Phase II study on the combination of trabectedin and olaparib for advanced, platinum-resistant ovarian cancer Dr Giorgio Valabrega University of Torino, FPO,IRCCS Candiolo giorgio.valabrega@ircc.it Da sistemare con loghi e programma 1

AGENDA Rationale for novel therapies in EOC Rationale for Olaparib and Trabectedin in ovarian cancer Results from the phase Ib TOMAS trial Study Design UPDATE Modified from O’Shaughnessy J, et al. ASCO 2009

Rationale for exploring novel combinations in PR Ovarian cancer Pujade-Loraine JCO 2014 Presented by:

BACKGROUND Trabectedin chemotherapy Inflicts DNA damage via single strand breaks Tr PARP1 4. Replication fork collapse Double-strand DNA breaks PARP1 3. Inhibition of PARP1 Disables DNA base-excision repair 2. PARP1 upregulation Base-excision repair of DNA damage PARP1 PARP1 Modified from O’Shaughnessy J, et al. ASCO 2009

DMR leiomyosarcoma cells Preclinical activity of Olaparib and Trabectedin (1) DMR leiomyosarcoma cells Olaparib blocks both basal and trabectedin induced PARP1 ezymatic activity. The combination of trabectedin and olaparib increases DNA damage if compared to single agents This kind of damage is unrepairable and leads to DNA fragmentation, cell cycle arrest and finally to apoptosis The combination of trabectedin and olaparib shows antitumor and antimetastatic activity in in vivo models Pignochino Y, et al. Presented by:

Synergistic effect of trabectedin and olaparib in human cell lines (regardless BRCA mutations) Arroyo et al JBC 2015

Olaparib single agent in platinum resistant ovarian cancer Kaufmann JCO 2015 Gelmon Lancet Oncol 2011 Kaufman, JCO 2015

MITO-15: Phase II study on trabectedin in patients with BRCAness phenotype or BRCA mutated advanced ovarian cancer Aim of the study Evaluate activity of trabectedin in patients with mutated BRCA and BRCAness phenotype advanced ovarian cancer (AOC) Patients and methods Patients with BRCA mutations or BRCAness phenotype with at least 2 previous responses to platinum therapy were stratified as patients with <3 previous responses to platinum (PR) or patients with ≥3 previous platinum responses (PS). Trabectedin 1.3 mg/m2 (3 hour iv infusion) administered every 3 weeks until progression Lorusso Ann Oncol 2016 Lorusso D et al. ESMO 2014 Abstract 886PD.

Response to trabectedin in according to BRCA status: Trabectedin is effective also in BRCA WT patients Lorusso D et al. ESMO 2014 Abstract 886PD.

Feasibility of Olaparib and trabectedin: TOMAS trial – Study design Run-in period First Cycle Subsequent Cycles Trabectedin Trabectedin -9 -5 -4 -1 2 1 day 1 7 14 21 7 14 21 Olaparib Wash out Olaparib Secondary Study Objectives Pharmacokinetic Pharmacodynamic Evaluation of preliminary evidence of activity (progression-free survival, growth modulation index, best overall tumor response; clinical benefit rate; duration of response and overall survival) To identify potential relationships (predictive/prognostic) between several bio-markers in the tumor tissue and genotype and the observed results. Typical 3+3 design Trabectedin doses: 0.675-1.3 mg/m2 as a 24-h i.v. infusion q 3 wks Olaparib tablets doses: 100-300 mg q12 h Primary Study Objective Maximum tolerated dose of the combination of trabectedin and olaparib.

TOMAS trial – Study population Patients ≥ 18 yrs affected by advanced, unresectable/metastatic bone and soft tissue sarcomas progressing after at least first-line treatment for advanced disease Histotype N (%) Leiomyosarcoma 8 (29) Osteosarcoma 6 (21) Ewing Sarcoma 4 (14) Synovial Sarcoma UPS 1 (4) Sarcoma NAS Liposarcoma MPNST SFT Malignant Myoepithelioma TOT 28 Characteristic N (%) Total 28 (100) Sex -Male -Female 17 (61) 11 (39) Age -Median -Range 50 19-78 Previous lines -Mean 3 2 1-8

TOMAS trial – most relevant toxicities

MTD: trabectedin 1.1 mg/m2 q3wks + olaparib tablets 150 mg q12h TOMAS trial – Results DLTs at dose level 5 (Trabectedin 1.3 mg/m2 + Olaparib tablets 200 mg q12 h): Grade 4 Thrombocytopenia Grade 4 Neutropenia lasting >7 days Expansion of lower dose levels including intermediate dose levels MTD: trabectedin 1.1 mg/m2 q3wks + olaparib tablets 150 mg q12h

TOMAS trial – Results n° of cycles Treatment ongoing Treatment ended Presented by:

TROOPS Trial Design Trabe 1,1 mg/mq 24h ic 1/21 + Olaparib 300 mg/die EOC P-res and P-ref Trabe 1,1 mg/mq 24h ic 1/21 + Olaparib 300 mg/die Key inclusion criteria: serous or endometrioid, BRCA WT or mut < o = 2 previous lines Stratification: Platinum refractory(cohort A) vs platinum resistant (cohort B) PIs: M. Aglietta, G. Grignani, D.Lorusso, G.Valabrega Presented by:

Statistical considerations Cohort A Sample size calculated according to a Bayesian phase II design on two outcome measures: ORR and PFS at 4 months. (20 patients foreseen in this cohort, 10 patients before applying stopping rules) Cohort B Sample size calculated according to Simon optimal 2 step design with 4 months PFS as main endpoint (46 patients foreseen in this cohort, 15 patients in first stage) Presented by:

Endpoints COHORT A (PFI < 4 weeks) Primary endpoints: PFS at 4 months and RR Secondary endpoints: OS, PFS, Duration of response, clinical benefit rate, CA 125 decrease, Qol, safety COHORT B Primary endpoints: PFS at 4 months Presented by:

Endpoints (2) Translational endpoints (molecular and genetics, exploratory analises on the probably small subgroup of BRCA mut/HRD+ ) Presented by:

Presented by:

Current status of the protocol Financial support confirmed by AZ and Pharmamar CRO (also for Pharmacovigilance) defined Insurance defined Regulatory submission scheduled by 13/03/2018 First patient likely to be enrolled end of May 2018 Presented by: