXAA in combination with carboplatin plus paclitaxel [53].

As a cohort and single-arm extension for this trial, thirty patients with the same condition received 50% higher doses of DMXAA, 1800 mg/m2 plus carboplatin and paclitaxel with the same doses. The partial tumor response rate in patients that was obtained through two separate assessments (namely, independent assessment and investigators assessment) turned out to be 37.9% and 46.7%, respectively. Higher doses of DMXAA improved median overall survival slightly (14.9 months). Overall, DMXAA and carboplatin plus paclitaxel were well tolerated by patients in both studies[54]. The side effects were mostly attributed to the carboplatin and paclitaxel, and no significant increase in toxicity was observed. Therefore, for subsequent evaluation in Phase III studies a dose of 1800 mg/m2 DMXAA was recommended[55].

In a randomized, multicenter study, the combination of docetaxel and Vadimezan was evaluated. In short, the outcome of this study was that the combination of docetaxel with DMXAA showed an acceptable toxicity without adverse drug interactions and elicited anti- CRMPC activities[56].

In a multicenter, single-arm, phase II trial, sponsored by the Swiss Group for Clinical Cancer Research, seventeen patients with extensive-stage small-cell lung cancer were treated with ASA404 (1800 mg/m2) and carboplatin (area under curve= 6) plus paclitaxel (175 mg/m2) for 21 days in 6 cycles. Although this Phase III study was initially intended to be carried out on fifty-six NSCLC patients, it was prematurely/reluctantly stopped, before its completion, mainly, because of obtaining disappointing inconsistent results from two separate NSCLC Phase III studies.

The primary goal of this study was to achieve a progression-free survival (PFS) rate of 59% at 24 weeks, which considered as a promising result to continue. However, at 24 weeks, PFS rate was only 41% (95% CI, 18% -65%). Response to the tumor was 94%. The 1-year survival rate was 57%, and overall median survival time was 14.2 months (95% CI, 8.2-16.0 months). Although, the response rate was high, the combination of ASA404 and C/P did not result in an increased PFS. All toxicities were expected[57].

Phase III clinical trials of ASA404: combination therapy

Promising results from Phase I and II, especially on NSCLC patients, triggered the undertaking of two large, randomized, double-blind, placebo-controlled Phase III trials, using DMXAA in combination with paclitaxel and Carboplatin chemotherapy—as briefly discussed in this paper and extensively explained, by Hida T and McKeage, in their work, respectively[51, 53, 55]. These studies that were sponsored by Novartis Pharmaceuticals, called ATTRACT-1 (Antivascular Targeted Therapy: Researching ASA404) and ATTRACT-2. In the ATTRACT-1 study, 1299 patients divided into the two groups of paclitaxel (200 mg/m2) and carboplatin (area under the curve= 6.0) with or without DMXAA (1.800 mg/m2), and were treated as first-line treatment intravenously every three weeks for six cycles. After six

cycles of treatment patients received either only ASA404 or placebo. Overall survival (OS) was the primary goal, and overall response rate (ORR) and progression-free survival (PFS) were the secondary goals. The analysis of the final results did not show significant differences in overall survival (OS) between the ASA404 and placebo groups—13.4 vs. 12.7 months, respectively. Median PFS was also reported in both groups 5.5 months and 25% ORR. Overall, although the drug was well tolerated in both groups, it failed to exhibit any efficacy to the addition of ASA404 to the standard chemotherapy for the first-line treatment of advanced NSCLC[58]. Like ATTRACT-1, the study of ATTRACT-2 using Vadimezan or placebo with docetaxel (75 mg/m2) as a second line treatment of the same disease on 900 patients was reluctantly stopped before its completion for similar reasons[59].

Expert opinion

One of the most prospective tumor-VDAs drugs is the Vadimezan, DMXAA, which was synthesized as flavone-8 acetic acid analogs. However, the potency and anti-tumor activity of Vadimezan have been seen to be much greater than flavone-8 acetic acid. Even though in its clinical dosages, Vadimezan exhibits no significant toxicity, it can irreversibly and profoundly prohibit the tumor blood flow [60]. This unique prohibition of blood flow property of Vadimezan can desirably cause hemorrhagic necrosis in tumor tissues of experimental models, without harming healthy vascular tissues [41]. In vivo study, injection of Vadimezan causes significant tumor responses in 80% of tumor mice models[61]. Pharmacokinetics of Vadimezan has been completely characterized, and it has been shown to be very complex, but yet very predictable[62]. It is very severely dose-dependent, and its plasma protein binding is high but yet saturable. Also, in its higher doses, it can bind with other proteins present in red blood cells[63, 64]. Other pre-clinical studies have shown additional outcomes for Vadimezan

