Overview
Critical stages of trabectedin drug development
Preclinical Studies
Clinical Studies
Efficacy Studies
Publication, year | No. of patients | Study features | Results and conclusions |
---|---|---|---|
Phase 1 single agent | |||
Van Kesteren, 2000 | 52 | First report on pharmacokinetics of trabectedin in all solid tumors | Biologic half-life = 89 h Recommended Phase 2 dose = 1500 µg/m2 as 24 h CIV infusion |
Delalogue, 2001 | 29 | First report of activity of trabectedin in soft tissue sarcoma | PR = 4/29, SD = 10/29, DCR = 48%, median time to progression = 2.8 months |
Taama, 2001 | 52 | Established optimal regimen of trabectedin 1.5 mg/m2 as a 24-h CIV infusion once every 3 weeks | PR = 3/52 (5.7%), SD = 4/52 (7.7%), DCR = 7/52 (13%) lasting ≥3 months |
Ryan, 2001 | 21 | Report on pharmacokinetics of trabectedin given as 72 h CIV infusion every 3 weeks | Biologic half-life = 69 h No objective responses; anti-tumor activity noted by PET scan in epithelioid mesothelioma Recommended Phase 2 dose: 1050 µg/m2
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Villalona-Calero, 2002 | 42 | Report on pharmacokinetics of trabectedin in escalating doses, daily, given as 1-h IV infusion for 5 days every 3 weeks | Biologic half-life = 27 h Antitumor activity was noted in 3 patients with leiomyosarcoma and primary peritoneal and ovarian carcinomas Recommended Phase 2 dose: 325 µg/m2/day daily × 5 every 3 weeks |
Twelves, 2003 | 72 | Report on pharmacokinetics of trabectedin given as 1 or 3 h IV infusion | Pharmacokinetics linear, not cumulative Recommended dose for Phase 2 clinical trial is 1.65 mg/m2
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Forouzesh, 2009 | 63 | Report on the maximum tolerated dose of trabectedin at different dosing and infusion schedules | Trabectedin, 0.61 mg/m2 and 0.58 mg/m2, are the respective maximum tolerated doses (MTD) for trabectedin administered as a 1- and 3-h infusion in weekly regimens |
Phase 1 combination regimen | |||
Blay, 2008 | 41 | Phase 1 study of trabectedin and doxorubicin in soft tissue sarcoma | ORR = 12%, median PFS = 9.2 months |
Messersmith, 2008 | 15 | Phase 1 study of trabectedin and gemcitabine in advanced solid tumors | Lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy |
Von Mehren, 2008 | 36 | Phase 1 study of trabectedin and pegylated liposomal doxorubicin in advanced malignancies | ORR = 6/36 (16.7%), SD = 14/36 (38.9%), DCR = 20/36 (55.6%) |
Sessa, 2009 | 39 | Phase 1 study of trabectedin and cisplatin in solid tumors | The administration of trabectedin and cisplatin on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay |
Sessa, 2009 | 29 | Phase 1 study of trabectedin and doxorubicin in advanced STS and breast cancer | The most promising results in STS with ORR = 18%, SD = 56%, DCR = 74% |
Phase 2 single agent | |||
Ryan, 2002 | 20 | Phase 2 study of trabectedin in GIST Phase 2 study of trabectedin, 1500 µg/m2, administered as a 24-h CIV infusion every 3 weeks | SD = 2/20 (10%), median PFS = 1.25 months, median OS = 8.6 months (w/o imatinib) |
Yovine, 2004 | 54 | Phase 2 study of trabectedin, 1500 µg/m2, administered as a 24-h CIV infusion every 3 weeks | PR = 3.7%, SD = 17%, median PFS = 1.9 months |
Garcia-Carbonero, 2004 | 36 | Phase 2 study of trabectedin, 1500 µg/m2, administered as a 24-h CIV infusion every 3 weeks | CR = 1/36 (2.8%), PR = 2/36 (5.6%), ORR = 8%, median PFS = 1.7 months, median OS = 12.1 months |
EORTC Blay, 2004 | 28 | Phase 2 study of trabectedin in GIST Trabectedin, 1500 µg/m2, administered as a 24-h CIV infusion every 3 weeks | SD = 9/28 (32%), median PFS = 1.7 months, median OS = 19.3 months (may be due to imatinib use) |
EORTC Le Cesne, 2005 | 104 | Phase 2 study of trabectedin, 1500 µg/m2, administered as a 24-h CIV infusion every 3 weeks | PR = 8/104 (7.7%), SD = 45/104 (43.3%), DCR = 51%, median PFS = 3.4 months, median OS = 9.2 months |
Morgan, 2007 | 270 | A randomized Phase 2 study comparing trabectedin given at 580 µg/m2 on a weekly schedule to the “standard” 1500 µg/m2 24-h continuous infusion every 3 weeks schedule | Median PFS = 2.3 months, in 580 µg/m2 arm every week; median PFS = 3.3 months in 1500 µg/m2 arm every 3 weeks (p = 0.0418) |
ET 743-STS-201 Demetri, 2009 | 270 | A randomized Phase 2 study comparing different dosing schedules of trabectedin | Median TTP = 3.7 months for the every 3 week 24-h CIV group, compared with 2.3 months for the every week 3-h group (p = 0.0302). Median OS = not significant |
Monk, 2012 | 20 | Phase 2 study of trabectedin in uterine leiomyosarcoma only | PR = 2/20 (10%), SD = 10/20 (50%), median PFS = 5.8 months. Median OS ≥ 23.1 months |
