Lyso-thermosensitive Liposomal Doxorubicin Research Articles

Modulated Electro-Hyperthermia Accelerates Tumor Delivery and Improves Anticancer Activity of Doxorubicin Encapsulated in Lyso-Thermosensitive Liposomes in 4T1-Tumor-Bearing Mice.

Modulated electro-hyperthermia (mEHT) is an adjuvant cancer therapy that enables tumor-selective heating (+2.5 °C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue.

Recent Preclinical and Clinical Progress in Liposomal Doxorubicin.

Doxorubicin (DOX) is a potent anti-cancer agent that has garnered great interest in research due to its high efficacy despite dose-limiting toxicities. Several strategies have been exploited to enhance the efficacy and safety profile of DOX. Liposomes are the most established approach. Despite the improvement in safety properties of liposomal encapsulated DOX (in Doxil and Myocet), the efficacy is not superior to conventional DOX. Functionalized (targeted) liposomes present a more effective system to deliver DOX to the tumor. Moreover, encapsulation of DOX in pH-sensitive liposomes (PSLs) or thermo-sensitive liposomes (TSLs) combined with local heating has improved DOX accumulation in the tumor. Lyso-thermosensitive liposomal DOX (LTLD), MM-302, and C225-immunoliposomal(IL)-DOX have reached clinical trials. Further functionalized PEGylated liposomal DOX (PLD), TSLs, and PSLs have been developed and evaluated in preclinical models. Most of these formulations improved the anti-tumor activity compared to the currently available liposomal DOX. However, the fast clearance, the optimization of ligand density, stability, and release rate need more investigations. Therefore, we reviewed the latest approaches applied to deliver DOX more efficiently to the tumor, preserving the benefits obtained from FDA-approved liposomes.

Drug development of lyso-thermosensitive liposomal doxorubicin: Combining hyperthermia and thermosensitive drug delivery.

We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.

Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin.

To determine whether burn time per tumor volume (BPV) (min/mL), where burn time is the total time during which radiofrequency (RF) energy is being applied, is correlated with hepatocellular carcinoma (HCC) treatment outcomes using RF ablation and lyso-thermosensitive liposomal doxorubicin (LTLD). The HEAT study was a double-blind, randomized controlled phase III trial of RF ablation only versus RF ablation+ LTLD in patients with HCCs 3-7 cm in diameter. Effect of BPV on progression-free survival and overall survival (OS) was analyzed. BPV demonstrated statistically significant differences between study groups for OS (P= .038, hazard ratio [HR]= 0.85), but not for progression-free survival (P= .389, HR= 1.059). In a separate analysis, treatment groups were independently analyzed to determine the effect of BPV within each individual group. OS improved as BPV increased for patients receiving RF ablation+ LTLD (P= .017, HR= 0.836, confidence interval [0.722, 0.968]). This same association was not observed in patients receiving RF ablation only (P= .57, HR= 0.99). BPV may be a useful metric for RF ablation+ LTLD combination therapy for solitary HCC. The analysis suggested that the burn time for the tumor needs to be adjusted depending on the tumor volume. Because this is a post hoc study, the results are only suggestive and need to be confirmed with prospective studies.

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73-83. ©2017 AACR.

Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox\xae) using focused ultrasound in patients with liver tumours

BackgroundTARDOX is a Phase I single center study of ultrasound triggered targeted drug delivery in adult oncology patients with incurable liver tumours. This proof of concept study is designed to demonstrate the safety and feasibility of targeted drug release and enhanced delivery of doxorubicin from thermally sensitive liposomes (ThermoDox®) triggered by mild hyperthermia induced by focused ultrasound in liver tumours. A key feature of the study is the direct quantification of the doxorubicin concentration before and after ultrasound exposure from tumour biopsies, using high performance liquid chromatography (HPLC).Methods/DesignThe study is conducted in two parts: Part 1 includes minimally-invasive thermometry via a thermistor or thermocouple implanted through the biopsy co-axial needle core, to confirm ultrasound-mediated hyperthermia, whilst Part 2 is carried out without invasive thermometry, to more closely mimic the ultimately intended clinical implementation of the technique. Whilst under a general anaesthetic, adult patients with incurable confirmed hepatic primary or secondary (metastatic) tumours receive a single cycle of ThermoDox®, immediately followed by ultrasound-mediated hyperthermia in a single target liver tumour. For each patient in Part 1, the HPLC-derived total doxorubicin concentration in the ultrasound-treated tumour is directly compared to the concentration before ultrasound exposure in that same tumour. For each patient in Part 2, as the tumour biopsy taken before ultrasound exposure is not available, the mean of those Part 1 tumour concentrations is used as the comparator. Success of the study requires at least a two-fold increase in the total intratumoural doxorubicin concentration, or final concentrations over 10 μg/g, in at least 50% of all patients receiving the drug, where tissue samples are evaluable by HPLC. Secondary outcome measures evaluate safety and feasibility of the intervention. Radiological response in the target tumour and control liver tumours are analysed as a tertiary outcome measure, in addition to plasma pharmacokinetics, fluorescence microscopy and immunohistochemistry of the biopsy samples.DiscussionIf this early phase study can demonstrate that ultrasound-mediated hyperthermia can effectively enhance the delivery and penetration of chemotherapy agents intratumorally, it could enable application of the technique to enhance therapeutic outcomes across a broad range of drug classes to treat solid tumours.Trial registrationClinicalTrials.gov Identifier: NCT02181075, Edura-CT Identifier: 2014-000514-61.Ethics Number: 14/NE/0124.

Phase 1 trial of lyso-thermosensitive liposomal doxorubicin (LTLD) and magnetic resonance guided high intensity focused ultrasound (MR-HIFU) for pediatric refractory solid tumors.

TPS10579 Background: Prognosis for children and young adults with refractory solid tumors remains unacceptably poor. Current approaches have reached the limits of maximal dose intensification, and the acute and late side effects of therapy are substantial. MR-HIFU is an innovative therapy that uses an external applicator to focus ultrasound energy inside a tumor non-invasively and without radiation. The resulting heating is precisely controlled and accurately targeted with the aid of MR thermometry and anatomic imaging. The flexibility and control over local heating by MR-HIFU provide an ideal system to be used with LTLD, a novel formulation of liposomal doxorubicin with the unique property of rapid heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The potential synergistic effects include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high local concentrations of doxorubicin in the targeted tumor, inhibition of DNA repair, and stimulation of immune responses. Methods: This is the first pediatric trial of LTLD with MR-HIFU in refractory solid tumors (NCT02536183). Part A is a phase 1 dose escalation study to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of LTLD combined with MR-HIFU ablation in children. Part B combines LTLD at the MTD/RP2D with MR-HIFU induced mild hyperthermia (MHT) in an expanded cohort. Patients ≤21 (Part A) and ≤30 (Part B) years of age with refractory solid tumors at sites accessible to MR-HIFU, adequate organ function including cardiac function, and prior anthracycline dose of ≤ 450 mg/m2 are eligible. LTLD is administered intravenously over 30 min followed immediately by MR-HIFU on day 1 of a 21-day cycle. Patients can receive a maximum of 6 cycles (or lifetime of 600 mg/m2 of cumulative anthracycline) provided treatment is tolerated and have at least stable disease. Secondary objectives evaluate changes in quality of life and pharmacodynamic immune markers in children treated with LTLD and MR-HIFU. Clinical trial information: NCT02536183.

Lyso-thermosensitive liposomal doxorubicin for treatment of bladder cancer

Purpose: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox®) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer.Material and methods: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD + HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX + HT) and (iii) IV LTLD without hyperthermia (LTLD – HT). Drug formulations were delivered via 30 min IV infusion coinciding with 1-h bladder irrigation (45 °C water for HT groups, 37 °C for non-HT group), followed by immediate bladder resection. DOX concentrations were measured in consecutive sections parallel to the bladder lumen by liquid chromatography following drug extraction. Computer models were developed to simulate tissue heating and drug release from LTLD.Results: Comparing mean DOX concentrations at increasing depths from the lumen to outer surface of the bladder wall, the ranges for LTLD + HT, IV DOX + HT and LTLD – HT, respectively, were 20.32–3.52 μg/g, 2.34–0.61 μg/g and 2.18–0.51 μg/g. The average DOX concentrations in the urothelium/lamina and muscularis, respectively, were 9.7 ± 0.67 and 4.09 ± 0.81 μg/g for IV LTLD + HT, 1.2 ± 0.39 and 0.86 ± 0.24 μg/g for IV DOX + HT, and 1.15 ± 0.38 and 0.62 ± 0.15 μg/g for LTLD – HT. Computational model results were similar to measured DOX levels and suggest adequate temperatures were reached within the bladder wall for drug release from LTLD.Conclusions: Doxorubicin accumulation and distribution within the bladder wall was achieved at concentrations higher than with free IV doxorubicin by mild bladder hyperthermia combined with systemic delivery of LTLD.

Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.

The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX.Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls.Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT.Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.

RFA plus lyso-thermosensitive liposomal doxorubicin: in search of the optimal approach to cure intermediate-size hepatocellular carcinoma.

When heated during a radiofrequency ablation (RFA) procedure to ≥40°C, lyso-thermosensitive liposomal doxorubicin (LTLD) produces high drug concentration in the surrounding margins of the ablation zone. The hypothesis that the RFA + LTLD combination can effectively treat hepatocellular carcinoma (HCC) was investigated in the HEAT study: adding LTLD did not improve the efficacy of normal practice RFA. However, among the 285 patients with a solitary lesion who received at least 45-min RFA dwell time, the hazard ratio for overall survival was 0.63 (95% CI: 0.41-0.96; p = 0.04). The OPTIMA study is currently ongoing to test the hypothesis that adding LTLD to a standardized RFA lasting ≥45 min increases survival compared with standardized RFA alone.

3:54 PMAbstract No. 65 - Evaluation of hepatocellular carcinoma after treatment with microwave ablation plus transarterial embolization versus radiofrequency ablation plus transarterial embolization: a single center experience

Do geometric features of hepatocellular carcinomas correlate with survival following radiofrequency ablation (RFA) with and without lyso-thermosensitive liposomal doxorubicin (LTLD/Thermodox)? M. Castro, S. Leonard, H. Celik, P. Wakim, J. Karanian, W. Pritchard, N. Borys, R. Lencioni, M. O’Neal, W. Tak, B. Wood; NIH, Bethesda, MD; FDA/CDRH Laboratory of Cardiovascular and Interventional Therapeutics, Laurel, MD; Food and Drug Administration, Rockville, MD; Celsion Corporation, Princeton, NJ; University of Miami Miller School of Medicine, Miami, FL; BioClinica,Inc., Princeton, NJ; Kyungpook National University Hospital, Jung-gu, Daegu.

3:45 PMAbstract No. 64 - Do geometric features of hepatocellular carcinomas correlate with survival following radiofrequency ablation (RFA) with and without lyso-thermosensitive liposomal doxorubicin (LTLD/Thermodox)?

3:45 PMAbstract No. 64 - Do geometric features of hepatocellular carcinomas correlate with survival following radiofrequency ablation (RFA) with and without lyso-thermosensitive liposomal doxorubicin (LTLD/Thermodox)?

Abstract P6-13-15: Lyso-thermosensitive liposomal doxorubicin shows efficacy with minimal adverse events in patients with breast cancer recurrence at the chest wall

