ABSTRACT
Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ in their mechanism of action and therapeutic application. Combining these two agents may realize the full potential of VTT and produce an effective therapeutic regimen. Here, we review AAs and VDAs (monotherapy and in combination with conventional therapies). We also discuss the rationale of combined VTT and its potential to treat cancer.
Introduction
A functioning vascular supply is not only essential for the growth of solid tumors but also plays a critical role in metastatic spread (Citation1, 2). Early in their development, tumors utilize the vasculature of the host tissue in which the tumor arises. Once tumors reach a few millimeters in size, this host vasculature becomes inadequate in meeting the oxygen and nutrient demands of the growing tumor mass (Citation3). At this point, the tumor requires new tumor-specific blood vessels, which are formed primarily from the host vasculature via angiogenesis (Citation2). The tumor neovasculature that results is very different from vessels found in normal tissues (Citation3, 4): it is structurally chaotic with abnormal vascular density, contour irregularities, haphazard vessel interconnection, and loss of hierarchy. The tumor blood vessels are very primitive, with incomplete or missing basement membranes, and lack innervation and pharmacological receptors. Additionally, they are deficient in smooth muscle and pericytes and are, therefore, more reliant on endothelial cells to maintain the flat shape of vessel wall (Citation5). These attributes result in highly variable blood flow through the tumor vessels.
As tumor vasculature is essential for the development and progressive growth of tumors, this makes it a key anticancer target. Two important approaches in anticancer treatment have developed (Citation6–8): (1) the use of agents that inhibit the development of new vasculature (anti-angiogenesis and antivasculogenesis); and (2) treatments that destroy existing blood vessel networks (vascular disruption). Although both the anti-angiogenic agents (AAs; also known as angiogenesis inhibitors) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ markedly in their mechanism of action and therapeutic application. These differences give rise to the possibility that AAs and VDAs in combination may produce an effective therapeutic regimen. Although there are older previously published reviews assessing vascular targeted therapies (VTTs) in oncology (Citation8–10), here we conduct a broader review of the VTT field, with an update of clinical trials. In this review, we appraise both AAs and VDAs and focus on the rationale of combined VTT and its potential to treat cancer.
Anti-angiogenic agents
Tumoral angiogenesis was first suggested as a therapeutic target in the early 1970s (Citation1) and, to date, many AAs have been identified and characterized. The detailed steps of angiogenesis are not included here as they have been reviewed elsewhere (Citation11). AAs inhibit the tumor-initiated angiogenic process by interrupting essential aspects of angiogenesis to prevent further development or expansion of the tumor neovascular network (). Consequently, these agents can be effective at inhibiting tumor progression (Citation2, 12, 13). Most AAs target the angiogenic factors secreted by tumor cells (Citation14) and suppress tumor growth by inhibiting the migration and proliferation of endothelial cells (Citation15, 16).
Figure 1. Solid tumor undergoing treatment with combined vascular targeted therapies (VTT). The top portion of the figure illustrates anti-angiogenic agent (AA)-induced inhibition of tumor progression. The lower portion of the figure illustrates vascular disrupting agent (VDA)-induced necrosis of the central tumor cells (with a peripheral rim of viable tumor cells spared). The right-hand side of the figure illustrates the complementary effects of VDAs and AAs in combination (combined VTT): the destruction of blood vessels in the interior of the tumor and the prevention of new tumor vasculature formation, which together have negative effects on the tumor's growth and survival. ©2017 Link Health Group, LLC; Illustrated by Laura Maaske, Medimagery LLC.
In tumor development, angiogenic factors are upregulated by a variety of mechanisms, including loss of tumor suppressor gene function, oncogene activation, and hypoxic microenvironments (Citation14, 17). Vascular endothelial growth factor (VEGF) is considered the major driver of angiogenesis in solid tumors as it is essential for endothelial cell proliferation and vessel formation. VEGF induces vascular permeability and is vital to endothelial cell survival in new vessels. Thus, the inhibition of VEGF, or other components of the angiogenic pathway, is key in anti-angiogenic cancer treatment. There are three major approaches to achieve VEGF blockade including targeting the VEGF ligand with agents such as bevacizumab (Citation18) (humanized anti-VEGF antibody), targeting VEGF signal transduction with tyrosine kinase inhibitors (e.g., cediranib) (Citation19), and using soluble recombinant fusion proteins that act as decoys for VEGF receptors (e.g., aflibercept) (Citation20). Other important pro-angiogenic mediators, which may also serve as targets for anti-angiogenic therapies (Citation21), include platelet-derived growth factor (Citation22), fibroblast growth factor (Citation23), and angiopoietins (Citation24).
