NRG-DT001 phase Ib trial of neoadjuvant navtemadlin (previously AMG232 and KRT232) concurrent with preoperative radiotherapy in wild-type p53 soft tissue sarcoma of the extremity and body wall.
Authors: Welliver Meng Xu , Torres-Saavedra Pedro A. , Van Tine Brian Andrew , Kirsch David G. , Rudek Michelle A. , Wakely Paul , Schwartz Gary K. , Pollock Raphael E. , Kane John Michael , Jiang Steve B. , Rogers Alan D. , Houghton Peter , Batus Marta , Johnston Andrea Lea , Spraker Matthew , Howell Krisha , Harris Jonathan , Wang Dian 
Published: June 2022

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Background: NRG-DT001 is a phase Ib trial evaluating neoadjuvant navtemadlin with preoperative radiation therapy (RT) in patients (pts) with wild-type (WT) p53 soft tissue sarcoma (STS). The primary objective is to evaluate the safety and tolerability of the MDM2 inhibitor navtemadlin in combination with standard-dose RT in STS in two cohorts (A, extremity or body wall; B, abdomen/pelvis/retroperitoneum) to determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of navtemadlin in combination with RT. This report contains the results for cohort A. Methods: Eligible pts had grade 2-3 STS ≥ 5 cm, age ≥ 18, and Zubrod performance status 0-1. Dose levels were 120 mg 2x/week (DL-1), 120 mg 3x/week (DL1), 4x/week (DL2), and 5x/week (DL3) 1 week prior to and during RT (50Gy/5 weeks). Surgery was 5-8 weeks after RT. A 3+3 design was used to make dose escalation/de-escalation decisions at each dose level. Five additional pts were enrolled to the MTD to ensure safety (expansion cohort) with a dose limiting toxicity (DLT) rate of ≤ 1/5 considered safe. The DLT observation period was from the start of navtemadlin until 4 weeks after completion of drug+RT. Tumor Tp53 mutation status was determined by NGS sequencing. All eligible and treated p53 WT pts who experienced DLT or completed the observation period were considered DLT-evaluable. DLT included all grade 4-5 AE definitely, probably, or possibly related to navtemadlin. Any grade 3 AE definitely, probably, or possibly related to navtemadlin was also considered DLT if any of the 2 following situations occurred: a delay of treatment > 2 weeks or ≥ 2 dose reductions due to the grade 3 AE. The decision to escalate or de-escalate was made by consensus of the study team in accordance with the protocol. Results: Between 11/3/2017 and 9/10/2021, 4 (3 WT), 7 (4 WT) and 7 (4 WT) pts were enrolled at DL1, DL2, and DL3 respectively. An additional 9 (5 WT) pts were enrolled on DL3 expansion cohort. Preoperative RT was completed for all except 1 pt (pt refusal/DL3). On DL1 and DL2, 100% of pts completed navtemadlin. On DL3 (including expansion cohort), 78% (7/9) completed navtemadlin (1 AE, 1 pt refusal). On DL1, DL2, and DL3, 3/3, 3/4 (1 disease progression), and 5/6 (1 consent withdrawal; 3 pending) completed surgery. There were no DLTs in any dose level (DL1 0/3, DL2 0/4, DL3 0/9), establishing DL3 as the MTD/RP2D. Tumor necrosis rates will be reported at the time of presentation. Conclusions: Neoadjuvant navtemadlin concurrent with standard dose preoperative RT is well tolerated in patients with WT p53 STS at extremity or body wall, and the 120 mg PO daily of navtemadlin, 5 days per week dose should be used to design future trials of RT with extremity STS. Incorporating NGS sequencing results as an integral biomarker in a clinical trial of neoadjuvant radiotherapy and a radiosensitizer is feasible. Clinical trial information: NRG-DT001 NCT03217266.