5/2/2010. A New Paradigm for Drug Delivery: Intravascular Drug Release from Liposomes

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Samuel Osborne
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1 Conflict of Interest Statement New initiatives in thermotherapy Mark W. Dewhirst, DVM, PhD Duke University Medical Center Consultant and Chair of SAB for Celsion Corporation Research grants from GSK, Varian and Immunolite NIH research grants I will discuss use of a liposomal drug licensed from Duke by Celsion Including pre-clinical and clinical trial results Outline Thermo-sensitive liposomes Enhance drug delivery and anti-tumor tumor effect Recurrent Superficial Bladder Cancer Regional thermal therapy to enhance Mitomycin-C Soft Tissue Sarcoma Phase III clinical Trial results from EORTC A New Paradigm for Drug Delivery: Intravascular Drug Release from Liposomes David Needham Mark Dewhirst Jeff Mills, A. Wright Ana Ponce, Ben Viglianti, Ashley A. Manzoor CLINICAL: Zeljko Vujaskovic Kim Blackwell 1

Free doxorubicin exhibits limited penetration from microvessels Low Temperature Sensitive Liposome (LTSL) Hypoxia Doxorubicin Vessels Typical phospholipid DPPC:MPPC:DPPC-PEG 90:10:4 Primeau AJ et al.

Percent of DOX Released 100 90 80 70 60 50 40 30 20 10 Percent of DOX Released for DOXIL and DPPC:MSPC(10%) at t=4 minutes DOXIL DPPC:MSPC(10%) 0 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

2 Free doxorubicin exhibits limited penetration from microvessels Low Temperature Sensitive Liposome (LTSL) Hypoxia Doxorubicin Vessels Typical phospholipid DPPC:MPPC:DPPC-PEG 90:10:4 Primeau AJ et al. Clin Cancer Research 2005 Lyso-phospholipid DOX release temperature from LTSL is clinically feasible Enhanced drug delivery leads to dramatic improvement in anti-tumor tumor effect with LTSL+HT Percent of DOX Released Percent of DOX Released for DOXIL and DPPC:MSPC(10%) at t=4 minutes DOXIL DPPC:MSPC(10%) Temperature ( o C) Clinical Hyperthermia Range Release time << 20sec Free Drug Dox-LTSL Doxil Kong et al, Canc Res, 2000 Yarmolenko et al, Int J Hyperthermia, 2010 HCT Time (Days) PC Time (Days) FaDu Time (Days) SKOV Time (Days) 2

Drug penetration is much greater with LTSL+HT

intravascularly with LTSL+HT Free Dox + Heat

occurs via intravascular release Intravascular

drug Free Dox + Heat Dox-LTSL + Heat Green =

3 Drug penetration is much greater with LTSL+HT Prediction has been that drug is released intravascularly with LTSL+HT Free Dox + Heat Dox-LTSL + Heat 39 < T <42 C Manzoor and Dewhirst, unpublished Kong et al., Cancer Research 2000 Liposome Dox delivery occurs via intravascular release Intravascular drug release superior delivery compared with free drug Free Dox + Heat Dox-LTSL + Heat Green = vasculature Red = doxorubicin 20 mins confocal imaging 100 µm Drug Green = liposome Red = doxorubicin 3

Duke phase I trial design Chest wall recurrences of breast cancer Eligibility Criteria Chest wall recurrence Failed prior radiotherapy Failed prior chemotherapy (at least one course)

days (completed) Level 2-50 mg/m 2 every 21 days (cancelled)* *Celsion has initiated a phase I/II trial, which will go to expected MTD (50mg/m2) Summary of Phase I Results Toxicities

9-40.5 C Complete Response at 30mg/m2 Celsion Phase I-II II Study Design Eligibility: Breast Cancer patients who: Have documented recurrence of breast cancer on the chest wall (or its

intervals Pre cycle 1 Pre cycle 3 End of TX 15 Endpoints: Phase I To determine the maximum tolerated dose (MTD) of ThermoDox when used with mild hyperthermia among patients with Recurrent

