*4.3.2. Targeted cytotoxins*

important factor for bulk flow in CED. Intuitively, the less viscous the infusate is, the more smoothly it diffuses in the extracellular space. Subsequently, a larger diffusion volume is expected from the low‐viscosity drugs. However, Mardor and colleagues (65) demonstrated in a rat model that agents with high viscosity tend to have an increased volume of diffusion because they are more resistant to backflow. Therefore, when a drug is chosen as a candi‐ date for CED, its physico‐chemical characteristics such as molecular weight, viscosity, clearance rate should be taken into account. In addition, novel strategies are explored to improve the efficacy of CED through delaying the degradation or clearance of agents in the target sites. To achieve this goal, drugs are conjugated or encapsuled with nanoparticles or

A wide range of therapeutic agents, such as conventional chemotherapies, targeted toxins, viruses and oligonucleotides, have been investigated on CED for the safety and efficacy in the

Topotecan, a topoisomerase I inhibitor, is an ideal conventional chemotherapeutic agent for CED. Firstly, topotecan is more readily to accumulate in gliomas than in normal brain tissue. Secondly, it specifically kills glioma cells and is less toxic to normal brain. In addition, topoisomerase I is a natural‐product agent with a high molecular weight. As a result, topote‐ can is difficult to bypass BBB when administered intravenously. Whereas topotecan is less easily removed into systemic circulation and can be retained in the targeted site for a pro‐ longed time when it is infused via CED. Jeffery and colleagues conducted a Phase Ib trial to deliver topotecan to recurrent malignant gliomas (68). Sixteen patients were enrolled in that dose‐escalation trial. The treatment was well tolerated with the stable maintenance of quality of life and neurocognitive functioning of patients. Tumors substantially regressed without significant systemic and neurocognitive adverse effects in selected patients with recurrent malignant gliomas refractory to conventional treatment. The total response of the single topotecan infusion was 69%. The results were encouraging for relapse patients in whom previous treatment had failed, but the efficacy of this treatment requires to be confirmed in

Another conventional chemotherapeutic agent, paclitaxel, has also been delivered through CED to treat malignant gliomas. In a Phase I/II trial, a total of 20 cycles of intratumoral CED of paclitaxel was administered to 15 patients with histologically confirmed recurrent GBM (69). Among these 15 patients, complete response was observed in five cases and partial response in six cases, respectively. The response rate reached 73%. The poor response seemed to be associated with the backflow of paclitaxel into subarachnoid spaces, ventricles, and resec‐ tion cavities. Although effective, the local delivery of paclitaxel caused significant incidence of complications including transient chemical meningitis in six patients, infection in three patients and transient neurological deficits in four patients. The treatment‐related side effects have been suggested to be the results of infusate reflux. Strategies such as sealing the burr hole

liposomes (66, 67).

328 Neurooncology - Newer Developments

Phase II and III trials.

**4.3. Agents for convection‐enhanced delivery**

treatment for gliomas in clinical trials.

*4.3.1. Conventional chemotherapeutics*

Targeted cytotoxins represent a novel class of agents with high specificity for brain tumors. The potent protein toxins produced by bacteria are conjugated to carrier ligands, which specifically bind to the receptors on the surface of glioma cells. Less resistance to targeted cytotoxins was observed in glioma cells because the agents kill glioma cells through irrever‐ sible *de novo* protein synthesis, independent of any malignancy‐associated genetic alterations. The relatively small molecular weight and the highly soluble proteinaceous nature of targeted cytotoxins make them attractive for CED.

