Lead Investigator: Yoichi Naito, National Cancer Center Hospital East
Title of Proposal Research: Correlation of doxorubicin dose and survival in patients with soft tissue sarcoma; Data from two studies (a larger phase III study and a smaller phase II study) will be combined and analyzed.
Vivli Data Request: 7399
Funding Source: None
Potential Conflicts of Interest: Research Fund from Eli Lilly (ANNOUCE), Roche
Lecture fee from Novartis, Eisai, Chugai, Pfizer, Kyowahakko Kirin, Fuji RI
Advisory role for Eli Lily, Eisai, Chugai, Pfizer, MSD, AstraZeneca
All the Conflict of Interest regardless of the relationship to the current study are managed by each institutional COI committee and will be declared in the publication.
Summary of the Proposed Research:
Soft tissue sarcomas are rare malignancies arising from connective tissue such as muscle, tendons, fat, lymph vessels, blood vessels, and nerves. Based on the pathological diagnosis more than 100 subtypes of soft tissue sarcoma exist. More than 13,000 new soft tissue sarcomas will be diagnosed in the US each year. Estimated incidence is averaging 4–5/100 000/year in Europe. Such a neglected population in oncology should be intensively explored.
Doxorubicin (DOX) remains the standard of care for advanced soft tissue sarcoma. However, median survival in patients with newly diagnosed advanced soft tissue sarcoma is approximately 14-19 months with two-year survival rates of 20-30%. Consequently, there is an urgent need for new, effective treatments.
Olaratumab (OLA) is a monoclonal antibody (experimentally made antibody with uniform properties) targeting platelet-derived growth factor receptor alpha (PDGFRA) which is a protein that exists on the cell surface and acts as a receptor. In a randomized phase II study (an exploratory trial comparing two treatments) comparing doxorubicin (DOX) plus OLA with DOX alone, adding OLA to DOX showed significant overall survival (OS) benefit (median OS 26.5 months vs 14.7 months, p = 0.0003. This means that adding OLA improved survival by 11.8 months in median). However, a subsequent randomized phase III study ‘ANNOUNCE’ comparing DOX plus OLA with DOX plus placebo failed to demonstrate superiority of OLA (hazard ratio 1.05, median OS 20.4 months vs 19.7 months, p = 0.6945. This means that adding OLA did not improve survival).
The number of treatment cycles was different between the phase II and phase III study, suggesting the importance of treatment cycles and cumulative dose of DOX for advanced soft tissue sarcoma. However, there has been no study exploring the impact of number of cycles or cumulative dose of DOX on the survival.
Combined analysis of individual data from phase II and phase III study will provide the importance of treatment cycles and cumulative dose of DOX for survival of advanced soft tissue sarcoma. Moreover, the difference of impact on survival according to the subtype of soft tissue sarcoma will be demonstrated.
To clarify the importance of treatment cycles and total dose of DOX supports to make shared decision making with patients and treating physicians.
Statistical Analysis Plan:
We searched in the PubMed using the following keywords; “olaratumab”, “sarcoma”, “randomized”. 24 publications were collected. Screened by Lead Researcher, two publications were selected for the current study.
To evaluate the effect of doxorubicin on survival, data will be combined and pooled analyses will be performed.
Our analysis plan does not require maintaining the structure and the independence of the PII and PIII trials.
We will apply common survival analysis methods such as the Kaplan-Meier method, the log-rank test, the Cox regression. Therefore, effect measure is hazard ratio. When there is (time-varying) confounding, we will apply stratification or Inverse probability weighting. In some situations, the proportional hazard assumption may be invalid, we will consider other summary measures such as restricted mean survival time.
We do not assume there is outcome missing other than independent censoring such as administrative censoring. Independent censoring will be treated by common survival analysis methods.
We use common survival analysis methods for outcome-missing data and will exclude covariate-missing data.
Requested Studies:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Doxorubicin Plus Olaratumab Versus Doxorubicin Plus Placebo in Patients With Advanced or Metastatic Soft Tissue Sarcoma
Data Contributor: Lilly
Study ID: NCT02451943
Sponsor ID: 15677
A Phase 1b/2, With Phase 2 Randomized, Study Evaluating the Efficacy of Doxorubicin With or Without a Human Anti-PDGFRα Monoclonal Antibody (IMC-3G3) in the Treatment of Advanced Soft Tissue Sarcoma
Data Contributor: Lilly
Study ID: NCT01185964
Sponsor ID: 14055
Public Disclosures:
Naito, Y., Sakamaki, K., Morita, S., Mukohara, T. and Akimoto, T., 2023. 1923P Combined analysis of phase III ANNOUNCE study and phase II study exploring olaratumab in advanced soft tissue sarcoma. Annals of Oncology, 34, pp.S1034-S1035. doi: 10.1016/j.annonc.2023.09.1152