Abstract INTRODUCTION: Local-regional recurrence after definitive treatment of breast cancer is reported in 5 – 40 % of patients depending risk factors and initial treatment. Chest wall recurrence is associated with poor quality of life and limited treatment options. Lyso-thermosensitive liposomal doxorubicin (LTLD, Thermodox®) is an intravenously administered agent designed to selectively release doxorubicin when exposed to temperatures ≥39.5° C at a targeted tumor. Hyperthermia, the elevation of tissue temperature in the range of 40° C to 44° C, causes direct cytotoxicity, enhanced blood flow, and oxygenation. We are reporting the interim findings of an ongoing Phase I/II Study Evaluating the Maximum Tolerated Dose, Bioequivalence/Pharmacokinetics, Safety, and Efficacy of LTLD in Patients with Local-Regional Recurrent Breast Cancer. Final results will be presented in December. METHODS: Patients with breast carcinoma on the chest wall with progression following radiation were eligible; prior chemotherapy and hormone therapy were allowed. LTLD was administered intravenously followed immediately by hyperthermia in up to two treatment fields for 1 hour per field for a goal of 40–42°C. Response was measured using clinical assessment, CT, and digital photos. All subjects were assessed for safety. Up to six cycles of LTLD/hyperthermia were administered depending on disease progression or tolerance. A total of 11 patients were enrolled on the Phase I portion of the study and 9 were evaluable for efficacy review. To date, 17 patients are enrolled on the Phase II portion of the study and 13 are evaluable for efficacy review. Once 12 patients are found to be evaluable for PK the primary endpoint of bioequivalence can be evaluated. RESULTS: A dose of 50 mg/m2 was recommended by the DSMB at completion of the Phase I study. Seven subjects were dosed at 50mg/m2, two patients developed a localized reaction in the treatment area consisting of erythema, woody induration, and pain which resolved with discontinuation of treatment. Twenty patients were dosed at 40mg/m2 without recurrence of symptoms. To date, twenty-eight patients were enrolled in the phase I/II study; one subject was excluded due to dose modification following 2 cycles of ThermoDox at a dose of 50mg/m2 to 40mg/m2 at cycle 3. This subject had a durable partial response. The tables summarize the safety and efficacy data. All efficacy data is investigator reported. Combined Phase I/II Safety DataSafety Data40 mg/m2 (N=20)50 mg/m2 (N=7)Any AE Event (n, %)17 85.07 100.0Grade 3+ AE (n, %)10 50.06 85.7Serious AE (n, %)5 25.03 42.9Hematological AE (n, %)10 50.07 100.0Deaths due to AE (n, %)0 0.00 0.0 Combined Phase I/II Efficacy DataEfficacy Data40 mg/m2 (N=20)50 mg/m2 (N=7)Responders (Partial &amp; Complete) (n, %)10 50.03 42.9Complete Response (n, %)5 25.01 14.3Partial Response (n, %)5 25.02 28.6Durable Response (lasting ≥ 3 months) (n, %)3 15.00 0.0 CONCLUSION: These findings suggest that LTLD at a dose of 40 mg/m2 combined with hyperthermia offers a promising and well tolerated treatment option for patients with recurrent chest wall disease from breast cancer. Additional data will be presented based on full trial accrual. Citation Format: Rugo H, Pabbathi H, Shrestha S, Aithal S, Borys N, Musso L, Zoberi I. Lyso-thermosensitive liposomal doxorubicin shows efficacy with minimal adverse events in patients with breast cancer recurrence at the chest wall. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-15.

Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model.

IntroductionRadiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40°C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone.PurposeThe purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence.ConclusionThe mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 μg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues.

Liposomal Doxorubicin Plus Radiofrequency Ablation for Complete Necrosis of a Hepatocellular Carcinoma

Radiofrequency ablation (rfa) is a standard treatment for small, unresectable hepatocellular carcinomas (hccs). However, rfa for larger tumours is less successful, and intravenous lyso-thermosensitive liposomal doxorubicin during rfa is one technique postulated to potentially address that limitation. This drug-plus-device combination therapy was used to completely treat a hcc in a patient who underwent liver transplantation 79 days later.

Abstract P6-13-01: Lyso-thermosensitive liposomal doxorubicin + local hyperthermia for radiation-pretreated chest wall recurrence

Abstract Background: Chest wall recurrence (CWR) causes much morbidity when not controlled by local measures. Lyso-thermosensitive liposomal doxorubicin (LTLD) provides accelerated release of doxorubicin (Dox) at ≥ 39° C, and is being studied for CWR based on the pioneering thermochemotherapy work of Dewhirst and colleagues at Duke. We now report on its tolerance, pharmacology, and preliminary antitumor effects in a dose-escalation study combined with local hyperthermia (LH) for radiation-refractory CWR. LH selectively increases liposomal permeability in tumor microvasculature, and promotes release of Dox from LTLD, and Dox tumor uptake, in addition to LH anti-tumor effects. Methods: This phase I study entered patients (pts) with CWRs &amp;lt; 3 cm deep failing all standard Tx including surgery, radiation, and chemotherapy: pts received up to 6 LTLD/LH treatments every 21 days at a starting dose of 40 mg/m2 (cohort 1) and escalated to 50 mg/m2 (cohort 2). LTLD was infused IV over 30 minutes (min); followed within 30 min by microwave or ultrasound LH. The thermal dose goal was 40°C-42°C for 60 min. Pharmacokinetic samples for total plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and 24 hours after starting infusion. Left ventricular ejection fraction was monitored every other cycle. Results: Eleven pts with a median of 4 prior chemotherapy regimens (range 2 — 12) were enrolled; all but one had prior anthracycline (AC). All pts received ≥ 2 cycles. The within subject variability in Dox and Doxol exposure was small with mean Cycle 2 vs Cycle 1 ratios ranging from 0.99 to 1.06. Cmax/dose (ng/ml)/(mg/m2) Cycle 1 Cycle 2 Dox 499.82 512.00 Doxol 0.46 0.45 AUClast/dose ((ng*hr/ml)/(mg/m2) Dox 1338.12 1381.82 Doxol 7.96 8.04 Grade 3 and 4 toxicities included reversible neutropenia in 17 (40.5%) and one case (each) of mucositis (grade 1), chest wall thermal burn, and chest wall cellulitis (both grade 4); these occurred in only ≥ 5% of 42 cycles given. No cardiomyopathy or hand-foot toxicity occurred. The rate of clinically-significant (≥ 6 point) QoL improvement on the FACT-B after 2 cycles was 54.5% (95% CI: 25.1%–83.9%), including 1 lasting &amp;gt; 3 months. The local objective response rate was encouraging: 45.5% (95% CI: 16.1%–74.9%), with 1 complete and 4 partial local responses. Conclusion: LTLD + LH is safe in CWR after prior radiation and doxorubicin. A phase II study is planned for pharmacologic evaluations and to add pts with less or no anthracycline treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-01.

