RAPID: Phase 2 Platform Trial Of Promising Drugs For AYA Patients With R/R 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:

• 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.
• Median progression-free survival (PFS) for each treatment arm will be compared to each sarcoma subtype's historical control arm.
• Overall survival (OS) for each treatment arm.
• Investigational Agent Safety Determine the incidence of adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities for each investigational agent tested.
• 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.
• 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.
• 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.

Exploratory Objectives:

• Disease control rate (DCR) at 3 months. Prospectively validate existing unpublished data that suggests 3-month DCR (non-progression rate) is equal or superior to ORR in predicting the PFS and OS, particularly for cytostatic investigational agents more likely to induce tumor stability than regression.
• Predictive and Prognostic Indices Build predictive and prognostic indices based on exploratory radiological and protein biomarkers to predict ORR, DCR, PFS, and OS. This may involve longitudinal modeling by UT MD Anderson's IDSO in close collaboration with radiology and pathology experts.
• Biological Specimen Resource and Imaging Database Initiate the creation of a Biological Specimen Repository, consisting of tumor tissue, RNA, DNA, serum, and cells, as well as corresponding PET/CT and pathology images correlated with these specimens for ongoing translational studies in genomics, proteomics, and imaging to establish their relationship to PFS, DCR, and OS.
• Clonal Evolution and Adaptation to Therapy To investigate how tumors and circulating tumor cells evolve to survive and evade chemotherapy.
• Develop a Decision Support System (DSS) to optimize the prioritization of future drugs for inclusion in the RAPID platform trial.

The intent of the DSS is to improve the criteria used by the ASC to prioritize drugs or biologics for potential investigation within RAPID. Among various possible methods, the DSS may re-weight how preclinical models (e.g., cell lines, xenografts, PDXs) and clinical correlates (biopsies, patient-derived organoids, or in-situ microdevice data) are used to select drugs based upon their reliability in predicting clinical efficacy.

Inclusion criteria

Eligibility Criteria

A. Age ≥ 10 years (Safety data from ≥3 adult patients must exist before enrolling children).

B. Must have relapsed or chemo-refractory ES, DSRCT, or SRCS. C. Must have received at least 2 prior chemotherapy regimens (typically VIDE or VDC/IE) D. Measurable disease by RECIST (i.e., tumor ≥1 cm in minimal dimension) E. ECOG performance status is 0-2 for adults (Karnofsky/Lansky score ≥60 for children <16 years of age) F. >1 week washout period from any investigational agent and resolution of drug-related AE/SAE to ≤ grade 2.

Exclusion criteria

A. Uncontrolled or severe cardiac, neurologic, pulmonary, pancreatic, renal, or liver disease.

B. No known personal family history of Long QT syndrome C. History of organ transplant (other than autologous stem cell transplant for cancer), active pneumonitis, myelodysplastic syndrome, or leukemia (acute or chronic) D. Immune or auto-immune-related disorders requiring treatment (treatment for eczema is allowed) E. Investigational agents within 7 days of starting study treatment. F. Major surgery within 28 days before treatment consent (Treatment cannot start with a persistent open wound) G. Leptomeningeal disease or untreated brain metastases. H. Unable to safely hold anticoagulant medication, if taken, for biopsy. I. Psychiatric illness/social situations that would limit compliance with study requirements.

J. Prisoners or participants who are legally institutionalized.