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Associated Trial(s):- NCT01343277 - A Study of Trabectedin or Dacarbazine for the Treatment of Patients With Advanced Liposarcoma or Leiomyosarcoma
- NCT00060944 - A Randomized, Multicenter, Open-label Study of Yondelis (ET-743 Ecteinascidin) Administered by 2 Different Schedules (Weekly for 3 of 4 Weeks vs. q3 Weeks) in Subjects With Locally Advanced or Metastatic Liposarcoma or Leiomyosarcoma Following Treatment With an Anthracycline and Ifosfamide
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Status: OngoingResearch Proposal
Project Title: Contextual Evaluation of Letetresgene Autoleucel in MRCLS Using Independent Patient-Level Data from Trabectedin Trials
Scientific Abstract: Background: Myxoid/round cell liposarcoma (MRCLS) is a rare, biologically distinct subtype of liposarcoma. Trabectedin is commonly used; however, MRCLS-specific outcomes are incompletely characterized in the published literature. Letetresgene autoleucel (lete-cel), an engineered T-cell therapy targeting NY-ESO-1, has demonstrated antitumor activity in MRCLS but has not been evaluated in randomized head-to-head trials. Objective: This project will leverage independent participant-level data from trabectedin clinical trials (previously accessed via the YODA Project) and from lete-cel studies including IGNYTE-ESO (NCT03967223) and the MRCLS pilot study (NCT02992743) to generate a contextual benchmark for efficacy outcomes in advanced MRCLS. Study Design: Comparative analysis of outcomes in advanced MRCLS. Participants: MRCLS patients in NCT01343277, NCT00060944 vs NCT03967223, NCT02992743. Primary and Secondary Outcome Measures: objective response and disease control (RECIST v1.1) and time-to-event outcomes (e.g., duration of response, progression-free survival, overall survival, and time to next treatment) using a common index date (first dose/infusion) and harmonized endpoint definitions. Statistical Analysis: Comparative analyses will use propensity score methods to adjust for measured baseline differences between cohorts; if feasible, the primary analysis will use propensity score matching, and otherwise inverse probability of treatment weighting will be applied, with additional sensitivity analyses as appropriate. Results will be interpreted as contextual evidence.
Brief Project Background and Statement of Project Significance:
MRCLS is a biologically distinct subtype of liposarcoma characterized by specific chromosomal translocations and unique patterns of treatment sensitivity. Despite this, most historical clinical trials grouped MRCLS together with other liposarcoma subtypes, limiting the ability to interpret outcomes for this rare population.
Trabectedin clinical trials enrolled patients across multiple sarcoma subtypes and generally did not report MRCLS specific outcomes in the published literature. Recognizing this gap, a prior YODA approved research project (2024-0560) successfully re analyzed patient level data from these trials and identified a well defined cohort of MRCLS patients, enabling the first comprehensive evaluation of trabectedin efficacy in this population.
That prior work established:
- The feasibility of histology specific re analysis using patient level data
- A clearly characterized MRCLS cohort suitable for future contextual analyses
- A strong scientific rationale for using these data as an external reference in MRCLS research
Given the rarity of MRCLS and the practical limitations of conducting randomized controlled trials, especially for biomarker-defined therapies, cross-study contextual analyses using independent patient-level data can provide clinicians with additional perspective when interpreting outcomes reported for emerging cell therapies. In this project, we will use independent IPD to align eligibility and harmonize key efficacy endpoint definitions across two different therapies (lete-cel and trabectedin) and to adjust for measurable differences in baseline characteristics, thereby generating an external benchmark for MRCLS outcomes. Findings will be interpreted as contextual evidence rather than definitive comparative effectiveness, as differences in trial design, assessment schedules, supportive care, sample size, and follow-up, as well as residual confounding from unmeasured factors, may influence cross-trial comparisons.
This extension proposal leverages the previously established and well-characterized MRCLS trabectedin cohort to provide an independent benchmark for interpreting outcomes observed with letetresgene autoleucel IGNYTE-ESO, primary results of which are now available. By building directly on prior YODA-approved feasibility work, the project is positioned to deliver timely, transparent contextual evidence without initiating new patient enrollment.