AAs can inhibit the growth of newly formed blood vessels in tumors by targeting either the endothelial cells directly or by targeting other tumor-associated stromal cells (Citation25, 26). In 2004, the US Food and Drug Administration (FDA) approved the first AA, bevacizumab, for the treatment of colorectal cancer (Citation27). Since then, the FDA has approved bevacizumab for several other indications, including cervical cancer, renal cell carcinoma, recurrent glioblastoma, non-small cell lung cancer (NSCLC), and platinum-resistant ovarian cancer. A number of other AAs have also been FDA-approved, as shown in . These agents are currently being investigated in a variety of tumor types, while a number of new AAs are in clinical development ().
Table 1. Select anti-angiogenic agents that are FDA-approved for cancer treatment.
Table 2. Vascular targeted therapies in active clinical development.
AAs as monotherapy
There are a small number of AAs with FDA-approval as single-agent therapy in cancer treatment. Bevacizumab is approved as monotherapy for patients with recurrent glioblastoma following prior cancer treatment. The approval was based on the durable objective response rates observed in two single-arm trials (NCT00345163 and NCI 06-C-0064E) (Citation28–30). Ramucirumab is approved for use as a single agent for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, whose disease has progressed during or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy (NCT00917384). (Citation31, 32).
Due to the complexity of the pathways available for neovascularization, it is unlikely that inhibiting only a single mechanism (or pathway) of angiogenesis will be sufficient to control a tumor (Citation13). AA monotherapy is unlikely to be curative even after prolonged administration at high doses; however, it has clinical utility when used as maintenance therapy in cancer patients previously treated with first- or second-line chemotherapy in order to extend progression-free survival (PFS) (Citation33, 34).
AAs in combination with conventional therapies
AAs are more effective when combined with other conventional therapies, such as chemotherapy or radiotherapy, and may be added to treatment regimens to increase their efficacy or to reduce developing therapeutic resistance. The effectiveness of AAs in combination therapy may be due to the inhibition of potential tumor regeneration arising from residual cells that remain following initial anticancer treatment. While AAs in combination with chemotherapy have been extensively reviewed previously (Citation35–38), it is important to highlight that the majority of studies showed an increased benefit with this combination (Citation39, 40), with only a small number showing no additional benefit (Citation41–45). The sequencing schedule of AAs in combination with chemotherapy can be neoadjuvant, concurrent, (Citation46, 47) or adjuvant depending on the cancer type and which AA and chemotherapeutic agents are used (Citation48, 49).
Radiotherapy failures occur due to local tumor progression and/or tumor cell dissemination to distant sites (Citation50). Thus, inhibition of progression or spread can result in improvement of radiation treatment outcome. Numerous preclinical studies have investigated the therapeutic potential of combining AAs with radiation treatments (Citation40–42). There are relatively few clinical studies focusing on AAs in combination with radiotherapy; however, it is generally accepted that the combination of AAs and radiation therapy is superior to either treatment alone (Citation51–53). There have been a number of Phase I (NCT00307736), II (NCT00847119 and NCT00281840) and III (NCT00943826 and RTOG 0825) clinical trials that have investigated bevacizumab in combination with chemoradiation (Citation54–61) and have shown an increased benefit. However, in a Phase II trial (NCIC CTG BR.20) with vandetanib (ZD6474) in combination with chemoradiation in small cell lung cancer patients, vandetanib failed to show any efficacy (Citation62). The importance of sequencing between AAs and radiation has been investigated in both preclinical and clinical studies, although due to the lack of standardization for drug doses, treatment times and combination schedules that are applied with radiation, it is difficult to draw definitive conclusions. However, most studies have demonstrated that an adjuvant schedule may be more effective than concomitant or neoadjuvant administration (Citation63–65).
