MDM2 Inhibitor AMG-232 (KRT-232) and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03217266|
Recruitment Status : Recruiting
First Posted : July 14, 2017
Last Update Posted : June 11, 2021
|Condition or disease||Intervention/treatment||Phase|
|Soft Tissue Sarcoma||Drug: MDM2 Inhibitor KRT-232 Radiation: Radiation Therapy||Phase 1|
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 radiotherapy.
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 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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||46 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib Trial of Neoadjuvant AMG 232 (KRT-232) Concurrent With Preoperative Radiotherapy in Wild-Type P53 Soft Tissue Sarcoma (STS)|
|Actual Study Start Date :||November 3, 2017|
|Estimated Primary Completion Date :||December 31, 2022|
|Estimated Study Completion Date :||December 31, 2022|
Experimental: Treatment (MDM2 inhibitor KRT-232, radiation therapy)
Patients receive MDM2 inhibitor KRT-232 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.
Drug: MDM2 Inhibitor KRT-232
Radiation: Radiation Therapy
Undergo radiation therapy
- Maximum tolerated dose/recommended phase 2 dosage [ Time Frame: At 4 weeks after treatment completion ]
- Local failure [ Time Frame: At 2 years ]Will be described by cumulative incidence plots or descriptive statistics.
- Disease free survival [ Time Frame: At 2 years ]Will be described with Kaplan-Meier plots.
- Overall survival [ Time Frame: At 2 years ]Will be described with Kaplan-Meier plots.
- Tumor genetic mutations in cell-free circulating tumor deoxyribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
- Serial serum macrophage inhibitory cytokine-1 levels [ Time Frame: Up to 2.5 years ]Will be tabulated and descriptive statistics and calculated for each dose level.
- AMG 232 (KRTI-232) exposure-response relationships [ Time Frame: Up to 2.5 years ]
- Percent of necrosis in final surgical resection specimen [ Time Frame: At 2 years ]Will be summarized using binomial proportions.
- Pathologic complete response in final surgical resection specimen [ Time Frame: At 2 years ]Will be summarized using binomial proportions.
- Tumor volume changes [ Time Frame: Up to 2.5 years ]Will be compared by paired t test.
- Clinical outcomes by genomic biomarkers [ Time Frame: Up to 2.5 years ]
- mdm2/4 expression [ Time Frame: Up to 2.5 years ]Will be correlated with protein levels and assessed using Pearson's correlation.
- Tumor genetic mutations in deoxyribonucleic acid ribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03217266
|Principal Investigator:||Meng X Welliver||NRG Oncology|