This project advances the YODA Project's mission to enable responsible access to clinical trial data for independent research that improves the evidence base. By leveraging shared participant-level data to generate MRCLS-specific benchmarks not available in the published literature, the study increases transparency, reduces research waste, and supports better-informed clinical and evidence-based decision-making in rare cancers.
Specific Aims of the Project:
Although trabectedin has demonstrated activity in MRCLS, histology-specific outcomes have been incompletely characterized due to aggregation of MRCLS with other sarcoma subtypes in most clinical trial reports. A prior YODA-approved project successfully identified and analyzed MRCLS patients treated with trabectedin using independent patient-level data provided by Johnson & Johnson, establishing a robust external reference cohort.
Letetresgene autoleucel is an emerging therapeutic approach under investigation in MRCLS, but interpretation of clinical outcomes is challenged by the rarity of the disease and the absence of randomized comparative trials. The overarching goal of this project is to leverage existing high-quality clinical trial data to contextualize outcomes observed with letetresgene autoleucel relative to an established therapy in MRCLS.
The specific aims of this project are:
Aim 1: To characterize clinical outcomes in MRCLS patients treated with trabectedin using independent patient-level data clinical trials previously approved for access through the YODA Project.
Aim 2: To integrate patient-level data from MRCLS patients treated with letetresgene autoleucel from the IGNYTE-ESO (NCT03967223) pivot trial, and the MRCLS pilot study (NCT02992743) into the YODA secure analysis environment and harmonize key efficacy endpoints across datasets.
Aim 3: To perform adjusted and sensitivity analyses comparing outcomes between letetresgene autoleucel and trabectedin cohorts, with a focus on contextual interpretation and non-inferiority rather than formal superiority testing
Study Design:
Other
Explain:
Based on the findings from Project 2024-0560, two clinical trials were used to create a cohort of MRCLS patients for response analysis. The two trials are: NCT01343277 (ET743-SAR-3007) and NCT00060944 (ET743-STS-201). Patients in the control arms of these trials will also be helpful for contextualizing the results. In addition to the pooled trabectedin benchmark, we will analyze individual participant-level data from studies that evaluated letetresgene autoleucel (lete-cel) in MRCLS (NCT03967223, NCT02992743). This two-dataset design will enable presentation of outcomes for MRCLS patients treated with an emerging engineered T-cell therapy alongside outcomes observed with an established systemic therapy or the respective control arms, providing clinicians with a clinically interpretable context in a setting where randomized head-to-head trials are unlikely. Letetresgene autoleucel is a dual biomarker specified therapy, requiring a specific HLA subtype (HLA A*02:01, 02:05, and 02:06) and NY-ESO-1 expression. HLA subtype has been shown to not be a factor that influences MRCLS prognosis. Additionally, MRCLS has been shown to be 100% positive for NY-ESO-1. So, lack of known HLA subtype and NY-ESO-1 status from the trabectedin will not be a concern for this analysis. To support a fair contextual comparison across the two studies, we will define a common analysis "time zero" (e.g., first dose/infusion), align key inclusion criteria to the extent permitted by available variables, and harmonize endpoint definitions (e.g., RECIST v1.1 response-based endpoints and time-to-event endpoints). We will then use adjusted analyses (e.g., propensity score weighting and complementary matching-based sensitivity analyses) to account for measurable differences in baseline characteristics between the lete-cel and trabectedin cohorts. All comparative results will be framed as contextual evidence rather than definitive comparative effectiveness, recognizing that differences in trial design, assessment schedules, supportive care, and residual confounding from unmeasured factors may influence cross-trial comparisons.
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations Other
Software Used: R, RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
Data Source from YODA Project will consider the following Inclusion/Exclusion Criteria as used in previous cohort identification:
Inclusion Criteria:
Patient with a diagnosis of myxoid round cell liposarcoma (MRCLS)
Patients with advanced (locally unresectable or metastatic) disease
Exclusion Criteria:
All patients with a sarcoma diagnosis, other than MRCLS, will be excluded, such as diagnoses of leiomyosarcoma, pleomorphic liposarcoma, well differentiated or dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma
The relevant independent patient level data for the lete-cel patients will be uploaded to the platform to allow the necessary analyses as described herein.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary Outcome Measure:
Objective Response (OR), defined as CR or PR according to RECIST v1.1, from index date until documented disease progression will be based on confirmed (tumour) responses.