Early clinical studies have shown promising results for immunotherapy and AA combination therapy. The majority of these investigations utilized the AA bevacizumab. A Phase I study (NCT00790010) combining ipilimumab, a monoclonal antibody that activates the immune system by targeting CTLA-4, and bevacizumab in advanced melanoma patients yielded a 19.6% objective response rate and a median survival of 25.1 months (N = 46) – an outcome nearly twice that expected for ipilimumab alone (Citation46). High-grade colitis was observed in two patients, but this was not unexpected as colitis is an adverse effect of ipilimumab treatment. Results of a Phase Ib study (NCT01633970) presented at the 2015 Genitourinary Cancers Symposium, which combined atezolizumab, a monoclonal antibody against the protein programmed cell death-ligand 1 (PD-L1), with bevacizumab in clear cell metastatic renal cell carcinoma patients showed that the combination led to immune modulation in the tumor microenvironment, was well-tolerated, and offered promising clinical activity (Citation47).
Vascular disrupting agents
The pivotal role of tumor vasculature and its selective destruction were first highlighted by Woglum in 1923 (Citation66). While the feasibility of the VDA concept was suggested by experience with colchicine in the 1930s (Citation67), it wasn't until more recently, that the effects of VDAs on tumor pathophysiology began to be extensively studied and described (Citation51, 68–74). A number of other reviews of the VDA field have been published recently (Citation75–77). These agents damage the established tumor neovasculature, thus depriving tumors of oxygen and essential nutrients, resulting in rapid and widespread ischemia and necrosis in tumors, while leaving the blood flow through normal tissues unaffected (Citation68, 78–81). Although VDA treatment leads to extensive necrosis in the inner regions of tumors, typically a rim of viable tumor cells remains at the tumor periphery in areas where tumor and normal tissues interface (Citation69, 82–88) (). Tumor cells survive in these regions and serve as a source for tumor regrowth because the nearby normal tissue vasculature that supports their nutritional needs is unaffected by VDA treatment. Hence, the potential value of VDAs requires the addition of other therapies or agents, as covered in this review.
Small-molecule VDAs exploit the unique features of the tumor endothelium to induce selective vascular dysfunction (Citation68, 79). Many of these agents are tubulin-binding VDAs and include first-generation VDAs, such as combretastatin A4-phosphate (CA4P or fosbretabulin), and second-generation VDAs, such as OXi4503 (combretastatin A1-diphosphate or CA1P). Newer compounds have been evaluated in vitro/in vivo (Citation89, 90) but face the same shortcomings as other VDAs. The principle mechanism of action of tubulin-binding VDAs is believed to be the selective disruption of the cytoskeleton of proliferating endothelial cells, thereby changing the shape of the cells (Citation91). Binding to tubulin causes microtubule depolymerization, cytoskeletal rearrangements, and activation of actin stress fibers in endothelial cells, leading to changes in cell morphology (Citation69, 85, 91, 92); this, in turn, leads to the rounding up and detachment of the affected endothelial cells (Citation84, 93). In addition, leakage of plasma proteins results in increased interstitial fluid pressure (IFP), which is sufficient to contribute to vascular occlusion via a direct increase in resistance to blood flow. Loss of cell-to-cell contact also results in the exposure of abnormal basement membrane, which activates platelets and induces the coagulation cascade to form thrombi. Taken together, the damage to the expanding tumor vascular network leads to an occlusion of blood flow, and the subsequent compromised supply of oxygen and nutrients induces necrosis of tumor cells downstream (Citation68, 78–81). Although several VDAs are in clinical development (Citation94) (), CA4P is the most extensively studied tubulin-binding VDA. Robust evidence of tumor blood flow reductions has been reported in both preclinical and clinical investigations with this agent (Citation74, 78, 88, 95–97). For most other VDAs, published clinical evidence of meaningful blood flow reduction is limited (Citation97–107).
