Yondelis (trabectedin)

Silencing p53 with siRNA abolished all synergistic effects in A2780 cells. Niraparib and trabectedin combination therapy impairs DNA repair in BRCA-proficient ovarian cancer, leading to synthetic lethality through p53-dependent apoptosis.

P3, N=126, Recruiting, Universität Münster | Trial primary completion date: Dec 2025 --> Aug 2026

P2, N=198, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

Despite the availability of new agents such as pazopanib and trabectedin, the prognosis after recurrence remains poor. However, if TCR-engineered T-cell therapy is to be used in clinical practice, the standard approach following the failure of doxorubicin-based chemotherapy in patients with advanced SS must be defined. Future studies will be critical for establishing treatment strategies in this field.

P4, N=89, Terminated, North Eastern German Society of Gynaecological Oncology | Completed --> Terminated; A total of 204 patients were planned to be randomized. Due to slow recruitment of the trial, the recruitment was prematurely terminated after randomization of the 89th patient.

These strategies include BRD and extraterminal (BET) inhibitors, trabectedin, inhibitors of the EP300 histone acetyltransferase, and histone deacetylase inhibitors such as vorinostat. In the absence of clinical trials, the results from this review suggest that trabectedin-based or ifosfamide-based regimens, particularly in combination with doxorubicin, may offer a reasonable approach as frontline therapy for NUT sarcomas.

Principal component and hierarchical clustering analyses identified distinct immune profiles associated with RECIST1.1 and therapy duration, underscoring immune profiling's role in understanding treatment responses. These findings support further research into immune monitoring for future clinical trials.

P2, N=200, Recruiting, Sarcoma Oncology Research Center, LLC | N=40 --> 200 | Trial completion date: Mar 2025 --> Jul 2031 | Trial primary completion date: Dec 2024 --> Dec 2030

P1/2, N=250, Recruiting, Sarcoma Oncology Research Center, LLC | N=45 --> 250 | Trial completion date: Mar 2025 --> Jul 2031 | Trial primary completion date: Dec 2024 --> Dec 2030

P2, N=80, Recruiting, Sarcoma Oncology Research Center, LLC | Trial completion date: Dec 2024 --> Mar 2029 | Trial primary completion date: Sep 2024 --> Sep 2028

The treatment of liposarcomas has garnered increasing attention worldwide in the last 20 years. The treatment approach has shifted from surgical resection to multidisciplinary therapy. The molecular and biological characteristics of different tumor subtypes have attracted more research attention, providing an important reference for the choice of treatment. The findings of this study contribute to providing a comprehensive understanding of liposarcomas treatment among researchers. Moreover, they offer valuable perspectives that can guide future research.

IL 12 and trabectedin also significantly enhanced the response of TNBC to anti-PD-L1 therapy. These data suggest that MDSC depletion augments the ability of IL-12-activated NK cells to drive the infiltration of DC and CD8+ T cells into TNBC for an antitumor effect.

The patient received doxorubicin-based systemic chemotherapy as first-line therapy, which resulted in stable disease. After disease progression, the patient received eribulin monotherapy, which resulted in stable disease for 15 months...Therefore, the patient was started on trabectedin monotherapy during 16 months of stable disease, and thereafter received pazopanib after they presented with progressive disease on prior trabectedin monotherapy. It is likely that there are more patients with undiagnosed EWSR1::NFATC2 sarcoma. To make a definitive diagnosis, a thorough investigation should be performed.

P2, N=100, Recruiting, Italian Sarcoma Group | Trial completion date: Sep 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Dec 2025

P2, N=16, Recruiting, Italian Sarcoma Group | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Aug 2025

P2, N=23, Completed, Italian Sarcoma Group | Active, not recruiting --> Completed

P1/2, N=48, Active, not recruiting, Sarcoma Alliance for Research through Collaboration | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=130, Completed, Italian Sarcoma Group | Active, not recruiting --> Completed

P2, N=198, Not yet recruiting, UNICANCER | Initiation date: Oct 2024 --> Feb 2025

These findings explain the unusual mechanism underlying trabectedin's effectiveness against MLPS by pinpointing the chimera's role in inducing the differentiation block responsible for MLPS pathogenesis. Additionally, the findings hint at a potential mechanism of resistance acquired in vivo.

Case 1: A 44-year-old male started trabectedin as second-line therapy after initial chemotherapy, which included doxorubicin. He then began trabectedin and has maintained a response for 10 months to date. Compared to other chemotherapies, trabectedin demonstrated potentially higher efficacy and a favorable safety profile for patients with myxoid liposarcoma harboring the FUS/CHOP fusion gene.

This pooled analysis of LMS patients treated with the combination of T+O in the TOMAS and TOMAS2 trials highlighted a subgroup of patients with uLMS who experienced prolonged benefit from T+O, with about one third of patients free from progression for more than one year. Furthermore, patients with defects in the homologous recombination pathway benefitted from T+O as well. These results are in line with similar studies involving PARP1 inhibitors and chemotherapy in uLMS, supporting the further development of PARP1 inhibitors and DNA-damaging agents combination in the treatment of advanced uLMS.

Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

P=N/A, N=7, Completed, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Recruiting --> Completed | N=100 --> 7 | Trial completion date: Dec 2025 --> Jul 2024 | Trial primary completion date: May 2025 --> Jul 2024

P2, N=198, Not yet recruiting, UNICANCER

Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model...Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.

P3, N=333, Recruiting, Intensity Therapeutics, Inc. | Not yet recruiting --> Recruiting

Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

P2/3, N=190, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

P2, N=102, Completed, National Center for Tumor Diseases, Heidelberg | Active, not recruiting --> Completed

Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.

P1/2, N=45, Recruiting, Sarcoma Oncology Research Center, LLC | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=10, Recruiting, Mario Negri Institute for Pharmacological Research | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

The study results indicate pretreatment PNI and CRP levels as prognostic factors for trabectedin treatment in advanced STS.

In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed.

This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.

Maraviroc treatment did not affect OC cell viability, but strongly potentiated the antiproliferative activity, apoptosis induction, cell cycle blockage, DNA damage, and ROS formation by trabectedin. In A2780cis cisplatin-resistant cells, the cross-resistance to trabectedin was overcame by the combination with maraviroc. Maraviroc enhanced trabectedin cytotoxicity in OC 3Dimensional spheroids and THP-1-monocytes. Both maraviroc and trabectedin interact with drug efflux pump MDR1/P-gp, overexpressed in recurrent OC patients. Maraviroc increased trabectedin intracellular accumulation and the MDR1-inhibitor verapamil, like maraviroc, increased trabectedin cytotoxicity. In OC tumor xenografts the combination with maraviroc further reduced tumor growth, angiogenesis, and monocyte infiltration by trabectedin. In conclusion, this study offers a preclinical rationale for the use of maraviroc as new option to improve trabectedin activity in relapsed chemoresistant OC patients.

P3, N=333, Not yet recruiting, Intensity Therapeutics, Inc.

Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

Trabectedin combined with PLD significantly improves OS and PFS in patients with BRCA-associated and platinum-sensitive recurrent ovarian cancers. The potential use of trabectedin combined with PLD should be selected according to the PFI and BRCA mutation status of patients.