Secondary Outcome Measures:
Disease control, defined as participants with the following responses will be summarized: CR, PR, or SD >= 12 weeks, according to RECIST v1.1.
Time to Response (TTR) per RECIST v1.1, defined in responders, as the duration between the date of first dose and the initial date of the confirmed response.
Duration of Response (DoR) per RECIST v1.1, defined in responders as the duration from the initial date of the confirmed response to the earliest date of progressive disease (PD) or death due to any cause.
Progression-Free survival (PFS) per RECIST v1.1, defined as the interval between the index date (first dose/infusion)and the earliest date of disease progression or death due to any cause.
Duration of Stable disease (SD) per RECIST v1.1 defined as the interval between the initial date of the stable disease and the last date that stable disease is recorded.
Overall Survival (OS) defined as the duration between the index date (first dose/infusion)and date of death due to any cause.
For time-to-event endpoints, participants not experiencing the event of interest will be censored at the last date the participant is known to be event-free.
Time to Next Treatment (TTNT): defined as the time from the index date (first dose/infusion) to the earliest date of initiation of the next anti-cancer therapy. Participants without a subsequent anti-cancer therapy are censored at the last known follow-up date (or last disease assessment date if follow-up date is unavailable).
Main Predictor/Independent Variable and how it will be categorized/defined for your study: Cohort (lete-cel or trabectedin/control)
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
Subgroups of interest are: age, race, sex, prior lines of therapy, subsequent therapies, control or treatment arm, and other available relevant disease- specific subgroups. Subgroup analyses will only be performed if data are available.
Statistical Analysis Plan:
The primary comparative analysis will employ Propensity Score Matching (PSM) to adjust for baseline differences between the letetresgene autoleucel and trabectedin study cohorts (control and trabectedin). Propensity scores will be estimated using logistic regression, incorporating key prognostic covariates known or suspected to influence both treatment assignment and outcomes. Matching will be performed using a 1:1 nearest-neighbor algorithm without replacement and a caliper of 0.2 standard deviations of the logit of the propensity score. Covariate balance will be assessed using standardized mean differences (SMD), with an SMD <0.2 considered indicative of acceptable balance.
If the number of matched pairs is insufficient to support a robust analysis (e.g., <20 matched pairs or poor covariate balance post-matching), alternative analytic strategies will be employed:
1. Inverse Probability of Treatment Weighting (IPTW): Propensity scores will be used to construct stabilized weights to create a pseudo-population in which covariates are balanced across treatment groups. Weighted outcome analyses will be conducted using appropriate regression models (e.g., weighted Cox proportional hazards for time-to-event outcomes).
2. Multivariable Regression Adjustment: In the unmatched full cohort, outcomes will be modeled using regression techniques (e.g., logistic regression for binary outcomes, Cox models for survival outcomes), adjusting for the same covariates included in the propensity score model.
Patient inclusion/exclusion:
Patients from the 2 selected studies presented in the previous analysis (NCT01343277, NCT00060944) will be included as well as two lete-cel studies (NCT03967223, NCT02992743) . Both the ITT (intent to treat) and mITT(modified intention to treat) patients will be used. For the 2 lete-cel studies the ITT population is defined as all participants that started the leukapheresis procedure and the mITT population is the ITT population that went on to receive lete-cel.
Subject disposition including the number of patients screened/enrolled, randomized and treated. Reasons for treatment discontinuation and study discontinuation will be displayed (where available).
Study population analyses:
Demography, baseline characteristics, disease characteristics at initial diagnosis, prior and on-study anti-cancer therapy, disease burden at baseline, and exposure will be summarized (where available) using appropriate descriptive statistics.
The primary analysis population for comparative effectiveness will be defined using propensity score (PS) methods to address measured baseline differences between the letetresgene autoleucel and trabectedin study cohorts. If adequate overlap and covariate balance can be achieved, the primary analysis will be conducted in the PS-matched cohort (matched set). If PS matching is not feasible or yields an insufficient matched sample or unacceptable balance, the primary analysis will be conducted in the PS-weighted cohort using inverse probability of treatment weighting (IPTW) with stabilized weights. Unless otherwise specified, this primary analysis population will be used consistently across all comparative endpoints; endpoint-specific analysis sets (e.g., responder-only populations for response-duration endpoints) will be defined where applicable.
Primary Outcome:
Overall response rate (ORR) is defined as the percentage of participants with OR relative to the total number of participants in the analysis population, the corresponding Clopper- Pearson (exact binomial) 2-sided 95% confidence interval (CI) will also be provided.
Secondary Outcomes:
Disease control rate (DCR) is defined as the percentage of participants with CR, PR, or SD >= 12 weeks relative to the total number of participants in the analysis population, the corresponding Clopper-Pearson (exact binomial) 2-sided 95% confidence interval (CI) will also be provided.
Time-to-event endpoints DOR, TTR, TTNT, PFS and OS will be summarized and displayed graphically using Kaplan-Meier methodology to estimate the median, and the 25th and 75th percentiles if data warrant. Two-sided 95% CIs will be produced. Duration of SD will be summarized descriptively with median, minimum and maximum, also the number and percentage of patients with SD<12 weeks and SD >= 12 weeks will be reported.
An assessment of each study will be made as to whether there is available data for each individual endpoint.
Given most clinical trials do not report on this rare subgroup and thus there is very limited published efficacy data available then it's critical that individual patient data (IPD) is used for this analysis to identify the subgroup of patients with advanced MRCLS who received current SOC trabectedin dosing. We acknowledge that there could be differences between studies, such differences will be inspected and described in the report, and depending on the level of heterogeneity, alternative analysis methods may be used if required.
Narrative Summary:
Myxoid/round cell liposarcoma (MRCLS) is a rare cancer with limited treatment options after standard chemotherapy. Trabectedin is commonly used, but outcomes specific to MRCLS are rarely reported. A prior YODA-approved project identified and analyzed MRCLS patients treated with trabectedin using independent clinical trial data provided by Johnson & Johnson. This study builds on that work by enabling a contextual comparison with MRCLS patients treated with letetresgene autoleucel. The goal is to assess whether outcomes with letetresgene autoleucel are comparable to an established therapy, helping inform treatment options in this rare disease.
Project Timeline:
Key Milestones and timing:
- Anticipated Project start date -- May 2026
- Statistical Analysis Plan (Final) -- Q2 2026
- Statistical Analysis -- Q3 2026
- Provision of report describing results of the Research, which will take the form of an abstract, to Yale University -- Q3 2026
- Provision of report describing results of the Research, which will take the form of a publication, to Yale University -- Q1 2027, at point of submission for publication
o If accepted for publication, provision of final manuscript to Yale University - Upon expiration of the Data User Agreement between Yale University and US Worldmeds
Dissemination Plan:
Dissemination Plan:
- Abstract Submission to ASCO annual meeting June 2027
- Followed by a full manuscript submission in Q4 2027 to Clinical Cancer Research, Cancers or Sarcoma
Bibliography:
Bibliography:
D'Angelo SP, Druta M, Van Tine BA et al. Primary efficacy and safety of letetresgene autoleucel (lete- cel; GSK3377794) pilot study in patients with advanced and metastatic myxoid/round cell liposarcoma (MRCLS). J Clin Oncol. 2022; 40 (16_suppl). doi:10.1200/JCO.2022.40.16_suppl.11500
Demetri GD, von Mehren M, Jones RL, et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016;34(8):786-793. doi:10.1200/JCO.2015.62.4734
Demetri GD, Schöffski P, Grignani G, et al. Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine [published correction appears in J Clin Oncol. 2018 Feb 1;36(4):432]. J Clin Oncol.
2017;35(30):3433-3439. doi:10.1200/JCO.2016.71.6605
Gounder MM, Razak AA, Somaiah N, et al. Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial. J Clin Oncol. 2022;40(22):2479-2490. doi:10.1200/JCO.21.01829
Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA- A*02+ patients: a phase 1 trial. Nat Med. 2023;29(1):104-114. doi:10.1038/s41591-022-02128-z
Mackall C, Tap WD, Glod J et al. Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259t in HLA-A2+ patients with synovial sarcoma (NCT01343043).. J Clin Oncol. 2017; 35(15_suppl). doi:10.1200/JCO.2017.35.15_suppl.3000