A phase II randomized – non comparative – cross-over study on the activity of Trabectedin (T) or Gemcitabine + Taxotere (GT) in metastatic or locally relapsed uterine leiomyosarcoma pretreated with conventional chemotherapy (EudraCT number: 2009-016017- 24)
Study coordinators: R Fossati, A Gadducci, F Grosso Translational study coordinator: M D’Incalci
Data Management: R Fossati, M Negri, S Stupia
The management of pts with uterine LMS poses many difficulties. Despite 60% of pts present with disease limited to the uterus, cure rates range from 20 to 60%.
Pts with metastatic disease at diagnosis or who recur after initial treatment have a dismal prognosis and, except for a subset of selected pts with completely resectable disease, the median OS is < 1 year.
Recurrent uterine LMS: general findings
Treatment option for recurrent/metastatic of uterine LMS are limited.
The most active drugs are anthracyclines ± ifosfamide and gemcitabine + taxotere (GT) with response rate of 25-55% and 27-53% respectively.
Both these regimens have been increasingly used in the last years in the adjuvant setting.
For relapsed patients other drugs have been tested as single agent but negligible activity was observed.
Recurrent uterine LMS: general findings
Trabectedin (ET-743): Yondelis
Carter, 2007; Shoffski 2007
ET-743: DNA-binding agent, derived from a marine tunicate (Ecteinascidia turbinate) and now produced synthetically
ET-743 approved for advanced STS after failure of DOX/EPIDOX or IFO or who are unsuited to these agents
In clinical trials, ET-743 showed efficacy especially in LMS or
liposarcoma, as well as in platinum-sensitive recurrent EOC
Composto naturale isolato dal tunicato marino caraibico Ectenaiscidia turbinata
STRUTTURA E LEGAME AL DNA DI TRABECTEDINA
Liposarcoma
Leiomyosarcoma
L-sarcomas
ET-743: evaluation of its use in advanced STS
Study population: Pooled analysis of data from 3 phase II studies
involving 189 previously treated pts with advanced STS Median number of cycles: 4
Tumour control (OR+SD): 50%
6-months PFS: 19.8%
median OS: 10.3 months
2-year OS: 29.3%
Responses achieved in pts resistant to both DOX and IFO
ET-743 well tolerated, with AEs (Hepatic and haematologic) being non cumulative, reversible and manageable
Shoffski 2007
Clinical outcome of ET-743 in high-grade uterine sarcoma
Pooled data from literature on 13 pts with LMS and undifferentiated uterine sarcoma
Whole series: OR CBR
5/13 (38%) 7/13 (54%)
LMS: 5/11 (45%) 7/11 (64%)
Amant 2009
Role of ET-743 in the management of advanced uterine LMS
Study population: 56 pts previously exposed to a median of 3 CT lines (range1-5) received a ET-743 within an expanded access programme
Results: a total of 252 courses were delivered, and 36% of pts received more than 5 cycles
Grosso ASCO, 2009
Role of ET-743 in the management of advanced uterine LMS
Pts evaluable for response: 52 PR: 11 pts; SD: 15 pts
PR: 21%
Tumour control rate: 50%
6-month PFS: 41%
Grosso ASCO, 2009
A phase II randomized – non comparative – cross-over study on the activity of Trabectedin (T) or Gemcitabine + Taxotere (GT) in metastatic or locally relapsed uterine LMS pretreated with conventional chemotherapy
This study is aimed at evaluating the activity of T (arm A) having GT (arm B) as an internal control, in advanced uterine LMS.
In parallel translational studies will be performed to identified factors predictive of the activity of T in this specific histotype
A phase II randomized – non comparative – cross-over study on the activity of Trabectedin (T) or Gemcitabine + Taxotere (GT) in metastatic or locally relapsed uterine LMS pretreated with conventional chemotherapy
Primary objective: clinical benefit rate (defined as 6-month progression free rate) with T in pts with locally relapsed/metastatic uterine LMS pretreated with anthracycline ± ifosfamide and/or GT
For the subgroup population pretreated only with anthracycline ± ifosfamide the pts enrolled in the arm B will serve as a parallel internal control
Secondary objectives: RR, PFS, OS, and toxicity profile.
Objectives
This is a multicentre, randomized, non comparative phase II study.
To be eligible pts must have received at least one line of CT either in adjuvant setting or as first-line CT in advanced or recurrent disease
Study design
Pts who have not already received G or GT (but only doxorubicin + ifosfamide) will be randomized to receive T (arm A) or GT (arm B).
Pts who have already received G or GT (either as front line CT or after conventional doxorubicin + ifosfamide) will be anyway included in the study and treated within arm A.
Consequently, the arm A will include both pts on T as a first line for advanced/metastatic disease and those on T as a second line after G or GT.
