Studio ABRAMYO Phase I-II, multicenter open label study in patients with previously untreated metastatic breast cancer

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1 Studio ABRAMYO Phase I-II, multicenter open label study in patients with previously untreated metastatic breast cancer Paola Papaldo Istituto Regina Elena Roma

2 OS in HR+ BreastCancer ER pos.ve Andre F et al. JCO 2004;22: months Median survival was 28 months for patients treated from 1987 to 1993 and 45 months for those treated from 1994 to 2000.

3 OS in ER+: 28 months for pts treated from 1987 to months for pts treated from 1994 to 2000 First line studies PFS months OS monthts TvsF vs vs39.3 Howell JCO 2004 T vsex 5.8 vs vs37.2 ParidaensJCO 2008 An vs F500 + An 10.2 vs vs37.8 Bergh SABCS 2009 An vsf250 + An 13.5 vs15 P= vs47.7 P=0.05 MethaNEJM 2012 An vs F vs vs 54.1 Robertson SABCS 2014 L vsl + Palbociclib 10.2 vs20.2 P= vs37.5 ns Bell SABCS 2014 Ex vsex + Everolimus 4.1 vs10.6 P< vs31 ns BaselgaNEJM 2011 Piccart Ann Oncol 2014 ExvsF250 (60% III OT) 3.7 vs3.7 ChiaJCO 2008 Examestane 4 Carlini Canncer Inv 2007

7 Median OS for pts treated from 1987 to 1993 and for those treated from 1994 to 2000 HR-negative tumors 12 months (Andre F et al. JCO 2004;22: ) 11 monthsofpfs and 39 monthsofos (Glicorov, ESMO 2014)

8 European Science Foundation Definition of nanomedicine Nanomedicineuses nano-sized tools for prevention, diagnosis and treatment of disease and to gain increased understanding of the complex underlying pathophysiologyof disease. The ultimate goal is improved quality of life. Nanopharmaceuticalcan be developed either as drug delivery system or biologically active drug products

9 Rationale of liposome-encapsulated doxorubicin citrate + nab-paclitaxel The combination of anthracyclinesand taxanesis among the most active in metastatic breast cancer treatment. The use of this combination is limited by myelosuppression, alopecia, acute nausea and vomiting, stomatitis, allergic reactions and, cumulative cardiotoxicity. There is a need for non-/less toxic, active and well tolerated first-line therapy for patients with ER+/TN advanced disease.

10 Liposomal doxorubicin The liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin into the tumor compared with normal tissue There was a correlation between the plasma AUC(0- infinity) of total doxorubicin and the degree of myelosuppressionin pts receiving conventional doxorubicin, but this correlation was not found in patients receiving non-peg-doxo. It is characterized by more convenient pharmacokinetics and a different toxicity profile. Cardiotoxicityis reduced in LD as well as hematotoxicity, alopecia, nausea and vomiting

11 Nab-paclitaxel Improved TaxaneFormulation Rationale Increase IntratumoralDrug Levels Preferential Uptake by Tumorvs. Normal Cells Enhance Antitumor Activity Avoid Solvent Toxicities

-Selection of the appropriate dose level for the combination.

12 ABRAMYO StudySchema Phase I-II study of weekly nab (nanoparticle albumin-bound)-paclitaxel(nabpaclitaxel) in combination with liposomal encapsulated doxorubicin (LDox) in patients with HER2 negative metastatic breast cancer Max L-doxo 900 mg/mq Primary endpoints PHASE I: -Selection of the appropriate dose level for the combination. PHASE II: -PFS Secondary endpoints -ORR (CR and PR) -Duration of Response -FFS -Overall survival (OS) -Clinical Benefit (CR+PR+SD> 6 mesi) -Safety and tolerability -SPARC microenvironment signature (SMS) analysis whenever possible

13 Main inclusion criteria Histologicallyor cytologicallyconfirmed HER-2 negative, newly diagnosed breast cancer Metastatic breast cancer with measurable disease (by RECIST criteria) No prior chemotherapy for metastatic disease 12 months since adjuvant paclitaxeland/or anthracyclines therapy Previous anthracycline(adjuvant setting) maximum dose of doxorubicin 360 mg/mq and epirubicin 480 mg/mq

14 Statistical section The total patient sample size of Phase I: min 9 max 18 patients. Total patient sample size for Phase II -This part of the study is designed as a phase II trial according to the design described by A Hern. A sample size of 62 patientsis considered sufficient to give an 80% probability of rejecting a baseline 6-months PFS rate of 60% (median PFS 8 months) with an exact 5% one-sided significance test when the true 6-months PFS rate was 75% (median PFS 14 months). The drug regimen will be considered for further studies if at least 44 patients are free from progression at 6 months.

15 Patient Characteristics (update at 25/6/15) S T E P Pts Yrs Diagnosis DFS yrs CT neo/adj OT adj ER/PR % KI 67 % Line OT PC E+T-> CMF TAM 80/10 35% 1let+-Palb 3 met Site met MM /5 40% 3 (ex+eve) 3 PNG CMF - 70/80 25% 2 3 SMD CMF - 0/0 ND - 1 CCA EC-T AI 60/55 20% 1 2 FA TAM+LH 40/40 50% - 2 MMS TAM 90/60 20% - 1 SDE AC-T TAM 40/40 50% - 2 NL EC-T TAM 80/30 55% - 2 SDB* /0 80% - 2 AA ,5 6FEC TAM+LHR H 90/40 40%

16 Reported Toxicity per patient (update at 25/6/15; median cycles 7) CohortI (100/20 ) Cohort II (125/20) Cohort III (125/25) toxic event(s) 3pts Any G3 Grade Pts(%) pts(%) Any Grade Pts(%) 6pts G3 Pts(%) G4 Pts(%) Any Grade Pts 2pts G3 Pts G4 Pts Anaemia 2(67) - 3(50) - Neutropenia 3(100) 2 (67) 6 (100) 2(33) 4(67)* 1 1 Febrile Neutrop - - 2(33) - 2(33) Piastrinopenia (17) - - Nails micosys 1 (33) - 1(17) - - Stomatitis 3(100) 1(33) 2(33) - 1(17) 1 Nausea - - 4(67) Diarrhea 2(67) - 2(33) 1(17) - 1 Neuropathy 2 (67) 1 (33) 1 (17) Conjunctivitis - - 1(17) - - Asthenia 1(33) 1 (33) 3(50) 1 (17) - 1 Erythema - - 2(33) - - *1 patientreportedafebrileneutropeniag4 lasting> 5days= DLT 16

17 RESULTS (update at ; median cycles 7) S T E P Pts Yrs DFS yrs CT neo/adj OT adj KI 67% Line OT met Site met Cycl N Delaied cycles Omit adm. ORR PC E+T-> CMF T * 1 1 SD + brain met MM (eve) 3 12* - 1 RP PNG 63 4 CMF * 1 6 SD 2 SMD CMF - ND * - 5 SD CCA EC-T AI * 1 2 PD FA T+L * - 2 RP MMS T RP + PD QT lungo SDE AC-T T RP NL 39 3 EC-T T RP 3 SDB RM AA 52 6,5 FEC T+L * Ended treatmens 17

18 Impossibile visualizzare l'immagine. AIMS phase II Study Primary: Progression free survival defined as the time elapsed between treatment initiation and tumor progression or death from any cause, with censoring of patients who are lost to follow-up Secondary: -Objective tumor response rates (CR-PR) according to RECIST criteria - Duration of Response -Failure free survival measured from the start of therapy to the date of disease progression, relapse, or disease- or treatment-related death. - Overall survival - Clinical Benefit[CR+PR+stable disease (SD> 6 months)] - Safety and tolerability -SPARCmicroenvironment signature (SMS) analysis (whenever possible)

20 N-peg-doxo+ CTX vsadr + CTX nelle pts pretrattata con Antracicline Doxorubicina naïve(90%): NPLD/CTX 42% Doxo/CTX 45% Pretrattate con doxo(10%): NPLD/CTX 50% Doxo/CTX 20% (Batist G, JCO 2001)

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