Yondelis (trabectedin)

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.

Noteworthy, both drugs induced the deregulation of EZH2- and HMGA1-controlled genes. Altogether, these findings propose the combination of trabectedin and GSK126 as possible novel strategy for ATC therapy.

P2/3, N=190, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=70 --> 190

P1/2, N=48, Active, not recruiting, Sarcoma Alliance for Research through Collaboration | Recruiting --> Active, not recruiting

Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for liposarcoma, and pazopanib for non-liposarcoma. The present study demonstrated the potential of tailored therapy guided by mutation profiles established by comprehensive genomic profiling testing in optimizing second-line chemotherapy for STS. The findings of this study will hopefully contribute some valuable insights into enhancing STS treatment strategies and outcomes.

P4, N=89, Completed, North Eastern German Society of Gynaecological Oncology | Recruiting --> Completed | N=204 --> 89 | Trial completion date: Mar 2024 --> Aug 2023 | Trial primary completion date: Mar 2024 --> Aug 2023

P=N/A, N=100, Recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Not yet recruiting --> Recruiting

The long-term survival patient compared with the other mSTS patients exhibited a distinctive metabolic profile characterized by remarkably higher levels of ursodeoxycholic acid (UDCA) derivatives and vitamin D and lower levels of lithocholic acid (LCA) derivatives, as well as reduced levels of inflammatory C-Reactive Protein 4 (C-RP4) biomarker. Despite its exploratory nature, this study reveals a potential association between specific bile acid metabolic profiles and mSTS patients' prognosis. Enhanced clinical understanding of the interplay between bile acid metabolism and disease progression could pave the way for new targeted therapeutic interventions which may improve the overall survival of mSTS patients.

P2, N=10, Recruiting, Mario Negri Institute for Pharmacological Research | Not yet recruiting --> Recruiting | Trial completion date: Apr 2023 --> Feb 2024 | Trial primary completion date: Apr 2022 --> Feb 2024

Forty-five metastatic STS (mSTS) patients with prevalent leiomyosarcoma and liposarcoma histotypes receiving trabectedin treatment were enrolled...This score is statistically significant and independent of other prognostic factors such as age, sex, tumor grading, tumor histotype, frailty status, and therapy administered. A nomogram based on these 3 biomarkers has been developed to inform the clinical use of the present findings.

P2, N=16, Recruiting, Italian Sarcoma Group | Active, not recruiting --> Recruiting

P2, N=126, Active, not recruiting, Italian Sarcoma Group | Recruiting --> Active, not recruiting

Through the use of Partial least squares-Discriminant Analysis, cystathionine and hemoglobin were identified as specific metabolic signatures that effectively distinguish patients with stable disease from those with progressive disease. The findings from this study provide compelling evidence to support the utilization of pre-dose metabolomics in uncovering the underlying causes of pharmacokinetic variability of trabectedin, as well as facilitating the identification of patients who are most likely to benefit from this treatment.

Ifosfamide, trabectedin, gemcitabine, taxanes, dacarbazine, and eribulin exhibit certain activities in STSs. Vinca alkaloid agents (vindesine, vinblastine, vinorelbine, vincristine) have important therapeutic effects in specific STS subtypes, such as rhabdomyosarcoma and Ewing sarcoma family tumors, whereas their activity in other subtypes is weak. Other chemotherapeutic drugs (methotrexate, cisplatin, etoposide, pemetrexed) have weak efficacy in STSs and are rarely used. It is necessary to select specific second- or above-line chemotherapeutic drugs depending on the histological subtype. This review aims to provide a reference for the selection of chemotherapeutic drugs for multi-line therapy for patients with advanced STSs who have an increasingly long survival.

The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

The patient underwent 5 courses of pre-operative chemotherapy with vincristine/doxorubicin/ifosfamide, and one cycle of etoposide/ifosfamide with an initial partial response, which was lost after the fifth cycle. Although a formal RECIST response was not observed, we provide evidence on the possible efficacy of trabectedin in a very rare sarcoma histotype, lacking protocols on the proper management. To our knowledge, this is the first case report on trabectedin use in EWSR1::PATZ1 small round cell sarcoma, in the literature. Given its rarity, large, prospective trials on this histotype remain very unlikely to be run.

Antitumor activity of single-agent doxorubicin, ifosfamide, trabectedin, eribulin and selinexor as well as the combination of doxorubicin plus ifosfamide was tested in each model. To the best of our knowledge this is the first PDX model of MPL and this study suggests the potential relevance of eribulin for this disease. In addition, the comparison with a PDX model of PL highlights different response to treatment approaches, such as the first line treatment options for soft tissue sarcomas doxorubicin with or without ifosfamide. Further analyses are ongoing to understand the determinants of eribulin activity in MPL

No abstract available

In two preclinical mouse models of MPNST, we combined the oncolytic virus T-VEC with myeloid-cell targeting therapeutics, Pexidartinib or Trabectedin, to assess the combination therapy's antitumor efficacy and survival benefits. Our findings provide compelling evidence that myelomodulatory therapies can augment the antitumor T-cell response and improve the therapeutic benefits of oncolytic virotherapy in murine models of MPNST. These results provide valuable insights for designing and implementing future immunotherapeutic strategies in the management of MPNST.

No responses were seen to trabectedin. The metastatic course of F and S may be indolent. When systemic therapy is needed, gemcitabine-based regimen and pazopanib currently seem to be most active. Responses were seen also to ifosfamide and oral cyclophosphamide.

Our results indicate that trabectedin enhances oncolytic herpes simplex viroimmunotherapy in preclinical immunocompetent osteosarcoma models through immune-mediated anti-tumor mechanisms. Trabectedin removes the immunosuppressive barriers of anti-inflammatory, pro-tumor monocytes and macrophages and frees immune effector cells, namely NK and CD8 T cells, to induce tumor cell death. This immune-mediated mechanism may synergize with our observation of increased viral spread in human tumors to generate greater combinatorial efficacy in patients.

We highlight the clinical translation of innovative technologies, such as proteolysis targeting chimera (PROTAC) protein degraders or adoptive transfer of engineered immune cells. Adoptive cell transfer of engineered T-cell receptor cells targeting selected cancer/testis antigens has shown promising results against metastatic SyS in early clinical trials and further improvements are awaited from refinements involving immune cell engineering and tumor immune microenvironment enhancement.

The adverse reactions are comparable to those published for younger pts and efficacy remains beneficial. Albeit in a small sample, a high overall response rate was observed for BRCAmut pts.

Further evaluation of milademetan is warranted in populations that may benefit from MDM2 inhibition. Table: LBA89 Study findings Efficacy population Milademetan (n=86) Trabectedin (n=89) Median PFS by BICR, m 3.6 2.2 HR=0.89 (95% CI 0.61–1.29; p=0.53) Median PFS by investigator, m 3.7 2.1 HR=0.80 (95% CI 0.55–1.15; p=0.22) Median OSa, m 9.5 10.2 HR=1.27 (95% CI 0.80–2.04; p=0.31) ORR, n (%) 4 (4.7) 3 (3.4) p=0.67 DCR, n (%) 29 (33.7) 24 (27.0) p=0.33 Safety population n=86 n=79 Most common milademetan TEAEs, %NauseaThrombocytopeniaAnemiaVomiting 70.961.644.244.2 58.225.336.719.0 Most common grade 3/4 milademetan TEAEs, %ThrombocytopeniaNeutropeniaAnemia 39.525.618.6 13.926.619.0 TEAEs – fatal/grade 5, % 0 6.3 TEAEs leading to dose reductions, % 44.2 29.1 TEAEs leading to discontinuations, % 11.6 19.0

Clinical trial identification NCT03127215 Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors (NCT-PMO-1603) Estimated Primary Completion Date: December 2023 Estimated Study Completion Date: December 2023. Conclusions The TOP-ART score is a novel composite HRR biomarker developed and validated in an observational precision oncology cohort. It has the potential to broaden access to targeted treatments and is prospectively used to determine eligibility for the TOP-ART trial.

Common regimens were doxorubicin/ifosfamide-based (37.4%) for 1L and trabectedin-based for 2L (29.7%). HCRU data showed median one inpatient hospital admission, 3 days in hospital and four outpatient visits yearly. This large-scale study documents high unmet needs in patients previously treated for mSS and for more effective therapies.

A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.