Navtemadlin and Radiation Therapy in Treating Patients with Soft Tissue Sarcoma

Summary

Objectives

PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of navtemadlin (AMG-232 [KRT-232]) in combination with standard-dose radiotherapy in soft tissue sarcoma (STS) in two separate patient cohorts (A, extremity or body wall; B, abdomen/pelvis/retroperitoneum).
II. To determine the maximum tolerated dose/recommended phase II dose (maximum tolerated dose/recommended phase 2 dosage [MTD/RP2D]) of AMG 232 (KRT-232) in combination with radiotherapy.

SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity.
II. To determine percentage (%) necrosis and pathologic complete response (pCR) in final surgical resection specimen.
III. To determine % local failure (LF), disease free survival (DFS) and overall survival (OS) at 2 years.
IV. To determine pharmacodynamics (PD) effects of AMG 232 (KRT-232) when combined with radiotherapy by assessing serial serum macrophage inhibitory cytokine (MIC)-1 levels.
V. To determine AMG 232 (KRT-232) exposure (pharmacokinetics)-response relationships (PD, toxicity, and efficacy).

EXPLORATORY OBJECTIVES:
I. To determine tumor volume changes determined by magnetic resonance imaging (MRI) or computed tomography (CT) with and without contrast pre- and post-radiotherapy.
II. To characterize clinical outcomes in patients treated with AMG 232 (KRT-232) by genomic biomarkers.
III. To determine the correlation between mdm2/4 expression determined by next-generation sequencing (NGS) and the protein levels by immunohistochemistry (IHC).
IV. To explore the possibility of identifying tumor genetic mutations in (1) cell-free (cf) circulating tumor deoxyribonucleic acid (ctDNA), (2) deoxyribonucleic acid/ribonucleic acid (DNA/RNA) isolated from exosomes, and determine the concordance of these results and that from NGS.

OUTLINE: This is a dose-escalation study of navtemadlin.

STEP 1: Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin orally (PO) on day 2, days 2 and 4, days 2-4, days 2-5, or days 1-5 of weeks 1 to 5 in the absence of disease progression or unacceptable toxicity.

STEP 2: Patients with a wild-type p53 gene status are assigned to Group I, while patients with deleted/mutant p53 gene status are assigned to Group II.

GROUP I: Patients receive navtemadlin as in Step 1 and undergo radiation therapy daily on weeks 1-5 in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients undergo radiation therapy daily on weeks 1-5 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and then at 2.5 years.