Study coordinators: R Fossati, A Gadducci, F Grosso Translational study coordinator: M D Incalci Data Management: R Fossati, M Negri, S Stupia

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1 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: ) Study coordinators: R Fossati, A Gadducci, F Grosso Translational study coordinator: M D Incalci Data Management: R Fossati, M Negri, S Stupia

2 Recurrent uterine LMS: general findings 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.

3 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.

4 Trabectedin (ET-743): Yondelis 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 Carter, 2007; Shoffski 2007

5 TRUTTURA E LEGAME AL DNA DI TRABECTEDINA Composto naturale isolato dal tunicato marino caraibico Ectenaiscidia turbinata

6 L-sarcomas Leiomyosarcoma Liposarcoma

7 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

8 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

9 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

10 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

11 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

12 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 Objectives Secondary objectives: RR, PFS, OS, and toxicity profile.

13 Study design 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

14 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.

15 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%

16 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 cutoff that would satisfy the assumptions

17 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

18 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

19 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.

20 Study design T 1.3 mg/m 2 24-h infusion R Cross-over G 900 mg/m 2 g 1,8 + T 75 g/m 2 g 8 90 infusion 1h infusion Every 3 weeks

21 Study design 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.

22 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

23 Trabectin toxicity profile 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

24 Premedication 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

25 Traslational study The activity of trabectidin is dependent upon a functional nucleotideexcission 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)

SENSIBILITA A TRABECTEDINA DI DIFFERENTI LINEE CELLULARI (SAGGIO DI CLONOGENICITA ) % of control 125 100 75 50 25 0 0,001 0,1 10 1000 Trabectedin concentrations (nm) AA8

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.

26 SENSIBILITA A TRABECTEDINA DI DIFFERENTI LINEE CELLULARI (SAGGIO DI CLONOGENICITA ) % of control ,001 0, Trabectedin concentrations (nm) AA8 V3-3 VC8 CXR3 UV-96 VC8 BAC irs1sf V79 VC8#13-10 Cell line Genotype Defect Trabectedin IC50 (nm) irs1sf CXR3 XRCC3 XRCC3 - HR deficient HR restored AA8 wt DNA repair proficient V79 wt DNA repair proficient UV96 ERCC1- NER deficient V3-3 DNA-PKcs V-C8 V-C8 BAC V-C8#13-10 BRCA2 BRCA2 BRCA2 - NHEJ deficient HR deficient Complemented with human BRCA2, HR restored + Complemented with human BRCA2 on chromosome 13, HR restored

27 Traslational study Paraffin embedded tumoral tissue Microdissection RNA extraction Taq-Man qrt-pcr Quantification of mrna expression level BRCA1, XPG, ERCC1 Correlation with clinical outcomes OR, PFS, OS

28 Centralized pathological revision Fattori prognostici morfologici (atipia, necrosi, mitosi) ER PgR p53 Marcatori del ciclo cellulare: mdm2, p16, p21 WT1 KIT EGFR VEGFR

trabectedin, 0.25 and 1mg powder for concentrate for solution for infusion (Yondelis ) SMC No. (452/08) Pharma Mar S.A. Sociedad Unipersonal

trabectedin, 0.25 and 1mg powder for concentrate for solution for infusion (Yondelis ) SMC No. (452/08) Pharma Mar S.A. Sociedad Unipersonal 08 October 2010 The Scottish Medicines Consortium (SMC) has