Safety profile of biweekly schedule of liposomal Doxorubicin (Caelyx) in salvage therapy of adult solid tumors. Greige Yolla, Sr. Salloum Warde, Adaimy Ina, Serhal Mira, Kattan Joseph Department of Hematology-Oncology, Saint Joseph Hospital, Beirut, Lebanon LSMO 7, 13-14 Nov. 2008, Beyrouth, Lebanon

Reducing Anthracycline-Induced Cardiotoxicity Anthracycline analogs Weekly low-dose and prolonged continuous infusion ICRF-187 (dexrazoxane) = Cardioxane Liposomal drug delivery : CAELYX Anthracycline analogs (epirubicin, mitoxantrone) are associated with reduced, though significant, cardiotoxicity. Weekly low-dose and prolonged continuous infusion (24 to 96 hours) of doxorubicin results in reduction of cardiotoxicity. ICRF-187 (dexrazoxane) prevents free-radical formation and results in a significant reduction in cardiotoxicity. Liposomal drug delivery remains the most promising avenue for the reduction of anthracycline-induced cardiotoxicity.

Structure of CAELYX™/ Doxil® (PLD) Evades immune system Significantly prolongs t½ Remains encapsulated until it reaches tumor1 Concentrates in tumor Doxorubicin PEG CAELYX™/Doxil® (PLD) is a Stealth® pegylated liposomal formulation of doxorubicin. Pegylated liposomes are formed by grafting linear segments of methoxypolyethylene glycol onto the phospholipid surface. The methoxypolyethylene glycol protects the liposome from degradation in the circulation and from recognition and removal by the mononuclear phagocyte system. The end result is an extended circulation time. Pharmacokinetic data from 120 patients enrolled in 10 different clinical trials demonstrated that the half-life of PLD is 73.9 hours. Gabizon et al demonstrated that most, if not all, of the doxorubicin contained in pegylated liposomes remains encapsulated in the plasma.1 Pegylated liposomes are approximately 85 nm in diameter, allowing for preferential extravasation through endothelial gaps into the tumor tissue, targeting encapsulated drug to the tumor. 1Gabizon, et al. Cancer Res. 1994;54:987-992. PLD = pegylated liposomal doxorubicin hydrochloride. 1 Gabizon, et al. Cancer Res. 1994;54:987-992.

Cardiac Safety of CAELYX™/Doxil® (PLD) in animal models PLD (0.25-1 mg/kg) was less cardiotoxic than conventional doxorubicin (1 mg/kg) in rats1 The incidence of cardiotoxicity in rabbits treated with PLD (1 mg/kg) was 16% vs 67% with conventional doxorubicin (1 mg/kg)2 There was no evidence of cardiotoxicity in dogs treated with PLD (0.25-1 mg/kg) 1-5 weeks after treatment1, while mild to moderate cardiomyopathy occurred in all dogs treated with conventional doxorubicin (1 mg/kg)1 Several multiple-dose toxicity studies were conducted in animals. In a study with rats (Crl:CD® BR VAF/Plus), CAELYX™/Doxil® (PLD) (0.25-1 mg/kg) was found to be less cardiotoxic than conventional doxorubicin (1 mg/kg).1 In rabbits (New Zealand White), no deaths were congestive heart failure-related with PLD (1 mg/kg) vs 33% with conventional doxorubicin (1 mg/kg).2 The incidence of cardiotoxicity in rabbits treated with PLD (1 mg/kg) was 16% vs 67% in rabbits treated with conventional doxorubicin (1 mg/kg).2 Treatment of rabbits with PLD (1.5-fold the cumulative dose of conventional doxorubicin) did not produce a corresponding increase in the incidence and severity of cardiotoxicity, demonstrating its reduced cardiotoxic potential.2 There was no evidence of cardiotoxicity in a study of dogs (beagles) treated with PLD (0.25-1 mg/kg) 1 to 5 weeks after treatment; however, mild to moderate cardiomyopathy was observed in all dogs treated with conventional doxorubicin (1 mg/kg), which worsened during the 4 weeks following treatment.1 1Schering-Plough, data on file. 2Working PK, et al. J Pharm Exp Ther. 1999;289:1128-1133. PLD = pegylated liposomal doxorubicin hydrochloride. 1Schering-Plough, data on file. 2Working PK, et al. J Pharm Exp Ther. 1999;289:1128-1133.

