Future Prospects

patient, her widely disseminated chest wall tumor had completely disappeared.

This test dose (30 mg/m²) was only 60% of the expected maximally tolerated dose, and so there were no side effects of the drug. A second patient had a similar complete response at 30 mg/m².¹¹⁸

The Phase I/II DIGNITY trial studying ThermoDox^s for breast cancer¹¹⁶ has now continued the study in several sites and has demonstrated remarkable clinical benefit in a very late-stage, underserved patient population. As presented at the European Society of Medical Oncology (EMO) conference 2012,¹¹⁹the clinical utility of ThermoDox^s in this highly treatment-resistant setting points to its potential within a variety of superficial tumors, and could provide medical oncologists with an important tool to combat these often aggressive tumors. According to the lead clinician, the initial experience with hyperthermia and ThermoDox^s has been very encouraging and provides initial safety and early efficacy data in several patients showing responses in this highly refractory and debilitating disease. These patients previously received over an average of four prior chemotherapy regimens along with prior radiation therapy. The continuation of the ThermoDox^s trial will provide more efficacy data to potentially advance treatment for this patient population.

2.4.3.5 Phase II Colorectal Liver Metastases ABLATE

The third and final on-going human trial is a randomized, double blind, Phase II trial of RFA þ/– ThermoDox^s for Colorectal Liver Metastases Z2 cm maximum in diameter.¹²⁰ Again, the purpose of this study is to determine the safety and efficacy of ThermoDox^s, in combination with RFA in the treatment of recurrent or refractory colorectal liver metastases compared to RFA mono-therapy. The primary outcome of this trial is to evaluate local tumor control defined as complete ablation and where the patient does not experience recurrence within 1 cm of the ablation site.

2.5.1 New ThermoDox

^s

Trials and Preclinical Studies

As shown in Table 2.2, a full clinical program is underway for ThermoDox^s. In addition to the trials reviewed above, HCC (HEAT), RCW (DIGNITY) and CRLM (ABLATE), new research and preclinical development has started in bone metastases, pancreatic cancer and metastatic liver cancer. The exciting feature here is the adaptation of High Frequency Ultrasound (HIFU) as the source of targeted mild hyperthermia.

In combination with Philips Healthcare, a manufacturer of HIFU systems, Celsion began preclinical studies to assess the benefits of HIFU in combination with ThermoDox^sin metastatic bone cancer,¹²¹that have now (August 2012) just received clearance to initiate a clinical study. This is a joint development program for Celsion’s ThermoDox^s combined with Philips’ Sonalleve MR- HIFU (MR-guided high intensity focused ultrasound) technology for the palliation of painful metastases to the bone caused by lung, prostate, or breast cancers. It is expected that a Phase II study will be initiated in this indication, as well as looking into the treatment of pancreatic cancer with ThermoDox^s.

2.5.2 Other Drugs

While ThermoDox^swas the first drug to be encapsulated, mainly because of the huge history that we inherited in its liposomal formulations (like Evacet and

Table 2.2 ThermoDox Clinical Programs at Celsion Corporation (August 2012).

70 Chapter 2

on 01/09/2013 10:25:46. Published on 25 April 2013 on http://pubs.rsc.org | doi:10.1039/9781849736800-00033

Doxil), the LTSL is also capable of encapsulating and releasing many other drugs as well as imaging agents that report on heatability, perfusion and small molecule delivery.⁹⁷ In published and unpublished work, we and others have already explored the conditions and developed processes for encapsulating cisplatin,¹²² carboplatin and manganese prophyrins. It is expected that such membrane impermeable drugs, if well retained, in an LTSL formulation will prove to be an advantage, since drugs likecisplatinwhen encapsulated in the stealth liposomes proved to be less efficacious than free drug. As always, control over the triggered release of the encapsulated drug to increase bio- availability of the drug exclusively at the diseased site has always been one of the biggest challenges.¹²³ In the Stealth^s liposomal formulation (SPI-077) minimal clinical efficacy despite adequate tumor accumulation was observed.^124–126 That is, the steps taken to establish adequate drug loading, circulation half-life, drug retention in the bloodstream and passive tumor accumulation resulted in excessive retention ofcisplatinin the liposome so that it was not substantially released at the tumor site. Again, the two sides of the same coin compromise each other – good retention in order to reduce toxicity vs.not getting the drug out leading to reduced efficacy.

2.5.3 Other New Thermal-sensitive Formulations (Lipids and Polymers)

Modifications and potential improvements to the temperature-sensitive liposome formulation, including different lipid components, are currently ongoing. Others have created and developed their own thermal sensitive liposomes with similar release characteristics and temperatures, but made from different materials. Although the materials data for these formulations are not as complete, and so the absolute details of how they work remain speculative, mechanistically it would seem they have similar bilayer components to create nanopores at purported grain boundaries. Principal among these, Lindner et al.¹²⁷designed their temperature-sensitive liposomes composed of the novel lipid 1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Hossann et al.¹²⁸ studied the influence of DPPGOG on in vitro stability of the liposome composed of DPPGOG, DSPE-PEG²⁰⁰⁰and P-lyso-PC. They showed that the release rate of the contents was significantly increased by incorporating DPPGOG or P-lyso-PC in their TSL formulations. Also, Lindner et al.

formulated liposomes composed of HePC/DPPC/DSPC/DPPGOG and showed that HePC increases the release rate of their TSL in a similar way to lysolipid in the presence of fetal calf serum.¹²⁹ Interestingly, DPPGOG facilitates drug release from the liposome under mild hyperthermic conditions (41–421C) and leads to a substantially prolonged plasma half-life for the encapsulated drug. Thus, in Lindner’s formulations DSPE-PEG²⁰⁰⁰ is not required for long circulation half-life or stabilizing pores; this is apparently achieved by the DPPGOG lipid.

Materials Science and Engineering of the Low Temperature Sensitive Liposome 71

on 01/09/2013 10:25:46. Published on 25 April 2013 on http://pubs.rsc.org | doi:10.1039/9781849736800-00033

In other studies, temperature-sensitive liposomes have been designed using thermal-sensitive polymers: Hayashi et al.¹³⁰ studied temperature-sensitive liposomes composed of various phospholipids and coated with poly(N-isopropylacrylamide) that show a transition temperature near 321C;

Kono et al.¹³¹ also used polymers composed of dioleoylphos- phatidylethanolamine modified with copolymers ofN-isopropylacrylamide and N-acryloylpyrrolidine; and Paasonen et al.¹³² reported on polymer-coated liposomes with thermal-sensitive poly[N-(2-hydroxypropyl) methacrylamide mono/dilactate] (pHPMA mono/dilactate), which has a Tm at 421C. Thus, several new studies have introduced the idea of modifications to the bilayer composition or surface of liposomes with temperature-sensitive polymers that retain temperature-triggered release from the liposome. Such modifications may prove useful in the future, but require further, especially clinical, investigation.