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The Liposome Drug Delivery Platform in Cancer Therapy

Pharmacological Basis for Liposome Delivery of Anti-Cancer Agents. Slow Release: reduced peak levels of free drug and prolonged tumor exposureChange in Biodistribution: avoiding drug deposition in certain tissues will reduce tissue-specific toxicities Tumor Targeting: passive accumulation by enhan

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The Liposome Drug Delivery Platform in Cancer Therapy

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    1. The Liposome Drug Delivery Platform in Cancer Therapy Alberto A. Gabizon, M.D., Ph.D. Shaare Zedek Medical Center, and Hebrew University, Jerusalem, ISRAEL

    2. Pharmacological Basis for Liposome Delivery of Anti-Cancer Agents Slow Release: reduced peak levels of free drug and prolonged tumor exposure Change in Biodistribution: avoiding drug deposition in certain tissues will reduce tissue-specific toxicities Tumor Targeting: passive accumulation by enhanced permeability and retention (EPR) effect

    4. Extravasation and Release of Liposomal Drug Cargo in Tumor Interstitial Fluid

    6. PLD (Doxil, Caelyx)

    7. Marked Drug Deposition in Subcutaneous Tumor Implants 48 hr After i.v. PLD*

    9. Growth Inhibitory Effect of Caelyx is >4-fold that of Doxorubicin (DXR)

    10. Plasma Levels: prolonged half-life PLD vs. doxorubicin (Single Dose, 50 mg/m2)

    12. Stealth liposome localization in human tumors Gamma Scintigraphy 24 and 48 Hours after Injection of Radiolabeled Stealth Liposomes

    14. Comparative Toxicity Profile and Dose-Schedule

    18. Hand-Foot syndrome (PPE) in PLD-treated patients Increased incidence with repeated cycles and short intervals

    20. Hand-Foot Syndrome (Palmar-Plantar Erythema) Chemotherapy-induced dermopathy Characterized by tingling (dysesthesia), erythema, and swelling followed in severe cases by skin breakdown Affecting hands, feet and other skin areas under prolonged friction or pressure Common side-effect of PLD, dose-intensity and schedule-dependent Always reversible with complete healing Unrelated to chemotherapy vesicant effect

    22. No Significant Drop in LVEF (MUGA scan) in Patiens Receiving PLD>500mg/m2

    23. Cumulative Percentage of Cardiac Events vs Cumulative Dose The risk of developing a cardiac event was significantly lower with CAELYX™/ Doxil® (PLD) than conventional doxorubicin. At cumulative doses >500-550 mg/m2 there was a 40% risk of developing a cardiac event with doxorubicin compared with only an 11% risk with PLD. At all cumulative doses above 450 mg/m2 the risk for patients treated with PLD did not increase. Note: The risk of cardiotoxicity does not increase with increasing cumulative doses of PLD, enabling substantially longer duration of treatment. The maximum cumulative anthracycline dose for patients in the doxorubicin group was 763 mg/m2 and 1051 mg/m2 in the PLD group. Wigler, et al. ASCO. 177a. 2002. PLD = pegylated liposomal doxorubicin hydrochloride.The risk of developing a cardiac event was significantly lower with CAELYX™/ Doxil® (PLD) than conventional doxorubicin. At cumulative doses >500-550 mg/m2 there was a 40% risk of developing a cardiac event with doxorubicin compared with only an 11% risk with PLD. At all cumulative doses above 450 mg/m2 the risk for patients treated with PLD did not increase. Note: The risk of cardiotoxicity does not increase with increasing cumulative doses of PLD, enabling substantially longer duration of treatment. The maximum cumulative anthracycline dose for patients in the doxorubicin group was 763 mg/m2 and 1051 mg/m2 in the PLD group.

    24. Overall Survival: Platinum-Sensitive Patients

    26. Potential Advantages of PLD for Metastatic Breast Cancer Safe in anthracycline pretreated patients (with normal LVEF) Dose schedule/Toxicity profile favorable for long-term administration Lesser requirement for central venous access No alopecia Greater suitability for combinations (less myelosuppression than doxorubicin) Potential for combination with trastuzumab

    27. Example of response and prolonged remission on PLD (Doxil) maintenance (courtesy of F. Muggia, NYU)

    30. Caelyx/Doxil: Dose/Schedule and Combination Chemotherapy Single Agent Dose Schedule: Standard: 40-50 mg/m2 infusion q4wk – except Kaposi’s Sarcoma: 20 mg/m2 q3wk – MBC: 60 mg/m2 q 6 wk PK-based: Loading ? Maintenance (60mg/m2 ? 45-40mg/m2) q4wk Modifications: Stomatitis? ? dose; PPE? ? time interval Combination Therapy*: Favorable: Platinum (cisplatin, carboplatin, oxaliplatin) Temodal, Cyclophosphamide, Ifosphamide Avoid: Taxanes, Capecitabine (?) Unclear: Vinorelbine, Gemcitabine

    31. Caelyx+Cisplatin Combo Chemotherapy: An example of PK interaction with PD implication Caelyx can be given at full MTD (50 mg/m2) when combined with cisplatin 60 mg/m2, q4wk. Different toxicity profile from single agent Caelyx: - Neutropenia is the dose-limiting toxicity; - PPE is infrequent and mild. PK interaction: Caelyx Cmax unchanged but clearance accelerated with shorter t1/2

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