RANDOMIZED PHASE III TRIAL OF TRABECTEDIN VERSUS DOXORUBICIN- BASED CHEMOTHERAPY AS FIRST-LINE...

RANDOMIZED PHASE III TRIAL OF TRABECTEDIN VERSUS DOXORUBICIN-BASED CHEMOTHERAPY AS FIRST-LINE THERAPY IN TRANSLOCATION-RELATED SARCOMAS (TRS)

Sant P. Chawla, Andrew Hendifar, Michael Leahy, Antoine Italiano, Shreyaskumar Patel, Peter Hohenberger, Armando Santoro, Arthur P. Staddon, Nicolas Penel, Sophie Piperno-Neumann, Pilar Lardelli, Antonio Nieto, Carmen Kahatt, Jean-Yves Blay

Study Design

An adaptive design in chemonaïve patients with advanced TRS, stratified by performance status and subtype, then randomized to receive:

Trabectedin: 1.5 mg/m2 in 24h iv infusion q3wk Doxorubicin based chemotherapy (DXCT): single agent

75 mg/m2 q3wk, or 60 mg/m2 combined with ifosfamide 6-9 g/m2 q3wk

MRCL (n= 40) Other TRS (n= 40)

RANDOMIZATION (1:1)

Eligible patients

PS= 0 PS= 1-2 PS= 0 PS= 1-2

Study Objectives

Primary: Progression free survival (PFS) of trabectedin vs DXCT Secondary:

PFS at 6 months Response rate (RR) Overall survival Safety

PFS/RR analyzed by investigator assessment for all randomized patients

PFS/RR analyzed by independent review only for confirmed TRS patients

Results: Baseline Characteristics

Trabectedin (n=61) DXCT (n=60)

Age (yr) Median (range) 47 (19-78) 49 (19-78)

Sex Male / female 36 (59%) / 25 (41%) 38 (63%) / 22 (37%)

ECOG PS 0 28 (46%) 29 (48%)

1 32 (52%) 30 (50%)

2 1 (2%) 1 (2%)

Sarcoma type by Investigator

MRCL 28 (46%) 28 (47%)

Other 33 (54%) 32 (53%)

Sarcoma type by central pathology

MRCL 23 (38%) 17 (28%)

Other 28 (46%) 20 (33%)

Not confirmed* 10 (16%) 23 (38%)

* Wrong diagnosis 4 (7%) and 9 (15%) patients of the trabectedin and DXCT arms, no evidence of translocation in 3 (5%) and 2 (3%) patients, and lack of

available material for central review in 3 (5%) and 12 (20%) patients

Histology According Central Diagnosis (TRS Confirmed Patients N=88)

Trabectedin (n=51)

DXCT(n=37)

N % N %

MYXOID LIPOSARCOMA 23 45.1 17 45.9

SYNOVIAL SARCOMA 15 29.4 9 24.3

ALVEOLAR SOFT PART SARCOMA 2 3.9 2 5.4

CLEAR CELL SARCOMA 3 5.9 4 10.8

DESMOPLASTIC SMALL ROUND CELL 1 2.0 1 2.7

EXTRASKELETAL MYXOID CHONDROSARCOMA 5 9.8 2 5.4

LOW GRADE ENDOMETRIAL STROMAL SARCOMA 1 2.0 2 5.4

LOW GRADE FIBROMYXOID SARCOMA 1 2.0 . .

Results: Baseline Characteristics


Disease Extension Locally advanced 18 (30%) 13 (22%)

Metastatic 43 (70%) 47 (78%)

Prior surgery (radical/palliative) 33 (54%) 38 (63%)

Prior radiotherapy 24 (39%) 21 (35%)

Number of sites involved at baseline, Median (range) 2 (1-8) 2 (1-5)

Months from first diagnosis to randomization, Median (range) 10 (1-187) 8 (0-310)

Patient Exposure

Trabectedin (n=61) DXCT (n=57)Number of cycles 441 264Number of cycles per patientMedian (range)

5 (1-31) 6 (1-8)

Doxorubicin single agent

(n=36)

Doxorubicin plus ifosfamide

(n=21)

Number of cycles per patientMedian (range)

6 (1-8) 4 (1-8)

Time on treatment (weeks) Median (range)

19.3 (2.4-101.7) 19.2 (4.1-25.6) 14.3 (4.3-26.3)

Censoring

A high percentage of patients were censored in both arms Main reasons for censoring:

Surgical removal of lesions 24% in trabectedin arm and 16% in the DXCT arm

Administration of a new anticancer therapy (chemotherapy or radiotherapy) before progression of the disease

18% in trabectedin arm and 24% in DXCT arm Importantly, 35-40% patients in either arm ended up receiving

the drug in the other arm Patients in trabectedin arm also received DXCT Patients in DXCT arm also received trabectedin

Results: Response Rate

Investigator Assessment All randomized patients


Best objective response (RECIST)

PR 5 (8%) 15 (25%) 0.0150

SD 40 (66%) 33 (55%)

DCR 45 (74%) 48 (80%)

PD 11 (18%) 8 (13%)

NE 5 (8%) 4 (7%)

Results: Response Rate

Independent Review TRS confirmed patients

Trabectedin (n=51)

DXCT (n=37)

p-value

Best objective response (RECIST)

PR 3 (6%) 10 (27%) 0.0123

SD 39 (77%) 22 (60%)

DCR 42 (82%) 32 (87%)

PD 6 (12%) 1 (3%)

NE 3 (6%) 4 (11%)

Histology of PR patients2 MRCL

1 Synovial

5 MRCL4 Synovial

1 Desmoplastic Round cell

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Time (months)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Trabectedin (N=61 C=32)DXCT (N=60 C=34)Censored

Median: 16.1 months (95% CI, 5.5-21.9)

Hazard ratio: 0.85, p=0.5551. Log rank p=0.5533

Median: 8.8 months (95% CI, 5.5-12.7)

Results: PFS by Investigators

Results: PFS by Independent Review

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Time (months)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32


Hazard ratio: 0.86; p=0.6992. Stratified log-rank p=0.9573

Median: 18.8 months (95% CI, 5.7-not reached)

Median: 8.3 months (95% CI, 7.1-25.0)

Results: Overall SurvivalC

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Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48


Median: 27.3 months (95% CI, 21.3-39.6)

Median: 38.9 months (95% CI, 24.2-nr)


OS in Myxoid Liposarcoma

Median: 95% CI (-)

Median: 33.1 95% CI (21.2-39.6)


Results: Hematologic and Other Laboratory Toxicity

Trabectedin DXCT

Grade1-2 (%) Grade 3-4 (%) Grade1-2 (%) Grade 3-4 (%)

Laboratory disorders

Neutropenia 25.0% 55.0% 10.7% 75%

Febrile neutropenia - 1.6% - 12.3%

Thrombocytopenia 26.2% 16.4% 37.5% 14.3%

ALT increase 40.0% 53.3% 37.0% 1.9%

AST increase 51.7% 33.3% 37.0% 1.9%

ALKP increase 56.7% 5.0% 38.9% -

Bilirubin increase 20.0% 1.7% 13.0% -

CPK increase 34.5% 8.6% 8.2% 4.1%

Results: Non-Hematologic Toxicity

Trabectedin DXCT

Grade1-2 (%) Grade 3-4 (%) Grade1-2 (%) Grade 3-4 (%)

Treatment related AEs

Fatigue 59.0% 6.5% 61.4% 1.8%

Nausea 68.9% 1.6% 64.9% -

Vomiting 42.6% 1.6% 26.3% -

Mucositis 4.9% 1.6% 26.3% 8.8%

Alopecia 1.6% - 43.9% -

Summary

The study was underpowered to detect any statistical significant differences in the two arms due to high rate of censoring in both arms

Overall, no statistically significant differences in PFS/OS were observed

Median PFS was 19 mo. in trabectedin arm vs. 8 mo. in DXCT arm Median OS was 39 mo. in trabectedin arm vs. 27 mo. in DXCT arm

Safety profiles for trabectedin and DXCT were consistent with previous studies

Ability to administer trabectedin over prolonged periods without cumulative toxicity may allow for longer disease control

Trabectedin should be further explored in a definitive randomized study in myxoid liposarcoma patients

BACK-UP SLIDES

Censoring ReasonsEfficacy population


Surgery 12 (24%) 6 (16%)

