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#Abst1097#

#Abst1097#. wALT trial (Phase I-II): Weekly non- pegylated liposomal anthracycline and taxane combination in first-line breast cancer chemotherapy.

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#Abst1097#

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  1. #Abst1097# wALT trial (Phase I-II): Weekly non-pegylated liposomal anthracycline and taxane combination in first-line breast cancer chemotherapy Authors:M. S. Rosati 1, C. Raimondi 1, S. Quadrini 1, R. De Sanctis 1,L. Stumbo 1, B. Gori 1, E. Del Signore 1, M. P. Poleggi 2, M. Di Seri 1 2Oncology DH, Tarquinia (VT); 1 University of Rome “Sapienza”, Dpt of ONCOLOGY A, Policlinico “Umberto I”; Rome, ITALY

  2. Why metastatic breast cancer is incurable? Absolute or relative resistance? • Gompertzian growth-model • log-kill in Gompertzian like tumor • dose-dense sequential regimen

  3. ABSTRACT #1097# Background: Weekly administration of proved efficacy agents, through different pharmacodynamic-kinetic interactions, overcomes resistance with lower toxicities and greater benefits and preservation of quality of life. Based on this assumption we designed wALT (weekly liposomal-anthracycline and taxane) trial. Methods: Patients (pts) with previously untreated metastatic breast cancer were eligible. Prior adjuvant anthracycline or taxane exposure was permitted. We designed a phase I multicenter, open lable dose-finding study to examine the safety and efficacy of weekly combination (d 1,8,15 q4w) of paclitaxel (n=28 pts) or docetaxel (n=20 pts) with non-pegylated liposomal anthracycline; a phase II trial followed and a total of 48 patients was enrolled from January 2002. All Her2(+) pts received trastuzumab after 6 cycles until progression. Primary endpoint of phase I study was dose limiting toxicity (DLT) and safety assessment; phase II trial primary endpoint was overall response rate (ORR) while secondary endpoints were time to progression (TTP) and 2-years survival (2yOS). Patients characteristics were as follows: median age 56 years old (range 45-65), n=31 were PS 0, n=40 ER (+), n=29 (Her2+), n=32 had > 2 metastases sites, n=29 showed liver and n=34 bone metastases. Results: DLT was 50 mg/m2 for paclitaxel or30 mg/m2 docetaxel combined with 25 mg/m2 of non-pegylated liposomal anthracycline. We recorded 5.4 median cycle/pt. The 12.5% and 60.41% pts achieved complete and partial response respectively with a clinical benefit of 85.41%. Median TTP was 10.68 months and median 2y OS was 21.60 (65.6% pts). No survival differences were recorded between groups (paclitaxel vs docetaxel). WHO G3-4 toxicities includedneutropenia (68.75%) and complete alopecia (60.41%). Mucositis (12.53% vs 8.3%), onycholysis (22.91% vs 10.41%) and peripheral sensory neuropathy (25% vs 14.58%) were significantly higher for docetaxel than paclitaxel. A total of 29.3% pts showed left ventricular ejection fraction (LVEF) reduction but none > 10% with recover after treatment completion. Conclusions: Weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage a phase III study design.

  4. INTRODUCTION In an attempt to improve the efficacy of chemotherapy in breast cancer and to suppress cancer re-growth of resistant cells during and between each cycles, dose intensification has been extensively evaluated over the past decade. Tumor re-growth after subcurative therapy could be quite rapidafter each cycle of treatment that eradication of disease isdifficult, even when all of the cells are "sensitive" to thedrugs used. Considering the Gompertzian kinetic growth curve in which cell doubling time increases with tumour size, the Norton–Simon model predicts that the best way to destroy an heterogeneous mix of cancer cells is to eradicate the numerically dominant, faster- growing cells first, followed by eradication of the more slow-growing, resistant clone through a dose intensification [1]. Dose-dense treatments increase dose-intensity not by increasing the dose, as with dose escalation, but by decreasingthe time, evoiding regrowth of the resistant, slow-growing clones [2]. Moreover, metastatic disease is often incurable for the presence of multiple resistant clones [3]. Combined use of liposomal non-pegylated anthracycline and dose-dense regimen is supposed to overcame multidrug resistance. Although Metastatic breast cancer (MBC) treatment is extensively changing with biologic drugs development and gene profiling, anthracyclines remain the backbone of therapy for advanced breast cancer. Unfortunately, their extensive use as a detrimental part of adjuvant treatment, strongly limits rechallenge with conventional formulations for cumulative cardiotoxicity. Moreover, MBC patients who are likely to receive first line chemotherapy, are often good performance status (PS). To preserve acceptable QoL and obtain disease control, first line chemotherapy tolerability profile has not to exceed grade 2 toxicity (G2). Based on these assumptions, to preserve good QoL and overcame cancer resistance, in 2002 we designed the phase I-II of wALT trial (weekly non-pegylated Liposomal Anthracyclines and Taxane), a multicenter institution study, to establish the safety and efficacy of the combined non-pegylated liposomal anthracycline/taxane weekly administration in metastatic breast cancer (MBC).

