This phase Ib trial studies the side effects of MDM2 inhibitor AMG-232 (KRT-232) and
radiation therapy in treating patients with soft tissue sarcoma. MDM2 inhibitor AMG-232
(KRT-232) may stop the growth of cancer cells by blocking some of the enzymes needed for cell
growth. Giving MDM2 inhibitor AMG-232 (KRT-232) and radiation therapy before surgery may make
the tumor smaller and reduce the amount of normal tissue that needs to be removed.
I. To evaluate the safety and tolerability of MDM2 inhibitor KRT-232 (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
I. To observe and record anti-tumor activity. II. To determine % 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).
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
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
OUTLINE: This is a dose escalation study.
Patients receive MDM2 inhibitor KRT-232 orally (PO) on day 2, days 2 and 4, days 2-4, days
2-5, or days 1-5 of weeks 1 to 5. Patients also undergo radiation therapy daily on weeks 1-5.
Treatment continues 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.
Connective and Soft Tissue Neoplasm,
All Solid Tumors,
Soft Tissue Sarcoma,
soft tissue sarcomas
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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