in combination with conventional cytotoxic agents like etoposide, carboplatin, taxanes, vincristine, doxorubicin, cyclophosphamide, cisplatin, paclitaxel, and especially taxanes[49, 65]. Vadimezan doesn’t significantly change the pharmacokinetics of drugs such as paclitaxel, docetaxel, and carboplatin. Combination therapy of Vadimezan and paclitaxel/carboplatin in phase I/II for the treatment of NSCLC improves tumor responses and increases the 5-month median survival advantage, time to disease progression, and partial response in both patients with squamous NSCLC and those with non-squamous NSCLC[51, 53, 54]. These promising results led ATTRACT-1 and ATTRACT-2 to be designed and performed to visualize the functionality of Vadimezan in combination therapy with carboplatin/paclitaxel in the treatment of NSCLC. The overall purpose of these experiments was to determine the significant overall amount of survival levels (OS). However, the primary analyses of the results failed to demonstrate the significant difference in the overall survival levels (OS) between the Vadimezan group and the sham group, which, consequently, lead to the premature termination of the experiment[58].

An interesting question here is now: whether or not one should be surprised by the results of phase III experiments, considering the dramatic difference between the outcomes of Phase III experiments with those of Phase II experiments? Maybe not. In fact, the difference observed in two different median OS (8.8 months vs. 14 months) —which showed the P value of 0.33 in combination therapy of ASA404 with paclitaxel/carboplatin—was the central motivation for the start of phase III treatment studies[53]. This means that there is a little significant difference between the two different medians OS. The notion of carrying out costly large- scale experiments in hope for achieving some minute beneficial outcomes doesn’t look like
an economically wise undertaking. Similarly, such undertaking on only a specific

population, rather than on a vast variety of populations, doesn’t look like a logical move.

This scenario, consequently, brings us to the bigger question: why Vadimezan doesn’t have the expecting clinical outcome?

In this regard, some facts need to be pinpointed: Firstly, whether or not the functional mechanism of Vadimezan in human and animal models is the same. In vivo studies have shown a couple of first events, 24 hours after the injection of Vadimezan in the mice model— including inhibition of blood flow, increased permeability, increased 5-HIAA, and induction of apoptosis [20, 45, 66]. On the other hand, the injection of Vadimezan in mice increases TNF amounts, but in human, this rise is almost zero, in most cases[11]. Although the rise in TNF amount is negligible in rat trials, the corresponding tumor response is considerably significant, especially when dosages larger than those utilized in human trials are used in rat trials. Unlike in In vivo study case, in In vitro study, Vadimezan stimulates human peripheral blood leucocytes to produce TNF[67, 68].

These data demonstrate that, basically, Vadimezan should be active in humans. Because of this expectation, newer studies are in search for finding the reasons for the disappointing phase III results. These studies have demonstrated that STING receptors responsible for receiving Vadimezan signals in mice are, in fact, not functional in humans. Xanthenone-4- acetic analogs severely demonstrate species-selectivity. Analogs active in mice are inactive in humans. This finding reiterates the necessities of the proper animal model to investigate the effects of this class of drugs[69]. STING is the direct receptor of Vadimezan, which starts TBK1 and IRF3 signaling. Surprisingly, sensitivity to STING receptors is limited to murine species, and human STING is not capable of responding to Vadimezan[31]. This finding that Vadimezan cannot activate human STING is a strong deduction of the disappointing clinical results[70].

The preceding discussion, naturally, raises the following question: are the method of injections in mice and human clinical trials the same? The three chemical drugs of carboplatin, docetaxel, and paclitaxel have been decisively chosen for combination therapy of Vadimezan, based on the convincing results[49]. However, there is a big difference between these two trials. Whereas, in Vadimezan trial, the clinical trials that help inhibit both the unwanted side effects of drugs (i.e., vomiting) and high sensitivity to corticosteroids (such as dexamethasone) have been prescribed. in pre-clinical and in vivo trials, it hasn’t gone this way. The simultaneous injection of corticosteroids and VDA drugs causes the inhibition of anti-tumor effects[71]. Furthermore, corticosteroids can also inhibit the anti-tumor activity of Vadimezan in macrophages[72]. On the other hand, in a couple of phase II clinical trials of ASA404 and taxanes combination therapy performed on NSCLS patients, where corticosteroids in conjunction with ASA404 and taxanes were simultaneously used, an increased anti-tumor effects were seen [53-55]. Despite all the trials carried out so far, the effects of simultaneous utilization of steroids to treat NSCLC is still unclear. Considering the resulting outcomes so far, it is clear that more clinical studies need to be done to fully understand the impact of simultaneous injection of Vadimezan and corticosteroids on both rats and humans.