Study design
Study design
• Assumptions:
– Similar clinical benefit rate with trabectedin after either DOX + IFO or DOX + IFO followed by GEM + docetaxel
– inactive if clinical benefit ≤ 14%
– active if clinical benefit > 25%
Study design
• Sample size calculation according to exact one-stage design (RP A’Hern 2001)
– One sided α=5%
– Power=90%
– 109 pts to be enrolled in the T arm
– ≥ 22 patients experiencing clinical benefit is the cut-
off that would satisfy the assumptions
Study design
It is expected that approximately 40-50% of the eligible population has already received gemcitabine + taxotere and will not enter the randomized phase of the trial.
Arm B therefore will include about 40 pts
Main inclusion criteria
Histologically proven uterine LMS
Persistent or locally rellapsed and/or metastatic disease
≥ 1 previous systemic treatment with an DOX ± IFO or gemcitabine ± taxotere
Measurable disease (RECIST criteria)
ECOG PS <2
Age > 18 years
Pathology specimens available for centralized review and translational study
Adequate haematological, renal and liver function
Signed informed consent
Main exclusion criteria
Prior exposure to T
Peripheral neuropathy, Grade 2 or higher.
History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse.
Known CNS metastases.
Active viral hepatitis or chronic liver disease.
Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment,
uncontrolled arterial hypertension or arrhythmias.
Active major infection.
Other serious concomitant illnesses.
Study design
R
G 900 mg/m
2g 1,8 + T 75 g/m
2g 8 T 1.3 mg/m
224-h infusion
Cross-over
Every 3 weeks
90’ infusion 1h infusion
Each patient should receive at least 2 courses of treatment.
Arm A
Trabectedin until progressive disease, major toxicity, patient's intolerance or unwillingness to continue treatment or medical decision
Arm B
Gemcitabine + docetaxel for 6 cycles, unless there is evidence of disease progression, unacceptable toxicity or patient's intolerance or unwillingness to continue treatment, or medical decision.
Pts in response after 6 cycles could receive 2 additional cycles of combination therapy or continue with Gemcitabine alone.
At disease progression patients randomly assigned to one treatment arm can be crossed-over to the other.
Study design
After discontinuation of the study, pts in whom disease has not progressed should be followed every 3 months for disease status until progression.
Pts receiving surgical resection of lesions or radiotherapy to a large lesion before documented progression will continue to be followed until progression is documented
Study design
Main toxcicity in phase I-II study: Liver toxicity, Myelotoxicity,fatigue
Baseline and inter-cycle increase of alcaline phospatase and bilirubin predict serious toxicity in the following course (dose reduction)
Pre-treatment with desamethazone protect female rats form hepatic damage
Trabectin toxicity profile
Trabectedin
All subjects will be pretreated with 8 mg of dexamethasone po the day before receiving T and with 12 mg of dexamethasone iv on Day 1 of each treatment cycle, 30 minutes prior the infusion of T
Gemcitabine+Taxotere
Recommended pre-medication for the docetaxel is dexamethasone 8 mg orally twice a day starting the day prior to docetaxel and continuing for 3 days. Early intervention with diuretics is encouraged for signs of docetaxel related fluid retention.
GCSF 150 µg/m2 sc on days 9–15, or pegfilgrastim 6 mg sc on day nine or ten in patients receiving GT
Premedication
The activity of trabectidin is dependent upon a functional nucleotide- excission repair (NER) and homologous recombination [HR] repair activity.
BRCA plays an important role in DNA double-strand break repair by HR.
The endonucleases XPF/ERCC1 play a major role in NER activity.
XPG mutations and defective NER can confer resistance to trabectidin (Takebayashi 2001, Erba 2001).
In a retrospective analysis of 92 sarcomas from pts treated with trabectidin, samples with high expression of ERCC1 were associated with a better clinical outcome as well as tumors with low levels of BRCA1 (Schoffski et al. 2006)
Traslational study
SENSIBILITA’ A TRABECTEDINA DI DIFFERENTI LINEE CELLULARI (SAGGIO DI CLONOGENICITA’)
0 25 50 75 100 125
0,001 0,1 10 1000
Trabectedin concentrations (nM)
% of control
AA8 V3-3 VC8 CXR3 UV-96 VC8 BAC irs1SF V79
VC8#13-10
Cell line Genotype Defect Trabectedin IC50 (nM)
irs1SF XRCC3 - HR deficient 0.75+0.3
CXR3 XRCC3 + HR restored 7.7+3.7
AA8 wt DNA repair proficient 15.2+3.25
V79 wt DNA repair proficient 16.6+0.2
UV96 ERCC1- NER deficient 53.1+15.4
V3-3 DNA-PKcs - NHEJ deficient 8.2+1.9
V-C8 BRCA2 - HR deficient 0.25+0.22
V-C8 BAC BRCA2 + Complemented with human BRCA2, HR
restored 7.45+0.8
V-C8#13-10 BRCA2 + Complemented with human BRCA2 on
chromosome 13, HR restored 6.6+0.14
Microdissection
RNA extraction
Quantification of
mRNA expression level BRCA1, XPG, ERCC1
Taq-Man qRT-PCR Paraffin embedded
tumoral tissue
Correlation with clinical outcomes OR, PFS, OS