Synthetic flavonoids, particularly flavone acetic acid and its derivative DMXAA (also known as ASA404), represent another series of small-molecule VDAs that have been investigated extensively. The main action of flavonoids on endothelial cells in the tumor vasculature is thought to involve a cascade of direct and indirect events, which include release of vasoactive agents and cytokines, leading to induction of hemorrhagic necrosis (Citation99, 108). ASA404 is the only flavonoid agent to advance to Phase III clinical trials. While it failed in NSCLC (NCT00738387) (Citation109), it did show evidence of tumor blood flow reduction (Citation110–112).
In addition to the small-molecule VDAs, certain chemotherapeutic drugs, such as vinca alkaloids and arsenic trioxide, can directly damage the tumor vasculature (Citation113, 114). Furthermore, ligand-based VDA therapies use antibodies, peptides, or growth factors to deliver toxins, pro-coagulants, or pro-apoptotic effectors to the tumor vessels (Citation9, 68, 78, 79, 81, 115, 116).
It is also important to note that there are a small number of alternative tumor vasculature damaging methods that may be effective in tumor treatment such as hyperthermia (Citation51, 117), photodynamic therapy (Citation51, 118), focused ultrasound (Citation119, 120), and gold nanoparticles (Citation121).
Tumor imaging provides a platform for non-invasively assessing the damage induced by VDAs (Citation122, 123). As such, tumor imaging is a valuable tool in VDA development.
VDAs as monotherapy
In preclinical trials, VDA monotherapies have been shown to induce significant necrosis in solid tumors; however, limited effects on tumor growth or size are usually observed. Clinically, there is also limited evidence of tumor shrinkage using VDAs as single agents, although a complete response was observed in a patient with anaplastic thyroid cancer (ATC) treated in a Phase I trial (NCT00003768) with CA4P (Citation102). The VDA BNC105 is a tubulin polymerization inhibitor that preclinically demonstrated an ability to inhibit tumor growth (Citation124), but following a Phase II trial (no trial registration number) it was deemed ineffective as a monotherapy when used in mesothelioma (Citation125). Furthermore, as discussed above, VDA monotherapy is unlikely to be curative as these agents are not able to eliminate residual cells at the tumor's edge (Citation68, 71). Conceptually, two approaches could slow or prevent this regrowth: the first is targeting the remaining tumor cells using conventional chemotherapy or radiotherapy; the second is by inhibiting the process of angiogenesis initiated by the surviving tumor cells.
VDAs in combination with conventional therapies
Combining VDAs with conventional anticancer therapies has the potential to eradicate tumors. Radiotherapy and chemotherapy alone exhibit reduced efficacy against cancer cells in tumor areas of low vascular density because these regions contain either radiation-resistant hypoxic cells or have inadequate vasculature, impairing drug delivery. As a tumor grows, the pressures exerted on its vascular support network become increasingly severe. When the resultant physiological stresses are coupled with an increasing neoplastic cell burden, it is perhaps not surprising that bulky advanced tumors typically prove particularly difficult to control with conventional anticancer therapies such as radiation treatment (Citation11, 126, 127), chemotherapy and surgery (Citation50, 122, 128–130). In solid tumors, increases in size are often associated with increases in hypoxic cell fractions (Citation122, 130–135) likely due to size-dependent reductions in tumor blood flow (Citation132, 133). These hypoxic and acidic regions can cause radiation resistance (Citation136–138) and impair chemotherapeutic agent delivery and effectiveness (Citation139). By contrast, VDA investigations in a variety of rodent and human tumor models have demonstrated a reverse tumor size dependency; that is, unlike conventional anticancer treatments, VDAs are selectively more effective against large tumor masses when assessed by clonogenic cell survival or tumor growth delay () (Citation82, 140–143).
Figure 2. Tumor surviving fractions in rodent (a) and human (b) tumor models treated at various sizes with a single dose of ZD6126 150 mg/kg. Survival assays were performed 24 hours after treatment. Data points represent individual animals, and results for each tumor model were fit by linear regression. Data from Siemann and Rojiani, 2005 (Citation12); with permission.
The nature of the mechanisms underlying the enhanced efficacy of VDAs against advanced disease is less clear. VDAs may be more effective in larger than smaller tumors due to the smaller masses having more significant portions supported by vessels located within the surrounding normal tissues. Since these normal vessels are unaffected by VDA treatment (Citation82, 85, 86, 142, 144), the portion of a tumor mass at risk of incurring ischemic damage from VDA treatment would increase along with its size. An additional reason that larger tumors become more sensitive to VDA treatment is because, at these sizes, the tumor vasculature might be particularly susceptible to occlusion due to elevated IFPs. Such pressures are known to be associated with advanced tumor masses (Citation145).
The observed tumor size-dependent VDA efficacy supports the rationale that combining conventional therapies with VDAs will lead to enhanced tumor responses based on the complementary nature of the antitumor action of these treatment modalities. The lack of VDA effect in the periphery is likely due to this region being primarily supplied by normal host vessels that are unresponsive to VDAs. The presence of normal vessels should not hinder drug delivery to the tumor rim and will make hypoxia less likely; thus, tumor cells in the periphery are more likely to be more sensitive to systemically administered agents and radiation (Citation71, 88). By combining VDAs with conventional therapies, it should be feasible to utilize the advantages of one to overcome the shortcomings of the other. Such a combination may be particularly effective when applied to advanced tumors. For example, in the study by Siemann and Rojiani (Citation12), which combined a VDA and radiation therapy, it was observed that the smallest tumors were most radiation-sensitive while the largest tumors were consistently most responsive to VDA treatment. However, when the VDA and radiation were combined, treatment efficacy was enhanced for all tumor sizes, but most significantly for larger tumors.
The preclinical findings outlined above highlight that the therapeutic benefits of VDAs in combination with other anticancer treatments may be more evident in the treatment of larger tumor masses. There is now emerging evidence that this may also occur in the clinic (Citation146–148). In a randomized Phase II study of plinabulin and docetaxel in patients with advanced NSCLC, although the primary objective of overall survival prolongation was not met, patients with large tumors were shown to have improved outcomes Citation127.
VDA treatment in combination with chemotherapy has been investigated previously, showing enhanced responses compared with VDA treatment alone (Citation9, 51, 149). The increased effect of VDAs when combined with chemotherapy is most likely due to the two drugs targeting different cell populations. This is possibly also the case when VDAs and radiation are combined, since preclinical studies generally report an additive effect of the two treatments (Citation9, 51, 150).
A Phase II/III trial (FACT; NCT00507429) showed positive results for ATC patients (N = 80) treated with CA4P plus the chemotherapy combination of carboplatin and paclitaxel, or carboplatin and paclitaxel alone. Although not statistically significant, the median overall survival of the patients receiving CA4P plus chemotherapy was 5.1 months versus 4.1 months for chemotherapy alone (hazard ratio [HR] 0.71 [95% CI 0.42–1.22]) (Citation151). A Phase II trial (CA4P-UKCTC-207) also showed positive results for platinum-resistant ovarian cancer patients who received CA4P plus carboplatin, and paclitaxel. The combination of CA4P and chemotherapy was generally well-tolerated and appears to produce a higher response rate in patients than if the chemotherapy is given alone (Citation152).
The tumor vascular effect of combining radiotherapy with CA4P was evaluated in patients with advanced NSCLC using volumetric dynamic contrast-enhanced computed tomography (Citation153). The study showed that after CA4P, the increase in permeability after radiotherapy and reduction in tumor blood volume were greater at the rim of the tumor and were sustained for up to 72 hours. These findings suggest that radiotherapy enhanced the tumor antivascular activity of CA4P and resulted in sustained tumor vascular shutdown – a result that could lead to greater than additive effects.
Rationale for combined VTT
As already outlined, AAs and VDAs induce vascular effects by different mechanisms, resulting in distinct antitumor effects; it is possible that these differences could be exploited by combining their potentially complementary mechanism to produce an effective antivascular therapeutic regimen. As both the initiation of new vessel formation and the integrity of the existing blood vessel network are critical to the growth and survival of a tumor, a two-pronged attack comprising a combination of anti-angiogenic and vascular disrupting strategies would seem logical. Such a combination therapy has the potential to have negative consequences for a tumor's blood vessel support network and, hence, its growth and survival.