The other issue which might affect the clinical results of Vadimezan is the dilemma of whether or not the temporal aspects of the action of ASA404 has completely been considered? In pre-clinical studies, the injection of Vadimezan was either simultaneous or after the injection of therapeutic chemical drugs. The reason for such drug scheduling was to prevent the probable inhibitory effect of Vadimezan in the delivery of the chemical drug. Nevertheless, researchers have speculated that even Vadimezan with its positive effects on drug clearances might have a synergetic effect on the drug efficiency[48]. In any respect, in long terms following the vascular disrupture, Vadimezan causes hypoxia and, therefore,

induces angiogenesis and produces VEGF[40]. Now, the new question is that whether or not anti-angiogenesis agents can be utilized in conjunction with Vadimezan. The answer to this interesting question was, in fact, given in an annual meeting of ASCO in 2006. In that meeting, it was announced that the combination therapy of Vadimezan with bevacizumab improves the effect of Vadimezan in a murine xenograft model with human lung and colon cancers[73]. Relying on the findings so far, it is, therefore, safe to say that performing clinical experiments of combination therapy of Vadimezan in conjunction with anti-angiogenesis are considerably effective and could lead to quite desirable results.

The other thing, which seemed to have a role in Vadimezan phase III disappointing results, was the kind of the tumor that went under treatment in clinical trials. Highly vascularized tumors have higher sensitivity to the eradication of vasculature. The production of vasoactive mediators such as VEGF leads to hypoxia and thus causes angiogenesis in the tumor. For instance, due to genetic changes, renal cell carcinomas produce large amounts of VEGF so they can be very sensitive and exciting targets for Vadimezan therapy. In fact, it can be said that Vadimezan has an unimportant effect on the normal vasculature. On the other hand, we know that tumor vasculature is very much disorganized and non-homogenous[74]. The tumor center is suffering from hypoxia, but the border of the tumor is more like a normal vasculature. So, responses to Vadimezan in the viable rim region are reduced and is suitably called ‘viable ring’ effect[5, 75, 76]. On the second thought, it can be said that ‘viable ring’ effect is not specific for Vadimezan, as the other drugs in this class of VDAs have the same drawback[7]. No matter how much the VDA drugs disrupt tumor center vasculature, these drugs do not promise acceptable outcomes, as the peripheral tumor area can still get the needed oxygen and nutrition from the close by healthy tissues, and, therefore, continue their undesirable disruptions[5]. The viable rim region can clearly be viewed via microscopic techniques[77]. On the other hand, the peripheral tumor region is the only area of the tumor to

which novel therapeutic drugs with high molecular weights, such as antibodies, have access; Thus, Vadimezan combination therapy with these drugs seems to be an interesting and wise approach[5].

As such, Vadimezan combination therapy should not be limited to taxanes. A good understanding of the exact mechanism of Vadimezan action and the result of Vadimezan monotherapy can be useful for designing a more effective and productive combination therapy. Interestingly, the drug Vadimezan itself causes hypoxia in the tumor, and this desirable phenomenon makes the tumor more sensitive to the treatments that work more effectively under hypoxia condition. Thus, via appropriate timing and scheduling for Vadimezan combination therapy with radiotherapy, we can expect effective cure[78]. Moreover, due to its immune-stimulatory activity, Vadimezan has the potential for combination therapy with immunotherapy agents. The main problem with immunotherapy, though, is the size of tumors, which, fortunately, can be overcome by one of the available treatment methods, such as combination therapy. In short, Vadimezan can target the tumor center which is out of reach of immunotherapy, and, thereby, results in effective tumor treatment[79].


In conclusion, studies conducted on Vadimezan demonstrate high potentials for this drug. However, the failure of Phase III clinical trials highlights the significance of the need for scrutinizing the accuracy of the analytics of Phase I/II clinical results, through, perhaps, some new and/or different approaches. Moreover, as the exact mechanism of Vadimezan is not yet
demonstrated, in vivo studies should, therefore, stick to strict mechanisms. Finally, the

studies so far have made it quite clear that to treat complex and multi-feature diseases, like

cancer, we should use engineered and complex therapies. Vadimezan’s high efficiency for combination therapy with a wide spectrum of anti-tumor agents—such as anti-angiogenesis agents, chemical therapy factors, immunotherapy, radiotherapy, and other therapeutic factors-
–can bring on hope that through complete understanding of underling mechanisms of Vadimezan and through a wise choices of other anti-tumor agents for combination therapy with Vadimezan, curing tumors can become considerably effective and productive in, hopefully, the close feature.

Conflict of interest None to declare.


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Figure legend

Fig. 1. The chemical structure of DMXAA and related compounds[12].

Table 1- Proposed mechanisms of action for DMXAA.

Direct mechanisms
-Specific and irreversible destruction of tumor vessels.
-Decreasing tumor blood flow.
-Apoptosis of endothelial cells.
-Hemorrhagic necrosis and ischemia in tumor.
-Release of serotonin (5-HT).

Indirect mechanisms
-Induction of innate immune system.
-Production of inflammatory cytokines including TNF, IL-6, GCSF KC, IP-10 and MCP-1.
-NFκB and p38 (MAPK) activation.
-Production of nitric oxide.
-Reducing tumor energetics and membrane turnover.

Table 2. Summary of ASA404 Phase I single agent.

Dosage (mg/m2)
Main adverse effects
NCT Number (ref)

Single-agent, once a week.





MTD was 3700 mgm-2; one unconfirmed partial response at 1300 mgm-2; ASA404 is well tolerated.

Anxiety, urinary incontinence, and, visual disturbance at the highest dose level 4900 mgm-2.


NCT00003697 [39]

Single-agent, every three weeks.





Recommended doses for Phase II trials were 1200– 1800 mg/m2; ASA404 is well tolerated; one partial response at 1300 mgm-2.

Anxiety, visual disturbance, and Urinary incontinence.


NCT00863733 [40, 41, 57]

Single-agent crossover, once a week.


Refractory tumors



Recommended doses for Phase II studies were 1200– 1800; increase in plasma 5- HIAA was dose-dependent.

Moderate increases in the heart rate-corrected cardiac QT interval.
Visual disturbances.


NCT00856336 [41, 43]

Single-agent Open- label, single dose.


Advanced cancers


3000 mg [14C]

Two novel metabolites were identified; mass balance was 86.9% in urine and feces.


NCT01299701 [44]

Single-agent, single dose.


Cancer with Hepatic impairment



Not reported.

Not reported.



MTD: Maximum tolerated dose. *No paper is published.

Table 3. Summary of ASA404 combination therapy

Dosage (mg/m2)
Main adverse effect
NCT Number (ref)

ASA404 +PC every three weeks


NSCLC Japanese patients



Partial response in four patients (27%); stable disease in seven patients (47%);
a dose-dependent increase in plasma 5-HIAA.

Injection site pain, peripheral neuropathy neutropenia, and alopecia


NCT00674102 [48]

Docetaxel + ASA404


Advanced or recurrent solid tumors in Japanese patients



Partial response in one patients; stable
disease in five patients (55%); ASA404 had an acceptable tolerability in combination with docetaxel.

Alopecia, fatigue, neutropenia, decreased appetite,
constipation and injection site pain.


NCT01285453 [49]

Fluvoxamine + ASA404 I Solid tumors 17 Not reported Not reported Not reported Terminated NCT01299415

ASA404+ taxans I Solid tumor 54 Not reported Not reported Not reported Terminated NCT01290380

ASA404 +chemotherapy I Metastatic cancer 7 1200-1800 Not reported Not reported Terminated NCT01278758

ASA404 with paclitaxel + carboplatin chemotherapy


Metastatic cancer



Not reported

Not reported



ASA404 carboplatin/paclitaxel/


Refractory solid tumors

Not reported

Not reported



PC + ASA404 every 3 weeks





This study established the feasibility of combining ASA404 with a standard chemotherapy.

Infusion site pain, nausea, vomiting and anemia


NCT00832494 [50-52]

Docetaxel + ASA404


metastatic prostate cancer



Combination had acceptable toxicity; activity in CRMPC

Higher incidence of cardiac adverse events and neutropenia in Combination group


NCT00111618 [53]

ASA404 +PC





The trial was prematurely closed after 17 enrollments

No unexpected toxicities occurred


NCT01057342 [54]

Docetaxel + ASA404 second-line
Urothelial Carcinoma

Not reported
Not reported

ASA404+ Carboplatin/paclitaxel/


refractory solid tumors

Not reported

Not reported



PC + ASA404, first-line ATTRACT-1





Trial was stopped
for futility at the interim analysis.

Well tolerated


NCT00662597 [55]

Docetaxel+ ASA404, second-line






Trial was stopped
for futility at the interim analysis.

Not reported


NCT00738387 [56]

PC: Paclitaxel and carboplatin, NSCLC: advanced non-small cell lung cancer, CRMPC: castration-refractory metastatic prostate cancer, ES-SCLC: extensive- stage small-cell lung cancer.

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