Chemotherapy 6 (12%) 7 (19%)

Radiotherapy 3 (6%) 2 (5%)

Last tumor assessmenta 12 (24%) 5 (14%)

Otherb 2 (4%) 4 (11%)

Total 35 (69%) 24 (65%)

All randomized patients

Trabectedin (n=61) DXCT(n=60)

Surgery 11 (18%) 12 (20%)

Chemotherapy 5 (8%) 4 (7%)

Radiotherapy 3 (5%) 6 (10%)

Last tumor assessmenta 9 (15%) 6 (10%)

Otherb 4 (7%) 6 (10%)

Total 32 (52%) 34 (57%)

a Patients on follow-up for disease assessment or with event/subsequent therapy out of study window or without PD at last tumor assessment available in database at cut-off date.b Censored at randomization (e.g.: untreated) or withdrawn due to related/unrelated adverse event or refusal before treatment onset/disease progression or new treatment out of study window.

Subsequent Chemotherapy Agents in Censored Patients

Trabectedin(n=35)

DXCT (n=24)

N % N %

CEDIRANIB . . 1 4.2

CYCLOPHOSPHAMIDE 2 5.7 2 8.3

DACARBAZINE 2 5.7 2 8.3

DOCETAXEL 3 8.6 2 8.3

DOXORUBICIN 10 28.6 3 12.5

DOXORUBICIN HYDROCHLORIDE 3 8.6 2 8.3

EPIRUBICIN 1 2.9 . .

ETOPOSIDE 1 2.9 2 8.3

GEMCITABINE 5 14.3 3 12.5

IFOSFAMIDE 6 17.1 8 33.3

PAZOPANIB . . 1 4.2

SORAFENIB 1 2.9 1 4.2

SORAFENIB TOSILATE . . 1 4.2

SUNITINIB 1 2.9 2 8.3

TRABECTEDIN 4 11.4 9 37.5

VINORELBINE 1 2.9 . .

VORINOSTAT . . 1 4.2

Responders’ Histology

Patient Treatment arm Central Diagnosis

103013 Trabectedin Synovial sarcoma

182003 Trabectedin Myxoid liposarcoma

21021 Trabectedin Myxoid liposarcoma

103008 DXCT Synovial sarcoma

14034 DXCT Desmoplastic small round cell sarcoma


191006 DXCT Myxoid liposarcoma







Discontinuations and Dose Reductions

Trabectedin (n=61)

DXCT (n=57)

n % N %Deaths associated with treatment-related AEs

1 1.6 1 1.8

Discontinuations associated with treatment-related AEs

10 16.4 6 10.5

Delays associated with treatment-related AEs

32 52.5 8 14.0

Dose reductions associated with treatment-related AEs

24 39.4 6 10.5

• Administration delays and dose reductions occurred more frequently in the trabectedin arm, partially due to the prolonged treatment duration.

• Transaminase increase was the main reason for dose reduction

• Neutropenia was the most common cause of administration delay.

Results: Safety in DXCT

DXCT+Ifosfamide (n=21) DXCT (n=36)

Grade1-2 (%) Grade 3 (%) Grade 4 (%) Grade1-2 (%) Grade 3 (%) Grade 4(%)

Treatment related AEs

Fatigue 57.1% - - 63.9% 2.8% -

Nausea 52.4% - - 72.2% - -

Vomiting 19.0% - - 30.6% - -

Mucositis 9.5% - 4.8% 36.1% 11.1% -

Alopecia 38.1% - - 47.2% - -

Febrile neutropenia - 9.5% 14.3% - 5.6% -

Laboratory disorders

Neutropenia 23.8% 4.8% 42.9% 2.9% 34.3% 57.1%

Thrombocytopenia 23.8% 19.0% 9.5% 45.7% 5.7% -

ALT increase 31.6% 5.3% - 40.0% - -

AST increase 26.3% 5.3% - 42.9% - -

Alkaline phosphatase increase

52.6% - - 31.4% - -

Bilirubin increase 10.5% - - 14.3% - -

CPK increase - 5.9% - 12.5% 3.1% -

RANDOMIZED PHASE III TRIAL OF TRABECTEDIN VERSUS DOXORUBICIN- BASED CHEMOTHERAPY AS FIRST-LINE...

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