There are additional reasons for considering a combination of these two classes of agents. Firstly, treatment duration: AA treatment is a long-term therapy, noting that on treatment cessation, the remaining dormant tumor cells have the capacity to reinitiate pro-angiogenic activities and progress (Citation154), while the effects of VDA exposure manifest themselves within hours after treatment and these agents can be given intermittently (Citation155). Secondly, the limitations of AAs (disabling a single angiogenic target via an AA will ultimately be insufficient to fully impair angiogenesis) and VDAs (residual, viable tumor cells surviving at the periphery) may be minimized or overcome by combining the two therapies. Given their disparate mechanisms of action, the combined application of AAs and VDAs (combined VTT) is likely to lead to complementary antitumor effects (). Finally, tumor stage and size: AA therapy is better suited for treating early-stage tumors of micrometastatic disease (Citation156–158), while the efficacy of VDAs in large tumor masses can be significant (Citation82, 140–142).
Preclinical evaluations of the combination of VDAs and AAs have demonstrated that the application of an AA in conjunction with one that disrupts established tumor blood vessels leads to complementary antitumor effects. This strategy was first examined in several human tumor xenograft models (Citation115, 159) in a setting which combined ZD6474, a selective inhibitor of VEGFR2-associated tyrosine kinase, with the microtubulin-disrupting agent ZD6126. In these studies, the AA was administered on a daily basis, whereas the VDA was given intermittently during the course of treatment. The results showed that, although each agent alone was capable of inducing a tumor response, when ZD6474 and ZD6126 were combined, the resultant tumor growth delay was markedly increased (). In a Kaposi's sarcoma model (KSY-1), this combination also significantly increased host survival and resulted in long-term tumor control (Citation115). Similar outcomes were noted when VDAs were combined with VEGF ligand inhibitors. For example, combining bevacizumab with the VDAs CA4P or OXi4503 (combretastatin A1-diphosphate or CA1P) resulted in significantly greater tumor responses in the human clear cell renal carcinoma model (Caki-1) than could be achieved with single-agent treatments () (Citation160). The tumor response and subsequent parallel regrowth of Caki-1 xenografts treated with an AA and VDA () likely reflects additive anti-tumor activity resulting from the combination of the two agents. However, the response of the KSY-1 xenografts to combined AA-VDA therapy suggests effects beyond an additive anti-tumor response based on the apparent increase in tumor doubling time following the combined treatment.
Figure 3. (A). The response of KSY-1 xenografts in mice treated with ZD6474 and ZD6126 either alone or in combination. ZD6474 was administered on a daily basis for 5 days starting when the tumors reached 200 mm3. ZD6126 was given on Days (D) 1, 3, and 5. In the combination group, on days when both agents were administered, ZD6126 preceded ZD6474 by 1 hour. The results show the growth of the median tumors of groups of 8 mice. In the anti-angiogenic agent plus vascular disrupting agent combination, 3 of 8 tumors were controlled. Data from Siemann and Shi, 2004 (Citation115); with permission. (B). Response of Caki-1 tumors to Avastin® (2 mg/kg, twice weekly for 2 weeks), CA4P, or Oxi4503 (100 mg/kg or 25 mg/kg, respectively, thrice weekly for 2 weeks), or the combination of anti-angiogenic agent and vascular disrupting agent. Data shown represent median tumor responses of groups of 8 to 10 mice. Data from Siemann and Shi, 2008 (Citation160); with permission.
The combined VTT may provide benefit not only in solid tumors but also in leukemia, in which blood vessels serve as a protective sanctuary for acute myeloid leukemia (AML). Recent studies have investigated this combined treatment approach in xenotransplant animal models of human AML chloromas and primary AML. The results showed that OXi4503 alone was capable of regressing AML by a multi-targeted mechanism and that the addition of bevacizumab mitigated the resultant reactive angiogenesis (Citation161).
