Rapid Advancement Of Promising Innovative Drugs (RAPID): A Patient-Centric, Investigator-Initiated, Bayesian, Multi-Center, Open-Label, Phase 2 Platform Trial Of Promising Drugs For AYA Patients With Relapsed/Refractory Ewing Sarcoma & DSRCT

Primary Objective:

Objective response rate (ORR)

Determine the ORR endpoint (CR + PR) by the RECIST 1.1 criterion at three months for each substudy. To confirm sustained tumor shrinkage/disappearance, each patient's complete or partial response will be validated with a follow-up scan at least 4 weeks later, showing the same or better response (i.e., CR or PR for PR; CR for CR).

Secondary Objectives:

1. Duration and depth of objective response. Assess the average duration of response (DOR) and depth of response (CR rate) for patients who achieve an objective response.
2. Median progression-free survival (PFS) for each treatment arm will be compared to each sarcoma subtype's historical control arm.
3. Overall survival (OS) for each treatment arm.
4. Investigational Agent Safety Determine the incidence of adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities for each investigational agent tested.
5. Bayesian predictive probability of obtaining statistical significance if an arm continues enrollment. Simulations compare an inactive agent common control against each arm's investigational agent to determine the probability of obtaining statistical significance at some future sample size, given existing data and assumed prior distributions. Interim analyses conducted after 30, 40, and 50 patients are evaluable aim to predict if a confirmatory study with 240 patients, randomized 1:1 between treatment and placebo or best supportive care will succeed, will succeed, with success defined as reaching statistical significance using a onesided chi-squared, or Fisher's exact test, as appropriate, with a 0.025 significance level, to test for a difference in ORR between the investigational agent and control.
6. Estimate for each experimental agent, the posterior probability that its efficacy is superior to the non-randomized common control arm. An informative prior distribution for the common control arm was calculated using raw, patient-level data from the recently completed, ES-specific TK-216 trial. To maintain an accurate estimate of the ORR for inactive agents as the RAPID study proceeds, the 'inactive agent' common control arm's posterior probability of ORR will be updated each time a substudy drops for futility. This concurrent common control is used to mimic a placebo control, which can't ethically be conducted in the United States, given the highly aggressive nature of the sarcoma subtypes studied. Success of a substudy in the current trial will be defined by a posterior probability ≥ 0.95 of the ORR of the corresponding investigational agent being superior to the common control arm at the end of the substudy.
7. Quality of Life (QOL). Patient-reported QOL assessments evaluate how cancer and its treatment affect a patient's overall well-being, encompassing physical, psychological, social, and functional aspects.