4 Duke phase I trial design Chest wall recurrences of breast cancer Eligibility Criteria Chest wall recurrence Failed prior radiotherapy Failed prior chemotherapy (at least one course) Adequate cardiovascular and bone marrow function Dose Escalation Scheme Level 0-20 mg/m 2 every 21 days (completed) Level 1-30 mg/m 2 every 21 days (completed) Level 2-40 mg/m 2 every 21 days (completed) Level 2-50 mg/m 2 every 21 days (cancelled)* *Celsion has initiated a phase I/II trial, which will go to expected MTD (50mg/m2) Summary of Phase I Results Toxicities Grade 3 40mg/m2 No grade 4 toxicities No cardiotoxicity No hand foot syndrome Responses 20mg/m2 3/3 SD 30mg/m2 2/5 CR, 1/5 PR 40mg/m2 4/7 PR, 1/7 CR Avg T 90 in range of C Complete Response at 30mg/m2 Celsion Phase I-II II Study Design Eligibility: Breast Cancer patients who: Have documented recurrence of breast cancer on the chest wall (or its overlying skin) Have had: - a mastectomy - radiation and - 2 courses of chemotherapy Stratification: None P H A S E I II N = 9 N = cycle of ThermoDox + Hyperthermia in 21 day intervals Pre cycle 1 Pre cycle 3 End of TX 15 Endpoints: Phase I To determine the maximum tolerated dose (MTD) of ThermoDox when used with mild hyperthermia among patients with Recurrent Chest Wall (RCW) breast cancer. Phase II To determine the durable ( 3 months) complete local response (DCLR) rate following treatment with ThermoDox + mild hyperthermia among patients with RCW breast cancer. 4

Gen Eligibility: non-resectable HCC no more than 4 lesions at least 1 lesion > 3cm and none > 7cm no previous treatment Child-Pugh A or B Stratification lesion size: 3-5 vs >5-7 and RFA technique: -

5 Gen Eligibility: non-resectable HCC no more than 4 lesions at least 1 lesion > 3cm and none > 7cm no previous treatment Child-Pugh A or B Stratification lesion size: 3-5 vs >5-7 and RFA technique: - open surgical - laparoscopic or - percutaneous Phase III Study Design R a n d o m i z e 1 : 1 n= 300 n= 300 End Points: Primary: PFS (Progression Free Survival) ThermoDox plus RFA RFA alone Secondary: OS (Overall Survival), TTLR (time to local recurrence), Safety, PRO (Time to definite worsening). Bladder Cancer 61,420 new cases per year (75-85% non-muscle invasive) High rate of recurrence/invasion (approx. 13,000 deaths) Treatment goal for non-muscle invasive bladder cancer (stage Ta, Tis, T1) is to reduce recurrence/tumor progression and bladder preservation Bladder Cancer Current Standard Therapy Bladder Cancer Current Standard Therapy Transurethral resection of the bladder (TURB) + adjuvant intravesical immunotherapy (BCG) with/without IFN-α TURB + adjuvant intravesical chemotherapy (i.e. Mitomycin-C, thiotepa, doxorubicin, epirubicin, docitaxel) Intravesical BCG has been superior to chemotherapy in reducing the rate of recurrence and slowing disease progression, however more toxic with no effect on survival Recurrence rate ( up to 85 %) 35 % will develop invasive disease Response to second-line therapies is poor (20-40%) There is a need to develop better treatment strategies 5

Biologic rationale for combining heat with mitomycin C Phase III trial Mitomycin C + Hyperthermia 83 patients with primary or recurrent superficial (Ta-T1) TCC TURB followed by MMC or MMC + HT

JCO 2003 Study Rationale Chemotherapy + Hyperthermia is more effective than Chemotherapy alone BSD 2000 may be an appropriate alternative delivery system - less focused - more widely distributed

6 Biologic rationale for combining heat with mitomycin C Phase III trial Mitomycin C + Hyperthermia 83 patients with primary or recurrent superficial (Ta-T1) TCC TURB followed by MMC or MMC + HT Endovesical thermochemotherapy was more effective, BUT increased toxicity Wallner and Li, Cancer Research, 1987 Colombo et al. JCO 2003 Study Rationale Chemotherapy + Hyperthermia is more effective than Chemotherapy alone BSD 2000 may be an appropriate alternative delivery system - less focused - more widely distributed regional heating - smaller thermal gradients to improve patient comfort Objectives Primary Objective To assess the safety and tolerability of administering local bladder hyperthermia and intravesical mitomycin-c, as second-line treatment of recurrent TCC of the bladder. Secondary Objective To estimate the time to second recurrence. 6

7 Accrual Goal patients Patient Selection Inclusion Criteria 1. Non-muscle invasive TCC (Ta, Tis, T1), recurrent after 1 round of adjuvant treatment (i.e. BCG) or an inability to tolerate BCG 2. 2 wks since TURB/standard intravesical therapy 3. Age ECOG Performance Status 0-2 Schema Mitomycin C 40 mg instilled in bladder (1mg/ml) HT to target temperature of 42 2 C Q 40 min Schedule 6 wkly Fx (induction) + 4 monthly Fx (maintenance) Follow up end of induction and Q 3months during/after maintenance Toxicities PE, QOL, blood work Results Soft Tissue Sarcoma 11 patients enrolled 9 pt finished induction (6 weekly sessions) 9 pt. assessed 4 weeks post induction (7/9) NED on cystoscopy and cytology 7 pt. completed maintenance (6 still NED) No grade 3/4 toxicity Grade 2: Supra-pubic pubic pain (2/11) Bladder spasm Grade1: Hypertension GU symptoms Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma:a randomised phase 3 multicentre study Issels, Lindner, et al., The Lancet, on line publication ahead of print, patients accrued 149 non-extremity cm 136 >12cm 179 Grade 3 7

8 Improvement in local progression free survival Overall survival not affected except for patients who completed treatment course Primary Endpoint N=113/169 N=156/173 Schema for prospective thermal dose escalation trials Prospective thermal dose control increases CR rate human superficial tumors Test HT R A N D O M I Z E High HT 10x > low Thermal Rx Met Low HT >10 CEM43 CT 90 <1 CEM43 CT 90 T90 =39.7 C P=0.02, OR for response = 2.7 No More HT Jones et al, JCO, May 1, 2005 Followed RTOG guidelines for thermometry 8

9 High thermal dose yields superior local control duration in canine STS P = Hazard Ratio =2.3 Normal Tissue Tumor Temp Change [ C] Survivor Function Estimate >20 CEM 43 CT90 T90=40.5 C Time [minutes] T90=39.6 C <5 CEM 43 CT Time to Local Failure in Years Low Dose Group: Htmin=113.5 Stumvol=33 Grade=Low/Intermediate High Dose Group: Htmin=273 Stumvol=33 Grade=Low/Intermediate Thrall et al., Clin Cancer Res, 2005 Followed RTOG guidelines for thermometry Conclusion- HT addresses unmet needs Acknowledgements Use of HT to enhance liposomal drug delivery to tumors is promising Chest wall + mild HT HCC + thermal ablation MMC + HT may improve local tumor control for recurrent superficial bladder cancer Phase III trial results for sarcoma appear promising for improving local tumor control & progression free survival Considering implementing thermosensitive liposome into this patient population Thermal goals for effective therapy are being refined Progress is being made in non-invasive thermometry D Needham G Anyarambhatla G Kong J Mills F Yuan Q Chen D Papahadjopoulos M Gaber N Wu A Wright A. Ponce B. Viglianti D. Thrall E. Jones Z. Vujaskovic K. Blackwell L. Prosnitz T. Samulski O. Craciunescu S. Das P. Stauffer B. Soher J. MacFall H.C. Charles M. Kleiter Work supported by a grant from the NIH/NCI CA

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