TF‐CRM107 is the first targeted cytotoxin investigated in clinical trials. The agent is com‐ posed of diphtheria toxin conjugated to transferrin‐C and preferentially targets glioma cells due to the increased expression of transferrin receptor in tumor tissue. Preclinical works demonstrated that TF‐CRM107 eliminated glioma cells at picomolar concentrations *in vitro* and significantly inhibited the growth of subcutaneous glioma xenografts in a mouse model (71, 72). Delivery of TF‐CRM107 through CED was safe for patients with malignant brain tumors. In a dose‐escalating trial, the treatment was well tolerated (52). No significant neurological and systemic adverse events were observed. In the subsequent Phase II trial, 44 patients with refractory and recurrent malignant gliomas were enrolled (73). TF‐CRM107 (concentration of 0.67 μg/ml) was delivered continuously through CED at a rate escalating up to 0.2 ml/h per catheter (a total of 0.4 ml/h for 2 catheters) until a volume of 40 ml was infused. The outcome was encouraging, with a total response of 35% and a median survival of 37 weeks. Unfortunately, the multicenter Phase III trial failed to confirm the efficacy of TF‐CRM107 delivered by CED. The study was stopped because an intermediate futility analysis revealed that the chance of positive outcome was <20%.

Cintredekin besudotox (CB, also known as also known as IL13‐PE38QQR), a recombinant chimera protein consisted of IL‐13 coupled with a truncated form of *Pseudomonas* exotoxin (PE38QQR), is one of the most well‐studied targeted toxins. The toxicity and safety profile were carefully reviewed by Kunwar and colleagues (74). Fifty‐one patients with recurrent malignant glioma including 46 GBMs, who were infused with CB via CED after resection, were evaluated. The treatment was well tolerated, and the adverse effects were mostly transient and manageable. The authors categorized the adverse effects according to the onset time related to the procedures including the placement of catheters and delivery of the agents. Three symptomatic periods were defined: The first one was between surgery and CED; the second was during CED and up to 7 days after infusion; and the third period was 2–10 weeks after treatment. Adverse events including intracranial hemorrhage and infection were more likely observed in the first period, which was related to the placement of catheters. Whereas the mass effect due to the volume of infusion was responsible for neurological deficits during the second period. Neurological deficits were also found in patients during the third symptomatic period. It has been suggested that the treatment‐induced inflammation or the non‐specific toxicity for normal brain cells resulted in the side effects. This study not only confirmed the safety of the

delivery of CB via CED but also provided important information about the pathophysiologi‐ cal mechanism underlying the adverse events observed in the clinical trial with CED, which is helpful to minimize the complications in further studies. A multicenter Phase III trial (Phase III Randomized Evaluation of CED of IL13‐PE38QQR Compared to Gliadel® Wafer with Survival End Point in GBM Patients at First Recurrence, PRECISE) investigated the efficacy of CB infused via CED (75). Two hundred ninety‐six patients with recurrent GBM were random‐ ized to receive CED of CB or Gliadel® wafers. Unfortunately, although there was statistically significant improvement in progression‐free survival between patients treated with CB and those with Gliadel® wafers (17.7 vs. 11.4 weeks, *p* = 0.0008), no survival benefit was found, with the median survival of 11.3 months for CB and 10 months for Gliadel® wafers for the efficacy evaluable population (*p* = 0.310). But it is worth noting that 32% of catheter placements were not performed per protocol specifications and drug distribution was not evaluated with image monitoring. These two limitations may be possible explanation for the failure of the trial. Lately, Sampson and colleagues (76) retrospectively analyzed the catheter positioning and drug distribution in the PRECISE trial using BrainLAB iPlan Flow software that was not available during the trial. The study demonstrated that more than 50% of catheters did not meet all positioning criteria among 174 cases with sufficient data. In addition, the simulation analysis revealed that the average coverage volume was very low, with only 20.1% of the 2‐ cm penumbra surrounding the resection cavity covered on average. Therefore, lessons learned from PRECISE trial clearly indicate that the accurate catheter positioning and the real‐time monitoring of drug distribution are critical for the success of interstitial drug delivery via CED.

#### *4.3.3. Future prospects*

Until now, many other agents such as monoclonal antibodies (e.g., 131I‐chTNT‐1/B mAb), oligonucleotides (e.g., TGF‐beta2 antisense oligonucleotides) and viruses (e.g. LSFV‐IL12) have been investigated via CED in early‐stage clinical studies (77–79) and demonstrated benefit in selected patients. Well‐designed randomized trials are required to confirm the efficacy. In the future, so as to fulfill an effective treatment strategy, CED will require optimized infusates, improved catheters, standardization of catheter placement, mathematical models to predict drug distribution, as well as the real‐time monitoring of infusate delivery.
