Variability of Definitions for Survival Endpoints and Surrogate Properties for OS in Sarcoma Trials: a Meta-analysis (DATECAN-2)

December 30, 2020 updated by: Institut Bergonié

Survival Endpoints in Randomized Clinical Trials in Sarcoma Patients: Meta-analyses for the Assessment of the Impact Various Definitions on Trials' Results and of Surrogate Properties for OS

The DATECAN-2 project aims at assessing the surrogate properties for OS of several time-to-event endpoints through meta-analyses of completed and published randomized controlled trials. Two main cancer localization are concerned: breast cancer and soft-tissue sarcomas. The impact of survival endpoints' definitions on the trials' results and conclusions will also be evaluated.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background: In randomized phase III cancer clinical trials, the validated and most objectively defined evaluation criterion is overall survival (OS). Therapeutic progress, which in certain contexts has significantly reduced overall mortality, the development of new types of cytostatic treatments (as opposed to cytotoxic treatments), the current context of strategic trials and the multiplication of lines of treatment have resulted in the necessity of creating new evaluation criteria measuring treatment efficacy sooner and more precisely: for example, progression-free survival in second line treatment, duration of local control, and time until treatment failure. These types of surrogate endpoints are commonly used in phase II trials but are increasingly being used to replace overall survival in phase III trials. Their development is strongly influenced by the necessity of reducing clinical trial duration, cost and number of patients.

However while these survival endpoints are frequently used, they are often poorly defined and when they are, the definition can vary between trials. The lack of standardized definitions constitutes a clear limitation to their use as primary endpoints. Furthermore, this variability of definitions can have an important impact on trials' results by affecting power and estimation.

The ongoing DATECAN-1 project is aimed at providing guidelines for the definitions of survival endpoints in cancer trials (2009-2011 grant from the French League Against Cancer). Standardized recommendations will be available for survival endpoints commonly used for various cancer sites including pancreas, sarcomas and GIST (gastro-intestinal stromal tumors), breast, stomach.

Objectives: Following these guidelines, one can wonder how sensitive are these definitions? Or similarly, how do survival endpoints' definitions impact the conclusions of clinical trials? The objective of the DATECAN-2 study is to assess the impact of survival endpoints' definitions, as defined by the consensus guidelines, on trials' results and conclusions. The second objective is to study the surrogate properties for OS of these survival endpoints.

Methods: The evaluation of the impact of the variability of the definitions of survival endpoints on the results of clinical trials will be evaluated using individual data from datasets collected in the context of published (academic) clinical trials, as well as simulated datasets.

After approval by the sponsors, data will be analyzed using various endpoints' definitions including (i) the definition provided in the publication and (ii) the definition provided by the guidelines. We will identify which survival endpoint, as defined by the guidelines, was reported in the publication. Next, realistic data sets will be simulated that mimic data that could be observed in randomized cancer trials. We will generate data sets with varying proportions of events (number of deaths, progression, etc) depending on the survival endpoints of interest. Survival endpoints will be compared across treatment arms using the definition provided by the guidelines, and based on various scenarios (different proportions of events, length of follow-up, etc).

Using data from published data sets, we will evaluate survival endpoints in terms of surrogate candidates for OS. A hierarchy of the survival endpoints will be proposed according to their surrogate properties based on two criteria: the Fleming classification and the R2 value for validated surrogates. Depending on the number of clinical trials, single-trial or multiple-trials method will be employed. Single-trial methodology relies on Prentice criteria and Freedman's proportion of treatment effect (PTE) explained by the surrogate. In case of multiple trials, and when meta-analysis of clinical trials is feasible, surrogacy of candidate endpoints for OS will also be explored using weighted linear regression, which jointly estimates the level of association between endpoints and the trial-level association (R²) between treatment effects on the candidate surrogate and the final endpoint. Based on these results (R² and PTE), survival endpoints will be ranked according to their surrogate capabilities for OS.

Expected results: Analysis of the sensitivity of clinical trials' results to the survival endpoints' definitions and surrogacy properties are key features when designing and conducting clinical trials. Based on our results, we will be able to anticipate the expected impact of the definitions on effect size, sample size and power. We will be able to estimate these parameters more precisely and as such provide more efficient estimations. Similarly our assessment of the surrogate properties of the survival endpoints should help us for the selection of the best surrogate marker for OS, and thus limit biases. Overall, by producing less biased results and more efficient designs, our project should have an important role in the design and conduct of future randomized trials.

Study Type

Observational

Enrollment (Actual)

2846

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients included in phase III randomized clinical trials assessing patients with metastatic soft-tissue sarcoma

Description

No patient will be included.

This project concern Phase III clinical trials with following criteria :

Inclusion Criteria:

  • Phase III clinical trials that included overall survival (OS) as endpoint and another time-to-event endpoint as primary or secondary endpoint
  • Phase III clinical trials that included patients with metastatic soft tissue sarcoma

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Patients with a metastatic soft tissue sarcoma
All patients included in eligible clinical trials of the meta-analysis
Drug: undefined
Chemotherapy drug (meta-analyses of randomized trials)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: up to 18 months following randomization
Number of deaths
up to 18 months following randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival
Time Frame: Up to 12 months following randomization
Number of progressions or deaths. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Up to 12 months following randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institut Bergonié

Collaborators

National Cancer Institute, France
Institut du Cancer de Montpellier - Val d'Aurelle
Centre Georges Francois Leclerc
Ligue contre le cancer, France

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (ACTUAL)

January 1, 2017

Study Completion (ACTUAL)

January 1, 2017

Study Registration Dates

First Submitted

August 9, 2016

First Submitted That Met QC Criteria

August 16, 2016

First Posted (ESTIMATE)

August 22, 2016

Study Record Updates

Last Update Posted (ACTUAL)

January 25, 2021

Last Update Submitted That Met QC Criteria

December 30, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IB2012-DATECAN-2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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