LMS-02 A phase II single-arm multicenter study of Trabectedin in combination with Doxorubicin as first-line treatment of metastatic and/or locally advanced leiomyosarcoma of Uterine (U-LMS) or Soft Tissue (ST-LMS) origin: Results from both cohorts F.Duffaud, C. Chevreau, N. Penel, A. Le Cesne, C. Guillemet, C. Delcambre, A. Floquet, D. Cupissol, B. Lacas, P. Pautier French Sarcoma Group

LMS02 – background on LMS LMS is genomically complex with wide anatomic distribution and no known specific molecular targets 25% of soft tissue (ST) sarcomas overall are LMS, 35% of LMS are uterine-LMS (U-LMS) Poor prognosis when metastatic or locally advanced (median PFS 1 rst line  5 mo and median OS  12 mo) Moderate chemosensitivity Response rate for combination chemo in 1st-line therapy is < 50% for U-LMS and 35% for ST-LMS

LMS02 – rationale for study 1st line therapy of Soft Tissue Sarcomas: Efficacy of combination (doxo + ifo) Higher RR than doxo alone Higher PFS with higher doses of doxo and ifo 1 No survival improvement but higher toxicity New combinations without doxorubicin Gem+Tax for uterine LMS 2 - Gem Tax RR : 35.8%, Median PFS : 4.4 mo, -Median OS : 16mo+ Rationale for new doxorubicin-based combination Rx 1 Judson I. Ann Oncol LBA7 ESMO 2012; 2 Hensley M. Gyn Oncol 2008

LMS02 – rationale for study Trabectedin: activity in LMS after anthracycline failure  Disease control (PR + stable disease) : 56% in LMS, 61% in synovial sarcomas  Response rate: 10%  PFS at 6 months (2 nd and 3rd line): 29% in LMS, 36.5% in U-LMS To test a new association with active drugs in first line, the French Sarcoma Group designed this study in LMS exclusively - Stratification by primary site: uterus vs. extra-uterus - Strict 1st line of chemotherapy for metastatic disease

LMS02 – study objectives Primary end point : Disease control rate, defined as objective response + stable disease Secondary end-points : –Duration of response –PFS at 12 weeks –Overall Survival (OS) –Toxicity

LMS02 – methods Stratification: by primary tumor location (uterine vs. extra uterus/soft tissue) Each stratum considered as an independent phase II study (Simon’s optimum design) “Uterine” study, goal= 45 evaluable pts “Uterine” study, goal= 45 evaluable pts For probability of disease control rate >70%  = 10%,  = 10% 2 steps: n=21 pts, if ≥12 non PD/21 add 24pts, positive study if ≥ 27 non PD /45 Assume baseline RR = 50% “Soft Tissue” study, goal 62 evaluable pts “Soft Tissue” study, goal 62 evaluable pts For a probability of disease control rate of >60%,  = 10%,  = 5% 2 steps: n=27, if ≥ 12 non PD/27 add 35 pts, positive study if ≥ 29 non PD/62 Assume baseline RR = 40%

LMS02 – treatment plan Treatment schedule (according to Phase 1 study: JY Blay et al. Clin Cancer Res 2008;14:6656) Doxorubicin : 60 mg/m² IV D1, followed by Trabectedin : 1.1 mg/m² 3 hr IV infusion, D1  Dexamethasone I.V: 20 mg 30min prior to initiation of treatment  Pegfilgrastim (peg-G-CSF) 6 mg s/c, D2 Treatment duration 6 cycles, 21 days each cycle 2 doses reductions allowed for both drugs: Doxo 50 and 45; Trab. 0.9 and 0.7 Surgery for residual disease was allowed Follow-up Weekly: CBC-Platelets, complete liver function tests, CPK Disease evaluation (CT scan): every 2 cycles

LMS02 – main eligibility criteria Metastatic LMS or unresectable local relapse (Uterus or Soft Tissue) No prior chemotherapy (neither adj. nor meta.) Age ≥18 years, and “physiological” age  70 years Measurable disease (RECIST criteria 1.1) ECOG PS ≤ 2 Adequate organ function Signed written informed consent

LMS02 – enrollment status (19 centers) Patients accrued from Aug 2010 to March  62 pts included but 1 ST non LMS  Efficacy and safety analysis on 61 pts Patients accrued from Aug 2010 to Nov 2012  45 pts included But 1 extra uterine LMS  44 pts treated : safety and efficacy analysis on 44 pts SOFT TISSUE - STUDY SOFT TISSUE - STUDY UTERUS STUDY UTERUS STUDY

LMS02 Uterine and Soft Tissue LMS pts characteristics Patients (n)44 Uterine 61 Soft tissue Median age (range) 58 [35-73] 59 [32-77] PS 0 1/2 Female Grade 31 (70%) 37 (62%) 10 (23%) / 2(5%) 22 (37%)/1 (1%) 44 (100%) 40 (66%) NA 1(8%)/ 2 +3 (47%) Site of primary Uterine Extremity/RetroP/Pelvis Visceral /other Pelvic RT n (%) 44 (100%) 0 NA 11/17/7 NA 17/9 15 (34%) NA Metastatic disease n (%) lung/ liver bone/ cutaneous/other 36 (82%) 51 (83%) 32 (89%)/14(39%) 41 (80%)/24 (47%) 8/0/13 5/4/13

LMS02 Uterine and Soft Tissue treatment delivery Patients44 U-LMS 61 ST-LMS Median of cycle received [range] 6 [1-6] 6 [1-6] Dose reductions (nb of cycles) 30 (14%) 45 (13.8%) Compliance to treatment (nb of pts) Therapy completed (6 cycles) Therapy ongoing Progression Stopped for toxicity Death during therapy 30 (68%) 46 (75%) a 7 b 1 c 2 d Resection of mets. post-protocol chemo 7 (16%) 11 (18%) Toxic Death0 1 e a: 1 hematologic, 2 hematologic +cytolysis, 1 intestinal dilatation, 1 supraventricular tachycardia; b: 2 fatigue/asthenia, 1 thombocytopenia, 1 fatigue+ cytolysis, 2 thrombocytopenia+neutropenia, 1 febrile neutropenia, c: pulmonary embolism ; d:1 toxic death, 1 sudden and unexplained death; e: 1 pulmonary oedema

LMS02 – uterine LMS results Best Response (44 pts): 25 PR ORR : 56.8% 13 stable diseases Disease control rate : 86% Median duration of response : 5.5 months (3.8 – 6.6) PFS rate at 12 weeks: 84 % [95% CI : 73%-94%]

LMS02 – Uterine LMS PFS Median of PFS: 8.2 months

LMS02 – Soft Tissue LMS results Best Response (61 pts): 21 PR + 2 CR ORR : 38 % 33 stable diseases Disease control rate : 92% Median duration of response : 9.3 months [ ] PFS rate at 12 weeks: 92 % [95% CI: 82% - 96%]

LMS02 – Soft tissue LMS PFS Median of PFS: 10.6 months

LMS 02 – toxicities Toxicity % of cycles N = 105 (532 cycles available) G1-G2G3G4 Leucocytes Neutrophiles Platelets Hemoglobin Fatigue Nausea/vom Fever/infection Febrile neutropenia Transaminases increase Mucositis 32% 22% 49% 78% 48% 4% - 63% 10% 30% 19% 12% 7% 6% - 4% 14% 1% 17% 26% 4% 1% - 2% 1% - 44 platelet transfusions for 30 pts 67 erythrocytes transfusions for 38 pts

LMS 02 – conclusions Important objective RR per RECIST for 1 rst line therapy in LMS Compare favorably with other combinations for U-LMS Doxo-Ifo 1 ; U-LMS 1rst line ORR: 30%, DCR : 82% Gem-Tax 2 ; U-LMS 1rst line ORR: 36%, m PFS = 4.4 mo Compare favorably with other combinations for ST-LMS Ifo- containing 3 ; all-LMS 1rst line ORR: 17%, High rates of disease control and prolonged PFS in both LMS cohorts 86% and 92% of DCR, PFS rates at 3 mo of 84% and 92%, for Uterine and Soft Tissue cohorts respectively Supports the hypothesis that Doxo + Trab is an active regimen, in both cohorts of LMS Van Glabbecke , active agents 1rst line for LMS : 3 mo PFR ≥58% and 6 mo PFR >40% → Efficacy results of Doxo →Trab combi are very encouraging in U- and ST-LMS 1 Sutton G Gynecol Oncol 1996, 2 Hensley Gynecol Oncol 2008, 3 Sleijfer S, EJC : 72-83, 5 Van Glabbecke M, EJC :543

LMS 02 – conclusions Though well tolerated, Doxo + Trab is toxic but manageable in 1st line Less toxic than Doxo (75 mg) + Ifo (10 g), EORTC study a 46% febrile neutropenia, 35% anemia gr3-4, 33% thombocytopenia gr3-4 Compares favorably with Gem (900 mg)+Tax (100 mg), Hensley b et al for anemia and thrombocytopenia (24% anemia gr3, 14.5% thombocytopenia gr3-4 ) but 6% febrile neutropenia with Doxo+Trab vs. 0% with Gem+Tax, (only in 45pts) LMS02 results different than GEIS-20 study results GEIS-20: Doxo vs. Trab → Doxo combi (Martin-Proto et al. ECCO meeting 2013) Combination not superior to Doxo alone (ORR : 13% and 20%, mPFS 5.7 and 5.6 mo, for Combi and Doxo respectively) Trab → Doxo, all sarcoma subtypes, too small population Define appropriate 1st line regimen in LMS only A randomized phase III study, in 1st line, for LMS only, comparing best nex active combination regimens, is being developed a Judson I. Ann Oncol LBA7 ESMO 2012; b Hensley M. Gyn Oncol 2008