  5. PATIENTS PROFILE

  6. STUDY DESIGN (from 2002 to 2007) Standard ALT Non pegylated Liposomal Anthracycline (AL) 35 mg/m2 q3w Paclitaxel 135 mg/m2 q3w or Docetaxel 75 mg/m2 q3w wALT TRIAL (on study) 6 cycles AL 25 mg/m2 d1,8,15 q4w Paclitaxel 50 mg/m2 d1,8,15 q4w or Docetaxel 30 mg/m2 d1,8,15 q4w

  7. END-POINTS • Phase I (dose-finding): • Primary end points: • maximum tolerated dose (MTD) • dose limiting toxicity (DLT) • Phase II: • Primary end-points: • Overall response rate (ORR) • Paclitaxel arm vs Docetaxel arm RR • Secondary end-points: • Toxicity • Time to progression (TTP) • 2-years overall survival (2y-OS)

  8. PHASE I: RESULTS • Dose limiting toxicity (DLT) was defined as grade 4 neutropenia, febrile neutropenia, grades 3 or 4 non-haematological toxicity or treatment delay due to unresolved toxicity during each cycle. The DLT were G4 neutropenia (febrile, non-febrile) and sensory neuropathy in docetaxel arm. There was no case with more than a 10% LVEF decrease after a median of 15 administration/patients. • The maximum tolerated dose (MTD) was reached at the dose of non-pegylated liposomal doxorubicin of 25 mg/m2/week and paclitaxel of 50 mg/m2/week or docetaxel 30 mg/m2/week d 1,8,15 every 4 weeks.

  9. TOXICITY (PHASE I – II)

  10. Docetaxel vs Paclitaxel

  11. 75 70 65 60 55 50 45 40 LVEF before LVEF after CARDIOTOXICITY (PHASE I – II) Graph 1: Median % of pts who presented LVEF decline: 29.16% never > 10%

  12. PHASE II: RESULTS

  13. TTP Graph 2: Kaplan-Meier TTP curve (median TTP: 10.68 months)

  14. OS Graph 3: Kaplan-Meier OS curve (median 21,60 months). The 2-years OS is 65.6%

  15. PRO Significative clinical benefit (85,41%) TTP: 10.68 months Very well tolerated combination treatment CONTRA Not powered to investigate the role of combined Trastuzumab Small number of series (48 pts) Overexpression of Topoisomerase-2αneed to be investigated Not powered to investigate the role of continuig treatment after 6 cycles. Not powered to investigate differences between HER2(+) and HER2(-) wALT TRIAL: PRO E CONTRA

  16. CONCLUSIONS To the best of our kwnowledge, this is the first study with combined weekly non-pegylated liposomal anthracycline and taxane in MBC which seemed to be feasible and to improve clinical benefit. Considering the direct dose-response relationship in improvement of outcomes as one of the most important tools in chemotherapy, weekly dose-dense regimen has to be preferred. Weekly combined liposomal anthracycline and taxane showed acceptable toxicity profile with neutropenia as the major G4 toxicity but no primary prophylaxis with G-CSF needed[4]. These findings are extremely encouraging and are consistent with the hypothesis of that by shortening the time interval between each chemotherapy treatment could result in more effective eradication of malignant cells and thus resulting in improved survival. Use of non-pegylated liposomal formulation permits anthracycline rechallenge even in those pts who have previously received conventional epirubicin or doxorubicin whose cardiac toxicity limits the total dose. This is particularly important for that anthracyclines still represents the cornerstone of MBC. Our phase II results encourage phase III trial (trial will open to enrollment June 2008*) to establish if dose-dense scheduling with non-pegylated liposomal anthracycline and paclitaxel (the lower toxicity arm) is superior to conventional scheduling of chemotherapy in larger size of patients.

  17. REFERENCES and CONTACT Goldie J, Coldman A: Application of theoretical models to chemotherapy protocol design. Cancer Treat Rep 70:127-131, 1986 Norton L: A Gompertzian model of human breast cancer growth. Cancer Res 1988, 48:7067-7071. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: Phase II study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3 h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC [Abstract 512]. Proc Am Soc ClinOncol 2004; 23: 6s. Nisticò C, Bria E, Cuppone F et al Weeklyepirubicin and paclitaxelwithgranulocytecolony-stimulatingfactorsupport in previouslyuntreatedmetastaticbreastcancerpatients: a phase II study. AnticancerDrugs. 2007 Jul;18(6):687-92. * To learn more about wALT phase III trial enrollment, please feel free to contact Dr MS Rosati: mail: sofiarosati@tiscali.it, tel: +39 06 4441675; fax: +39 06 4941035

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