Download Lurbinectedin (PM01183)

XXIV Riunione Nazionale MITO
Ginecologia Oncologica: dai geni alla terapia
MECCANISMI DI AZIONE INNOVATIVI
DELLA TRABECTEDINA E DELL’ANALOGO
LURBINECTEDINA
Pisa, 4-5 Dicembre 2014
Cristiana Sessa
Oncology Institute of Southern Switzerland
Bellinzona
Lurbinectedin (PM01183)
Preclinical data
 New DNA minor groove covalent binder
 In vitro / in vivo activity against a broad tumor panel
 Antitumor activity in orthotopic primary grafts of
cisplatin – resistant epithelial ovarian cancer (EOC)
Chemical structures
Trabectedin
Lurbinectedin (PM01183)
The structural difference is in the part of the molecule that does not bind DNA
but interacts with DNA binding proteins (e.g. transcription factors, proteins
involved in DNA repair)
Ecteinascidins’ mode of action

Direct effect on cancer cells
by binding in the DNA minor groove, causing DNA
damage and modulating the transcription of cancer
relevant genes

Indirect effect on tumor microenvironment
by decreasing the number of tumor associated
macrophages
by inhibiting the transcription and production of
cytokines (e.g. IL6, IL2) chemokines (e.g. CCL2) and
angiogenic factors (e.g. VEGF, Angiopoietin 2)
www.esmo2012.org
Ecteinascidins and DNA repair system

Cell lines deficient in different NER proteins are less
sensitive to trabectedin and lurbinectedin

Cell lines deficient in HR proteins are much more
sensitive to trabectedin and lurbinectedin

Lack of correlation between in vitro and in vivo
sensitivity to trabectedin and lurbinectedin
Romano, IJC 2013
Pro-tumor functions of Tumor-Associated Macrophages
Solinas, Jounal of Leukocyte Biology, Vol. 86, Nov. 2009
www.esmo2012.org
Yondelis inhibits CCL2 and IL-6 production in TAM and
tumor cells from patients with ovarian cancer
©2005 by American Association for Cancer Research
www.esmo2012.org
Response of OVA1XR to
Lurbinectedin based treatments
* < 0.05
Vidal et al, CCR 2012
www.esmo2012.org
Antitumor activity of Lurbinectedin and Cisplatin
in A-2780 derived tumor xenografts
Vidal et al, CCR 2012
www.esmo2012.org
Lurbinectedin Phase I overview

Myelosuppression DLT at clinically relevant doses

Nausea and vomiting requiring preventive antiemetics

Combination with other cytotoxic feasible and active in
properly selected patients

PK different from trabectedin: long Ty2 β, low central
volume

AUC correlated with severity of neutropenia

High interpatient variability of PK to be further
investigated
Lurbinectedin (PM1183), an active compound in
platinum-resistant/refractory ovarian cancer (PRROC)
patients: Results of a two-stage, controlled Phase II
study
A. Poveda et al, Abstr. 5505
ASCO, 2014
PM1183-B-002-11 - Study Design
Primary endpoint: Response Rate
First Stage (n=22)
PM01183
PM01183
7 mg
mg FD q3wk
q3wkIV
IV
> 2 responses
(by either RECIST and/or Rustin criteria)
Second
SecondStage
Stage (ongoing)
(ongoing)
Randomization 1:1
PM01183
7 mg FD q3wk IV
N= 30 pts
CROSSOVER
Stratified by Resistant / Refractory
Topotecan
Standard or weekly
N= 30 pts
Lurbinectedin in platinum
resistant/refractory ovarian cancer
Efficacy
PM1183
(n=52)
%
Topotecan
(n=29)
%
p value
1(3)
10 (20
25 (50)
15 (26)
0 (0)
0
15 (52)
14 (48)
-
ORR (%) (95% CI)
22 (11-35)
-
0.006
Pt resistant
30 (16-49)
-
0.02
Pt refractory
5 (0-26)
-
1
PFS (mo) 2nd stage
2.8
2.0
0.026
OS (mo)
10
7.3
0.038
Best overall
response (%)
CR
PR
SD
PD
Lurbinectedin in platinum
resistant/refractory ovarian cancer patients
Conclusions
 PM1183 is an active drug in Pt-res/Pt-ref ovarian
cancer with an objective response rate of 30%
 The study has met the primary endpoint, showing
a statistically significant superiority over T in terms
of ORR, PFS and OS.
 The safety profile is predictable and manageable
 A Phase III study in Pt-res ovarian cancer is
planned.
Lurbinectedin pharmacological features
 Estensive microsomal-mediated metabolism in all
animal species
 Clearance is higher with increasing serum albumin
and lower with increasing α1 glycoprotein
 Role of concomitant medications (aprepitant)
 Caution in the concomitant use of LYP2C8 and
CYP3A4 substrates
 Also concomitant CYP2C19 substrates must be
avoided
Clinical development of Lurbinectedin in
ovarian cancer
Additional preclinical data needed
 comparison with trabectedin ± cisplatin in ovarian
xenografts
 potential causes of differences from trabectedin
indirect effects on tumor microenvironment
indirect effects on TAM
Additional clinical data needed
 confirmation of the preclinical results in resistant
ovarian cancer Phase III
 combination studies
 population PK profile
Ongoing combination studies with
Lurbinectedin in ovarian cancer
 Phase I multicenter clinical and pharmacokinetic study of
lurbinectedin with weekly paclitaxel ± bevacizumab in
patients with selected solid tumors
 Phase I multicenter clinical and pharmacokinetic study of
lurbinectedin with cisplatin in patients with advanced solid
tumors