1. 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
Da sistemare con loghi e programma 1

2. 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

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

4. 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

5. 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:

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

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

8. 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 Abstract 886PD.

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

10. 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: mg/m2 as a 24-h i.v. infusion q 3 wks
Olaparib tablets doses: mg q12 h
Primary Study Objective
Maximum tolerated dose of the combination of trabectedin and olaparib.

11. 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

12. TOMAS trial – most relevant toxicities

13. 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

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

15. 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:

16. 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:

17. 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:

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

19. Presented by:

20. 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: