Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Pharma Mar, S.A., Avda. de los Reyes 1, Polígono Industrial La Mina, 28770, Colmenar Viejo (Madrid), Spain
Pharmacotherapeutic group: Antineoplastic agent
ATC code: L01CX01
Trabectedin binds to the minor groove of deoxyribonucleic acid (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.
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.
In a placebo-controlled QT/QTc study, trabectedin did not prolong the QTc interval in patients with advanced solid malignancies.
The efficacy and safety of trabectedin in soft tissue sarcoma is based in a randomised trial in patients with locally advanced or metastatic lipo- 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, Confidence Interval (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 subjects assessed for OS, the median survival time was 11.9 months (95% CI: 11.2, 13.8). The median survival by histology tumour 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, n (%) | 258 (67.2%) | 123 (63.7%) | 0.927 (0.748-1.150) | 0.4920 |
| Secondary endpoints | n=345 | n=173 | ||
| PFS (months; 95% CI) | 4.2 | 1.5 | 0.55 (0.44, 0.70) | <0.0001 |
| ORR, n (), Odds ratio (95 CI) | 34 (9.9%) | 12 (6.9%) | 1.47 (0.72, 3.2) | 0.33 |
| DOR (months; 95% CI) | 6.5 | 4.2 | 0.47 (0.17, 1.32) | 0.14 |
| CBR, n (), Odds ratio (95 CI) | 34.2% | 18.5% | 2.3 (1.45, 3.7) | <0.0002 |
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.
The efficacy of Yondelis/PLD combination in relapsed ovarian cancer is based on ET743-OVA-301, a randomized phase 3 study of 672 patients who received either trabectedin (1.1 mg/m²) and PLD (30 mg/m²) every 3 weeks or PLD (50 mg/m²) every 4 weeks. The primary analysis of progression free survival (PFS) was performed in 645 patients with measurable disease and assessed by independent radiology review. Treatment with the combination arm resulted in a 21% risk reduction for disease progression compared to PLD alone (HR=0.79, CI: 0.65-0.96, p=0.0190). Secondary analyses of PFS and response rate also favoured the combination arm. The results of the main efficacy analyses are summarised in the table below.
Efficacy analyses from ET743-OVA-301:
| Yondelis+PLD | PLD | Hazard/Odds ratio | p-value | |
|---|---|---|---|---|
| Progression Free Survival | ||||
| Independent radiology review, measurable disease* | n=328 | n=317 | ||
| Median PFS (95% CI) (months) | 7.3 (5.9-7.9) | 5.8 (5.5-7.1) | 0.79 (0.65-0.96) | 0.0190a |
| 12 months PFS rate (95% CI) (%) | 25.8 (19.7-32.3) | 18.5 (12.9-24.9) | ||
| Independent oncology review, all randomised | n=336 | n=335 | ||
| Median PFS (95% CI) (months) | 7.4 (6.4-9.2) | 5.6 (4.2-6.8) | 0.72 (0.60-0.88) | 0.0008a |
| Overall Survival (Final analysis – n=522 events) | ||||
| All randomised | n=337 | n=335 | ||
| Median OS (95% CI) (months) | 22.2 (19.3-25.0) | 18.9 (17.1-21.5) | 0.86 (0.72-1.02) | 0.0835a |
| Overall survival in platinum-sensitive population (Final analysis n=316 events) | ||||
| n=218 | n=212 | |||
| Median OS (95% CI) (months) | 27.0 (24.1-31.4) | 24.1 (20.9-25.9) | 0.83 (0.67-1.04) | 0.1056a |
| Overall Response Rate (ORR) | ||||
| Independent radiology review, all randomised | n=337 | n=335 | ||
| ORR (95% CI) (%) | 27.6 (22.9-32.7) | 18.8 (14.8-23.4) | 1.65 (1.14-2.37) | 0.0080b |
* Primary efficacy analysis
a Log rank test
b Fisher’s test
Based on independent oncology review, patients with platinum-free interval (PFI) <6 months (35% in Yondelis+PLD and 37% in PLD arm) had similar PFS in the two arms with both showing median PFS of 3.7 months (HR=0.89, CI: 0.67-1.20). In patients with PFI ≥ 6 months (65% in Yondelis+PLD and 63% in PLD arm), median PFS was 9.7 months in the Yondelis+PLD arm compared with 7.2 months in the PLD monotherapy arm (HR=0.66, CI: 0.52-0.85).
In the final analysis, the effect of the Yondelis+PLD combination vs. PLD alone on overall survival was more pronounced in patients with PFI ≥6 months (platinum-sensitive population: 27.0 vs. 24.1 months, HR=0.83, CI: 0.67-1.04) than in those with PFI <6 months (platinum-resistant population: 14.2 vs. 12.4 months, HR=0.92, CI: 0. 70-1.21).
The benefit in OS with Yondelis plus PLD was not due to the effect of subsequent therapies, which were well balanced between the two treatment arms.
In the multivariate analyses including PFI, treatment effect on overall survival was statistically significant favouring the Yondelis+PLD combination over PLD alone (all randomised: p=0.0285; platinum-sensitive population: p=0.0319).
No data are available comparing Yondelis+PLD to a platinum-based regimen in platinum-sensitive patients.
No statistically significant differences were found between treatment arms in global measures of Quality of Life.
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% CI95% (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.
Systemic exposure after intravenous administration as a constant rate infusion is dose proportional at doses up to and including 1.8 mg/m². Trabectedin pharmacokinetic profile 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.
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.
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%.
A population pharmacokinetic analysis showed that when administered in combination with PLD, the plasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were not influenced by the concomitant administration of trabectedin.
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). A population pharmacokinetic analysis showed that plasma trabectedin concentrations observed in the Japanese population at dose level 1.2 mg/m² were equivalent to those obtained in the non-Japanese western population at 1.5 mg/m².
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 14C-labelled trabectedin indicates that renal impairment has little influence on the elimination of trabectedin or its metabolites.
The effect of hepatic impairment on the pharmacokinetics of trabectedin was assessed in 15 cancer patients at doses ranging from 0.58 to 1.3 mg/m² administered as 3-hour infusion. The geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in 6 patients with moderate hepatic impairment (increased serum bilirubin levels from 1.5 to 3 x ULN and increase of aminotransferases (AST or ALT) <8 x ULN) following administration of a single trabectedin dose of 0.58 mg/m² (n=3) or 0.9 mg/m² (n=3) compared to 9 patients with normal liver function following administration of a single trabectedin dose of 1.3 mg/m² (see sections 4.2 and 4.4).
Preclinical data indicate that trabectedin has limited effect on the cardiovascular, respiratory and central nervous system at exposures below the therapeutic clinical range, in terms of AUC.
The effects of trabectedin on cardiovascular and respiratory function have been investigated in vivo (anesthetised Cynomolgus monkeys). A 1 hour infusion schedule was selected to attain maximum plasma levels (Cmax values) in the range of those observed in the clinic. The plasma trabectedin levels attained were 10.6 ± 5.4 (Cmax), higher than those reached in patients after infusion of 1,500 μg/m² for 24 (Cmax of 1.8 ± 1.1 ng/ml) and similar to those reached after administration of the same dose by 3 hour infusion (Cmax of 10.8 ± 3.7 ng/ml).
Myelosupression and hepatoxicity were identified as the primary toxicity for trabectedin. Findings observed included haematopoietic toxicity (severe leukopenia, anaemia, and lymphoid and bone marrow depletion) as well as increases in liver function tests, hepatocellular degeneration, intestinal epithelial necrosis, and severe local reactions at the injection site. Renal toxicological findings were detected in multi-cycle toxicity studies conducted in monkeys. These findings were secondary to severe local reaction at the administration site, and therefore uncertainly attributable to trabectedin; however, caution must be guaranteed in the interpretation of these renal findings, and treatment-related toxicity cannot be excluded.
Trabectedin is genotoxic both in vitro and in vivo. Long-term carcinogenicity studies have not been performed.
Fertility studies with trabectedin were not performed but limited histopathological changes were observed in the gonads in the repeat dose toxicity studies. Considering the nature of the compound (cytotoxic and mutagenic), it is likely to affect the reproductive capacity.
Placental transfer of trabectedin and fetal exposure to trabectedin were observed in a study in pregnant rats that received a single i.v. 14C-trabectedin dose at 0.061 mg/kg. Maximum fetal tissue radioactivity concentration was similar to that in maternal plasma or blood.
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