Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01.
Mechanism of action
Trabectedin binds to the minor groove of DNA, bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Pharmacodynamic effects
Trabectedin has been shown to exert antiproliferative in vitro and in vivo activity against a range of human tumour cell lines and experimental tumours, including malignancies such as sarcoma, breast, non-small cell lung, ovarian and melanoma.

Electrocardiogram (ECG) investigations

In a placebo-controlled QT/QTc study, trabectedin did not prolong the QTc interval in patients with advanced solid malignancies.

Clinical efficacy and safety
The efficacy and safety of trabectedin in soft tissue sarcoma is based in a randomised trial in patients with locally advanced or metastatic liposarcoma or leiomyosarcoma, whose disease had progressed or relapsed after treatment with at least anthracyclines and ifosfamide. In this trial trabectedin was administered either at 1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks or at 0.58 mg/m2 weekly as a 3-hour intravenous infusion for 3-weeks of a 4-week cycle. The protocol specified final time to progression (TTP) analysis showed a 26.6% reduction in the relative risk of progression for patients treated in the 24-h q3wk group [Hazard Ratio (HR)=0.734, CI: 0.554-0.974]. Median TTP values were 3.7 months (CI: 2.1-5.4 m) in the 24-h q3wk group and 2.3 months (CI: 2.0-3.5 m) in the 3-h qwk group (p=0.0302). No significant differences were detected in overall survival (OS). Median OS with the 24-h q3wk regimen was 13.9 months (CI: 12.5-18.6 ) and 60.2 % of patients were alive at 1 year (CI: 52.0- 68.5%).

Additional efficacy data are available from 3 single-arm Phase II trials with similar populations treated with the same regimen. These trials evaluated a total of 100 patients with lipo- and leiomyosarcoma and 83 patients with other types of sarcoma.
Results from an expanded access program for patients with STS (study ET743-SAR-3002) show that among the 903 patients assessed for OS, the median survival time was 11.9 months (95% CI: 11.2, 13.8). The median survival by histology tumor type was 16.2 months [95% CI: 14.1, 19.5] for subjects with leiomyosarcomas and liposarcomas, and 8.4 months [95% CI: 7.1, 10.7] for subjects with other types of sarcomas. The median survival for subjects with liposarcoma was 18.1 months [95% CI: 15.0, 26.4] and for subjects with leiomyosarcoma 16.2 months [95% CI: 11.7, 24.3].

Additional efficacy data are available from a randomized, active-controlled phase III study of trabectedin vs. dacarbazine (Study ET743-SAR-3007), in patients treated for unresectable or metastatic lipo- or leiomyosarcoma who have been previously treated with at least an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and one additional cytotoxic chemotherapy regimen. Patients in the trabectedin arm were required to receive dexamethasone 20 mg intravenous injection prior to each trabectedin infusion. Overall, 384 patients were randomized to the trabectedin group [1.5 mg/m2 once every 3 weeks (q3wk 24-h)] and 193 patients to the dacarbazine group (1 g/m2 once every 3 weeks). The median patient age was 56 years (range 17 to 81), 30% were male, 77% Caucasian, 12% African American and 4% Asian. Patients in the trabectedin and dacarbazine arms received a median of 4 and 2 cycles, respectively. The primary efficacy endpoint of the study was OS, which included 381 death events (66% of all randomized patients): 258 (67.2%) deaths in the trabectedin group and 123 (63.7%) deaths in the dacarbazine group (HR 0.927 [95% CI: 0.748, 1.150; p=0.4920]). The final analysis showed no significant difference with a median survival follow-up of 21.2 months resulted in a median of 13.7 months (95% CI: 12.2, 16.0) for the trabectedin arm and 13.1 months [95% CI: 9.1, 16.2] for the dacarbazine arm. The main secondary endpoints are summarized in the table below:
Efficacy results from Study ET743-SAR-3007

Endpoints / Study population     Trabectedin   Dacarbazine    Hazard Ratio / Odds Ratio     p value 
Primary endpoint              n=384         n=193
Overall survival,
258 (67.2%)   123 (63.7%)        0.927 (0.748-1.150)       0.4920 n (%)
Secondary endpoints             n=345         n=173
PFS
4.2           1.5              0.55 (0.44, 0.70)      <0.0001
(months; 95% CI)
ORR,
n (%);                  34 (9.9%)     12 (6.9%)           1.47 (0.72, 3.2)         0.33 Odds ratio (95% CI)
DOR
6.5           4.2              0.47 (0.17, 1.32)        0.14
(months; 95% CI)
CBR,
n (%);                    34.2%         18.5%              2.3 (1.45, 3.7)       <0.0002 Odds ratio (95% CI)

Additional efficacy data are available from a randomized, open-label, multicenter phase II study [JapicCTI-121850] conducted in Japanese patients with translocation-related sarcoma (TRS), most common being myxoid round-cell liposarcoma (n=24), synovial sarcoma (n=18), mesenchymal chondrosarcoma (n=6), and extraskeletal Ewing sarcoma/PNET, alveolar soft part sarcoma, alveolar rhabdomyosarcoma and clear cell sarcoma (n=5 each). The study assessed the efficacy and safety of trabectedin vs. best supportive care (BSC) as second-line or later therapy for patients with advanced TRS unresponsive or intolerant to standard chemotherapy regimen. The patients received the trabectedin dose of 1.2 mg/m2 recommended for Japanese patients [1.2 mg/m2 once every 3 weeks (q3wk 24-h)]. A total of 76 Japanese patients were enrolled in the study, among which 73 patients were included in the final analysis set. The study primary endpoint was PFS, that showed a statistically significant improvement in favour of trabectedin over BSC [HR=0.07; 95% CI: 0.03-0.16; p<0.0001], with a median PFS in the trabectedin group of 5.6 months [95% CI: 4.1-7.5] and in the BSC group of 0.9 months [95% CI: 0.7-1.0]. The secondary endpoints included objective response analysed using the RECIST and Choi criteria. Using the RECIST criteria the ORR among patients treated with trabectedin was 3 (8.1%; 95% CI: 1.7.21.9%) and 0 (0%, 95% CI: 0.0-9.7%) among patients treated with best supportive care, while the CBR was 24 (64.9%, 95% CI: 47.5-79.9%) versus 0 (0%, 95% CI: 0.0-9.7%), respectively. Using the Choi criteria the ORR among patients treated with trabectedin was 4 (10.8%; 95% CI: 3.0-25.4%) and 0 (0%, 95% CI: 0.0-9.7%) among patients treated  with best supportive care, while the CBR was 7 (18.9%, 95% CI: 8.0-35.2%) versus 0 (0%, 95% CI: 0.0-9.7%), respectively.

Paediatric population
In SAR-2005 phase I-II study, a total of 50 paediatric patients with rhabdomyosarcoma, Ewing sarcoma or non-rhabdomyosarcoma soft tissue sarcoma were enrolled. Eight patients were treated with a dose of 1.3 mg/m2 and 42 with 1.5 mg/m2. Trabectedin was administered as a 24-hour intravenous infusion every 21 days. Forty patients were fully evaluable for response. One partial response (PR) centrally confirmed was observed: overall RR: 2.5% CI 95% (0.1%-13.2%). The PR corresponded to a patient with an alveolar rhabdomyosarcoma. Duration of the response was 6.5 months. No responses were observed for Ewing sarcoma and NRSTS [RR: 0% CI95% (0%-30.9%)]. Three patients achieved stable disease (one with rhabdomyosarcoma after 15 cycles, one with spindle cell sarcoma after 2 cycles, and one with Ewing sarcoma after 4 cycles).

Adverse reactions included reversible elevation of liver enzymes and haematological events; in addition, fever, infection, dehydration and thrombosis/embolism were also reported.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Distribution

Systemic exposure after intravenous administration as a constant rate intravenous infusion is dose proportional at doses up to and including 1.8 mg/m2. The pharmacokinetic profile of trabectedin is consistent with a multiple-compartment disposition model.

Following intravenous administration, trabectedin demonstrates a high apparent volume of distribution, consistent with extensive tissue and plasma protein binding (94 to 98% of trabectedin in plasma is protein bound). The distribution volume at steady state of trabectedin in human subjects exceeds 5,000 L.

Biotransformation
Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative metabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute to metabolism.
Trabectedin does not induce or inhibit major cytochrome P450 enzymes.

Elimination

Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half-life is long (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelled trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is 58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for plasma clearance of trabectedin (30.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedin in whole blood is approximately 35 l/h. This value is approximately one-half the rate of human hepatic blood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter-patient variability of the population estimate for plasma clearance of trabectedin was 49% and intra-patient variability was 28%.

Special populations
A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is not influenced by age (range 19-83 years), gender, total body weight (range: 36 to 148 kg), or body surface area (range: 0.9 to 2.8 m2). An analysis made on a limited number of patients shows that race and ethnicity are not expected to have clinically significant effects on trabectedin pharmacokinetics.


Renal impairment
There is no relevant influence of renal function measured by creatinine clearance on trabectedin pharmacokinetics within the range of values (≥ 30.3 ml/min) present in the patients included in the clinical studies. No data are available in patients with a creatinine clearance of less than 30.3 ml/min.
The low recovery (< 9% in all studied patients) of total radioactivity in the urine after a single dose of 14
C-labelled trabectedin indicates that renal impairment has little influence on the elimination of trabectedin or its metabolites.

Hepatic impairment
Although the population analysis showed no relationship between the serum liver enzymes concentrations and the plasma clearance of trabectedin, systemic exposure to trabectedin may be increased in patients with hepatic impairment; therefore close monitoring of toxicity is warranted.