CAELYX™/ Doxil® (PLD) Effect on LVEF A median CAELYX™/ Doxil® (PLD) dose of 660 mg/m2 (500 to 1500 mg/m2) was administered Median LVEF change by MUGA scan of –2% (–15% to +9%), no clinical cardiac symptoms Five patients had LVEF decreases of more than 10% No correlation was found between cumulative dose of PLD and change in LVEF Billingham scores ( semiquantitative histologic scoring system) of cardiac biopsies were 0 to 1.5 with no cardiac symptoms A median CAELYX™/Doxil® (PLD) dose of 660 mg/m2 (500 to 1500 mg/m2) was administered; patients underwent 10 to 30 months of PLD treatment. The median age was 59 years (27 to 78 years). Median LVEF change by MUGA scan of –2% (–15% to +9%), no clinical cardiac symptoms. Five patients had LVEF decreases of more than 10%; 3 with prior exposure to doxorubicin. Billingham scores of 6 patients who underwent cardiac biopsies were 0 to 1.5 with no cardiac symptoms. These patients had received overall cumulative doses of PLD of 490 mg/m2 to 1320 mg/m2. Patients were safely treated for up to 2.5 years with PLD without experiencing an increase in cardiotoxicity. This duration of treatment would not be possible with doxorubicin or epirubicin as cardiotoxic doses are reached within 6 months, necessitating a change to a different agent even if the patient is responding to treatment. Safra T, et al. Ann Oncol. 2000;11:1029-1033. PLD = pegylated liposomal doxorubicin hydrochloride. Safra T, et al. Ann Oncol. 2000;11:1029-1033.

Rationale CAELYX : classical dosage 50 mg/m2/4 w CAELYX : less cardiotoxicity But cutaneous toxicity = PPE ( Palmar-Plantar Erythro-dysesthesia ) CAELYX : PPE = 49% grade 3-4 = 23% Prevention : cold application on hands and foots time and work consuming

Toxicities evaluation Les criteres NCI de toxicites : Grade 1 2 3 4 PPE Reaction moderee: dermatite ou erytheme; sans douleur Reaction importante:desquamation, oedeme, saignement; Avec douleur Dermatite ulcerative ou douleur interferant avec les activites Risque vital

Recent Literature Reduce dosage to 40 mg/m2/4w PPE grade 3-4 decreases to 8,3 - 1,1% Ref : Campus SM. Gynecol.Oncol. 2001;81:206-212 Rose PG. Gynecol.Oncol. 2001;82:323-328

Recent Literature Split dosage to 20 mg/m2/2w PPE = 47% grade 3-4 = 4,7% PPE = 34% grade 3-4 = 0,02% Ref : Sehouli J. Ann Oncol 2006;17:957-961 Strauss HG. Anti-cancer drugs 2008;19:541-545

Included patients Since 1/1/2008 : Age from 18 to 75 ans Metastatic solid tumors Resistant to at least one line of chemotherapy Good cardiac, renal and hepatic functions

Medications CAELYX : 20 mg / m2 / 2 weeks Dilute in 250 cc 5% Dextrose in 30 minutes Premedications : Anti-emetic Solumedrol Zantac No cold application

Resultats 15 patients are included 6 M et 9 F Cancer types: Ovary 6 Breast 2 Sarcoma NSCLC HN 1 CUP

Resultats Mean age : 53 ( extremes 20 to 73 ) Total number of cycles : 78 Mean number of cycles per patient : 5,2 ( extremes 1 to 11 ) Dose in mg : 30 ---- 8 patients 35 ---- 3 patients 40 ---- 3 patients

Resultats Tolerability : Hematologic : Anemia : grade 2 : 1 patient Neutropenia grade 3 : 1 pt Mucositis : grade 2 : 1 patient Biologic : 0 PPE grade 1-2 : 2 patients = 0,13% PPE grade 3-4 : 0

Conclusions The new schedule 20 mg/m2/2w is well tolerated 0,13% PPE 0 toxicity PPE grade 3-4 Reponse and survival are ongoing