Gronchi, 2012 | 23 | Phase 2 study using trabectedin in the neoadjuvant setting in advanced localized myxoid liposarcoma | CR = 3/23 (13%), PR = 7/23 (30.4%), ORR = (43.4%), SD = 13/23 (56.5%), DCR (100%), no PD |
Phase 2 combination regimen | |||
Pautier, 2015 | 109 | Phase 2 study using trabectedin with doxorubicin as first-line therapy for uterine leiomyosarcoma and soft tissue leiomyosarcoma | Uterine leiomyosarcoma (n = 47): PR = 28/47 (59.6%); SD = 13/47 (27.6%); DCR = 41/47 (87.2%); soft tissue leiomyosarcoma (n = 61): CR = 2/61 (3.3%), PR = 22/61 (36.1%), ORR = 39.4%), SD = 32/61 (52.5%), DCR = 56/61 (91.9%) |
Retrospective study | |||
Huygh, 2006 | 89 | Retrospective study of 15 patients in Phase 2 study, and compassionate use of 74 patients Trabectedin 1500 µg/m2 administered as a 24-h CIV infusion every 3 weeks | ORR = 6/89 (7%; 1 CR, 5 PR), SD = 32/89 (36%), DCR = 43%, median PFS = 2 months, median OS = 8.2 months |
Schöffski, 2006 | 92 | Retrospective analysis of the NER and HRR status, using RT-PCR, in tumors of trabectedin-treated patients ERCC1 is part of the NER machinery and BRCA1 is part of the HRR system | Patients whose tumors expressed higher ERCC1 had improved 6-month PFS rate and median OS compared with patients whose tumors expressed lower levels of ERCC1 (32% vs. 15%, p = 0.07, and 12 vs. 7 months respectively) Patients whose tumors expressed lower levels of BRCA1 had improved 6-month PFS rate and median OS compared with patients whose tumor expressed high levels of BRCA1 (33% vs. 11%, p = 0.02 and 15 vs. 5 months, p = 0.0003, for PFS and OS respectively). ERCC1 and BRCA1 are independent predictors of PFS. Only BRCA1 predicted OS |
Grosso, 2007 | 51 | Retrospective analysis of patients with myxoid liposarcoma treated with trabectedin in 5 European and American insitutions | ORR = 26/51 (51%) (CR = 4%, PR = 47%), SD = 20 (39%), DCR = median PFS = 14 months |
San Filippo, 2011 | 66 | Retrospective study of trabectedin in uterine leiomyosarcoma only | PR = 11/66 (16%), SD = 23/66 (35%), DCR = 51%, median PFS = 3.3 months |
Le Cesne, 2015 French Sarcoma Group | 885 | Retrospective analysis from 25 French centers using trabectedin at 1.5 mg/m2 as CIV infusion for 24 h q 3 weeks | ORR = 150/885 (17%), DCR = 592/885 (67%), median PFS = 4.4 months; median OS = 12.2 months; 227 patients who continued trabectedin up to disease progression, had a median PFS of 11.7 months, median OS = 24.9 months Conclusion: Longer trabectedin treatment until disease progression is associated with a significantly improved PFS and OS |
Blay, 2015 | 129 | Retrospective analysis of patients treated with trabectedin in a second-line setting vs. third- or fourth-line setting | Conclusion: all efficacy outcomes were better in patients who received trabectedin as second-line treatment compared with patients with more extensive prior therapy |
Syed, 2015 | 18 | Retrospective analysis of patients treated with trabectedin in chemotherapy-resistant advanced chondrosarcoma | Mesenchymal type: median PFS = 36 months. Other subtypes: median PFS = 4 months |
Phase 2b | |||
Bui-Nguyen, 2015 | 133 | Phase 2b randomized trial using trabectedin vs. doxorubicin as first-line treatment for advanced metastatic soft tissue sarcoma | Study terminated because of lack of significance in outcome; doxorubicin remains standard first-line treatment |
Expanded access | |||
Samuels, 2013 | 1895 | Expanded access program for advanced soft tissue sarcomas following failure of prior chemotherapy | Patients with leiomyosarcoma and liposarcoma had significantly longer OS compared to all other histological subtypes (16.2 vs. 8.4 months, respectively), as well as a higher objective response rate (6.9% vs. 4%, respectively) |
Phase 3 soft tissue sarcoma | |||
Blay, 2013 | 121 | Phase 3 randomized study comparing doxorubicin and trabectedin as first-line therapy in translocation-related sarcomas | No significant difference in PFS or OS between the two arms of the trial. The response rate by RECIST was significantly higher in the doxorubicin (27%) arm compared to the trabectedin (5.9%) arm of the trial |
Demetri, 2015 | 518 | Pivotal Phase 3, 2:1 randomized study using trabectedin vs. dacarbazine in locally advanced, unresectable or metastatic leiomyosarcoma and liposarcoma; trabectidin 1.5 mg/m2 as a 24-h CIV every 3 weeks (n = 345) vs. dacarbazine 1000 mg/m2 IV over 20–120 min every 3 weeks (n = 173) | Statistically significant improvement in progression-free survival, gained US FDA approval on 23 October 2015 |