A likely explanation for the effectiveness of combined VTT is that, while the VDA significantly reduces the tumor mass, the AA impairs the rapid tumor cell regrowth from the surviving viable rim by interfering with the re-establishment of the tumor vasculature. The latter is in keeping with reported increased vascularity and VEGF levels in the viable rim following VDA treatment, suggesting increased angiogenic activity in those parts of the tumor that survive VDA therapy (Citation70, 162). There is also evidence that the enhanced therapeutic effects observed when VDAs and AAs are combined may be due, in part, to the ability of AAs to suppress the recruitment of endothelial progenitor cells to tumor regions that survive VDA treatment (Citation163).
Clinical evaluation of the combined VTT has focused primarily on the use of VDAs in combination with bevacizumab. The combination of ombrabulin and bevacizumab has been clinically evaluated in a phase I trial (NCT01193595) and has been reported to be well tolerated with early evidence of clinical activity (Citation164). Clinical data from completed phase I and II trials and ongoing phase II/III trials has shown CA4P in combination with bevacizumab to be well tolerated with effective clinical activity.
A Phase I study (NCT00395434) investigated CA4P and bevacizumab combination therapy in patients with advanced solid malignancies. A total of 15 patients enrolled in this study, receiving 45 mg/m2 (3 patients), 54 mg/m2 (4 patients), or 63 mg/m2 (8 patients) of CA4P on Day 1, Day 8, and then every 14 days, with 10 mg/kg bevacizumab on Day 8 and at subsequent cycles 4 hours after CA4P. Results showed that this combination was well-tolerated with hypertension being the most common dose-limiting toxicity. Importantly, this study found that reductions in tumor perfusion (assessed using dynamic contrast-enhanced magnetic resonance imaging) after CA4P were more sustained when bevacizumab was used in combination (Citation107).
A Phase II study (GOG-0186I; NCT01305213) investigated CA4P and bevacizumab combination therapy in patients with recurrent ovarian carcinoma. A total of 107 patients, previously treated with three or fewer regimens, enrolled in the study. Patients were randomized to receive CA4P (60 mg/m2) in combination with bevacizumab (15 mg/kg) or bevacizumab alone once every 3 weeks, until progression or toxicity. The results from this study showed that median PFS was 7.3 months for CA4P with bevacizumab versus 4.8 months for bevacizumab alone (HR 0.69 [90% CI 0.47–1.00]; one-sided P = 0.049). The study met its primary outcome measure, showing that combined VTT (CA4P with bevacizumab) significantly improved PFS compared with bevacizumab alone in recurrent ovarian carcinoma (Citation165).
Triple combination therapy
A number of recent clinical trials have investigated potential triple therapy combining VDAs and AAs with chemotherapy. A randomized Phase II study (the FALCON trial; NCT00653939) evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naiïve subjects with advanced non-squamous NSCLC (Citation166). The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and PFS rates were also comparable between the groups. This study demonstrated that treatment with CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile. The FOCUS study (NCT02641639), an ongoing, randomized, double-blind Phase II/III study, is investigating physician's choice chemotherapy (PCC; paclitaxel or pegylated liposomal doxorubicin) plus bevacizumab and CA4P compared with PCC plus bevacizumab and placebo in platinum-resistant ovarian cancer (Citation167). Study enrollment began in June 2016; interim results will be available in 2017.
Conclusions
It is well-recognized that a functional network of blood vessels is essential for the progressive growth and dissemination of cancer. Therapeutic interventions targeting either the process of tumor-induced new vessel formation or the established tumor vasculature can provide significant antitumor efficacy. However, a combination of the two classes may be required to realize the full antitumor potential of VTT. Preclinical and initial clinical data support the therapeutic potential of combining VDAs with AAs. Combining such VTT with conventional anticancer therapies offers a promising future opportunity for cancer treatment, particularly for patients with more advanced disease.
Declaration of interest
We have read and understood Cancer Investigations policy on declaration of interests and declare the following potential conflict of interest: Chaplin D.J. is currently employed by Mateon Therapeutics. DWS and MRH report no declarations of interest.
Dr. Susan J. Cravero from Link Health Group, LLC, provided editorial support, funded by Mateon Therapeutics.
This article is not under consideration for publication elsewhere, and its publication is approved by all authors.
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