Phase I Study of Heat-Deployed Liposomal Doxorubicin during Radiofrequency Ablation for Hepatic Malignancies

Purpose A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy. Materials and Methods Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m 2 and 60 mg/m 2 were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed. Results DLT criteria were met at 60 mg/m 2, and the MTD was defined as 50 mg/m 2. RF ablation was performed during the peak of the plasma concentration–time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. Conclusions LTLD can be safely administered systemically at the MTD (50 mg/m 2) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

Lyso-Thermosensitive Liposomal Doxorubicin: An Adjuvant to Increase The Cure Rate of Radiofrequency Ablation in Liver Cancer

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide. No more than 30% of HCC patients are considered suitable for curative treatment because of tumor size and severity of liver impairment, among other factors. Radiofrequency ablation (RFA) monotherapy can cure small (<3 cm) HCC tumors. An adjuvant that interacts synergistically with RFA might enable curative therapy for many HCC patients with lesions >3 cm. Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of the heat-enhanced cytotoxic doxorubicin within a heat-activated liposome. LTLD is infused intravenously prior to RFA. When heated to >39.5°C, LTLD releases doxorubicin in high concentrations into the tumor and the tumor margins. The RFA plus LTLD combination has shown a statistically significant dose-response effect for time to treatment failure in a Phase I trial in which most subjects (62.5%) had tumors >3 cm. RFA plus LTLD is currently being evaluated in a 600-patient randomized, double-blind, dummy-controlled trial.

Localised drug release using MRI-controlled focused ultrasound hyperthermia

Purpose: Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo.Materials and methods: Results are reported from ten rabbits, where a FUS beam was scanned in a circular trajectory to heat 10–15 mm diameter regions in normal thigh to 43°C for 20–30 min. MRI thermometry was used for closed-loop feedback control to achieve temporally and spatially uniform heating. Lyso-thermosensitive liposomal doxorubicin was infused intravenously during hyperthermia. Unabsorbed liposomes were flushed from the vasculature by saline perfusion 2 h later, and tissue samples were harvested from heated and unheated thigh regions. The fluorescence intensity of the homogenised samples was used to calculate the concentration of doxorubicin in tissue.Results: Closed-loop control of FUS heating using MRI thermometry achieved temperature distributions with mean, T90 and T10 of 42.9°C, 41.0°C and 44.8°C, respectively, over a period of 20 min. Doxorubicin concentrations were significantly higher in tissues sampled from heated than unheated regions of normal thigh muscle (8.3 versus 0.5 ng/mg, mean per-animal difference = 7.8 ng/mg, P < 0.05, Wilcoxon matched pairs signed rank test).Conclusions: The results show the potential of MRI-controlled focused ultrasound hyperthermia for enhanced local drug delivery with temperature-sensitive drug carriers.

Initial Results of a Phase I/II Study Evaluating the Maximum Tolerated Dose, Pharmacokinetics, Safety, and Efficacy of Hyperthermia and Lyso-thermosensitive Liposomal (LTSL) Doxorubicin in Patients with Breast Cancer Recurrence at the Chest Wall (RCW)

Initial Results of a Phase I/II Study Evaluating the Maximum Tolerated Dose, Pharmacokinetics, Safety, and Efficacy of Hyperthermia and Lyso-thermosensitive Liposomal (LTSL) Doxorubicin in Patients with Breast Cancer Recurrence at the Chest Wall (RCW)