(P 46) A NEED FOR STANDARDIZATION IN TRIAL DESIGN AND DATA REPORTING IN PHASE II TRIALS IN RARE TUMORS. LESSONS LEARNED FROM PHASE II TRIALS IN BONE SARCOMAS

Objective: Current therapeutic options for advanced and metastatic bone sarcoma (BS) are still limited, and the prognosis is unfavorable. Phase II trials are usually the first opportunity to evaluate the potential efficacy of new agents in this population with high unmet needs. However, there is high variability and no standardization of phase II designs. The selection of a homogenous study population and appropriate endpoints to prove drug activity and improvement in patients' survival are crucial steps in the trial design, also allowing for minimizing the risk of false-positive and false-negative results. We aimed to analyze the current landscape of phase II studies in BS and evaluate how their design can affect the results.

Methods: We have analyzed all phase II studies published between 2010 and 2022. Only studies including patients with bone were included, including studies including soft tissue sarcoma or Ewing sarcoma. Detailed information about study design, endpoints, population, and outcomes were extracted. Outcomes of interest included all primary endpoints, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and 3- and 6-month PFS rates (3mPFS; 6mPFS). For multiarm/multicohort studies, each arm/cohort was analyzed separately. Weight linear regression was used to assess surrogacy with OS.

Results: We identified 39 published studies, including 4 RCTs (1 comparative and 3-non comparative). Overall, 42 single-arm trials/cohorts with 1000 patients were included in the analysis. 61.9% of studies were sponsored by academia or collaborative groups (61.5% of them with support from the pharmaceutical industry), while 35.7% were industry-sponsored. 47.6% (20) included only adult patients, 16.7% (7) adolescents and young adults (AYA) and adults, 21.4% (9) children and AYA, and 14.3% (6) patients regardless of age. The majority, 73.8% (31), were dedicated to pts with osteosarcoma, only 14.3% (6) to chondrosarcoma, 3 to chordoma, and 2 to a mix of histologies. Most trials (61.9%, 26) were conducted in patients failing at least 1 line of palliative systemic therapy. The most tested drugs were targeted agents and chemotherapy, in 50% (21) and 21.4% (9), respectively.
targeted agents and chemotherapy, in 50% (21) and 21.4% (9), respectively.
Over 10 different primary endpoints were used, with ORR as the most common (28.6%, 12), followed by combined endpoints (21.4%, 9), 4mPFS (19.0%, 8), and 3mPFS (11.9%, 5). 19.0% (8) of trials met their primary endpoints. Among positive trials, 37.5% (3) were based on 4mPFS as a primary endpoint and 25.0% (2) on 3mPFS. None of the trials based on ORR has met its primary endpoint. OS was included as an endpoint in 66.7% (28) trials but reported in only 50% (21), while PFS was included in 57.1% (24) and reported in 42.9% (18); any PFS or PFS rate was available in 71.4% (30) trials. Due to the heterogeneity of endpoint reporting, surrogacy analysis was possible to conduct.
88.1% (37) trials provided full statistical assumptions and sample size calculations. 26 trials were designed as two-stage trials—46.2% (12) progressed to the second stage, and 5 met the primary endpoint. Interestingly, the same alternative hypothesis of a PFS rate of 40-45% was used in most trials based on the 3m, 4m, and 6 mPFS rates.

Conclusion: There is high heterogeneity in sarcoma trial designs, mainly in selecting the primary endpoint and hypotheses for size calculation. ORR is the most used primary endpoint in single-arm trials but its surrogacy with OS is not confirmed. Most positive trials were based on PFS rates as the primary endpoint, but there is a high need for standardization and benchmarking to set up thresholds for main endpoints to assess drug efficacy. Moreover, key endpoints like median PFS or OS are not reported in nearly 50% of trials. Overall, there is a high need for the standardization of trial design and the reporting of results so data from all phase II trials, including negative ones, can be used to improve our understanding of BS.