October 12 2021
NRG-DT001: A Phase Ib Trial of Neoadjuvant AMG 232 (KRT-232) Concurrent with Preoperative Radiotherapy in Wild-type P53 Soft Tissue Sarcoma (STS)
NRG-DT001 is an NRG Oncology-conducted phase 1 clinical trial examining the safety and tolerability of the investigational drug AMG 232 (KRT-232), an mdm-2 inhibitor, when combined with standard-dose radiotherapy in patients with soft tissue sarcoma (STS) prior to the patient receiving surgery for their disease. This trial has two cohorts: Cohort A will examine patients with extremity and/or body wall STS, whereas Cohort B will investigate patients with abdomen, pelvis, and/or retroperitoneum STS. Cohort A of this study is temporarily closed to accrual; however, patients are still being enrolled to Cohort B.
Typically patients with soft tissue sarcoma are treated with radiotherapy followed by surgery to remove the rest of the tumor; some patients will even receive additional chemotherapy treatment. NRG-DT001 takes advantage of the fact that the majority of STS harbor wild-type (WT) p53 tumor suppressor gene, and AMG 232 (KRT-232) is only able to effectively block the activation of the mdm-2 gene when p53 is in the wild-type form. Preclinical evidence suggests that combining AMG 232 (KRT-232) with radiotherapy could benefit anti-tumor activity for patients with p53 wild-type STS.
“This is one of the first trials that utilize NGS sequencing results as an integral biomarker, a true example of precision medicine. Only patients with NGS confirmed WT p53 gene would receive experimental therapy because only those patients could potentially benefit from the combined treatment approach based on the preclinical studies. The majority of STS remain asymptomatic for a long time and present as large tumors in various locations in the body, including locations where clean-margin resections are difficult to achieve. It is imperative to find a treatment option to improve the efficacy of cancer cell killing before surgery.” stated Meng Xu Welliver, MD, PhD, of the Department of Radiation Oncology at The Ohio State University James Cancer Center and Principal Investigator of the NRG-DT001 trial.
In addition to examining the safety and tolerability of the investigational drug in this patient population, NRG-DT001 aims to examine anti-tumor activity, percentage of necrosis, and pathologic complete response in final surgical resection specimens. Other secondary objectives include assessing the rate of local failure, disease-free survival, and overall survival at 2 years following treatment. Finally, this trial also aims to evaluate the pharmacodynamics effects of AMG 232 (KRT-232) when combined with radiotherapy and determine AMG 232 (KRT-232) exposure-response relationships with pharmacodynamics, toxicity, and efficacy. The trial also has several exploratory objectives determining the biomarkers associated with this disease in correlation to the investigational drug.
Learn more about this trial on ClinicalTrials.gov
Protocol documents and materials are located on the CTSU website.