Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma
NCT ID: NCT03217266
Last Updated: 2025-09-23
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1
39 participants
INTERVENTIONAL
2018-06-20
2025-09-04
Brief Summary
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Detailed Description
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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 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: Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy (RT) daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
GROUP II: Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
After completion of study treatment, patients are followed up every 3 months for 2 years, and then at 2.5 years.
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Step 1 (tumor tissue testing, navtemadlin)
Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-4, days 2-5, or days 1-5 of weeks 1 to 5 in the absence of disease progression or unacceptable toxicity.
Navtemadlin
Given PO
Radiation Therapy
Undergo radiation therapy
Step 2, Group I (navtemadlin, radiation therapy, surgery)
Starting with week 2, patients receive navtemadlin as in Step 1 and undergo RT daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Navtemadlin
Given PO
Radiation Therapy
Undergo radiation therapy
Surgical Procedure
Undergo surgery
Step 2, Group II (radiation therapy, surgery)
Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Radiation Therapy
Undergo radiation therapy
Surgical Procedure
Undergo surgery
Interventions
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Navtemadlin
Given PO
Radiation Therapy
Undergo radiation therapy
Surgical Procedure
Undergo surgery
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Appropriate stage for study entry based on the following diagnostic workup:
* History/physical examination within 30 days prior to registration;
* Imaging of the primary tumor by MRI and/or computed tomography (CT) with or without contrast and/or positron emission tomography (PET)/CT within 30 days prior to registration;
* Staging workup evaluated by chest CT and/or PET/CT showing no distant metastasis within 30 days prior to registration
* There is a planned definitive surgical resection of the primary tumor
* Eastern Cooperative Oncology Group (ECOG) or Zubrod performance status of 0-1 within 30 days prior to registration
* Absolute neutrophil count \>= 1500/uL (within 30 days prior to registration)
* Platelet count \>= 100,000/uL (within 30 days prior to registration)
* Hemoglobin: \>= 10 g/dL (transfuse as necessary to raise levels; no transfusions within 7 days of start) (within 30 days prior to registration)
* Calculated creatinine clearance \>= 60 ml/min (by Cockcroft-Gault formula) within 30 days prior to registration
* The patient has an adequate coagulation function as defined by international normalized ratio (INR) =\< 1.5 x upper limit of normal (ULN) or prothrombin time (PT) =\< 1.5 x ULN, and partial thromboplastin time (PTT or aPTT) =\< 1.5 x ULN (those receiving anticoagulation therapy except low molecular weight heparin are excluded) (within 30 days prior to registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) appropriate for age (except for patients with Gilbert's syndrome, who must have a total bilirubin \< 3 mg/dL) (within 30 days prior to registration)
* Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) or serum glutamate pyruvate transaminase (SGPT) alanine aminotransaminase (ALT) \< 2.5 upper limit of normal (ULN) appropriate for age (within 30 days prior to registration)
* Females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; exceptions: females not of child-bearing potential due to surgical sterilization (at least 6 weeks following tubal ligation, hysterectomy, or surgical bilateral oophorectomy with or without hysterectomy) confirmed by medical history; or female after menopause
* A "postmenopausal woman" is a woman meeting either of the following criteria:
* Spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators \[SERMs\], or chemotherapy)
* Spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level \> 40 mIU/mL
* Females of child-bearing potential and males must agree to use highly effective contraceptive precautions during the trial and up to 12 months following the last dose of study treatment; a highly effective method of birth control is defined as one that results in a low failure rate (that is, \< 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner
* The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
* TP53 sequencing by NGS performed by central pathology lab
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to AMG 232 (KRT-232)
* All subjects must agree to stop the use of all herbal medicines (e.g., St. John's wort), and supplements, within the 10 days prior to receiving the first dose of AMG 232 (KRT-232), and during the protocol AMG 232 (KRT-232) treatment (weeks 1-5); subjects may renew the use of the above at week 6; standard adult multi-vitamin is allowed
* All subjects must agree to stop the use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfenadine; within the 14 days prior to receiving the first dose of AMG 232 (KRT-232) and during protocol AMG 232 (KRT-232) treatment (weeks 1-5); other medications (such as fentanyl and oxycodone) may be allowed per investigator's assessment/evaluation
* All subjects must agree to stop the use of any known CYP2C8 substrates with a narrow therapeutic window within the 14 days prior to receiving the first dose of AMG 232 (KRT-232) and during protocol AMG 232 (KRT-232) treatment (weeks 1-5)
* All subjects are required to submit a list of medications consumed within 14 days prior to receiving the first dose of AMG232 (KRT-232) and during the protocol AMG232 (KRT-232) treatment (weeks 1-5)
* Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis), therefore could affect the absorption of AMG 232 (KRT-232) at the discretion of treating physician
* Patients with active infection requiring intravenous (IV) antibiotics within 2 weeks of registration
* Patients with known positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable hepatitis C virus RNA by a polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is generally done by hepatitis C antibody (HepCAb), followed by hepatitis C virus RNA by PCR if HepCAb is positive)
* Patients known to be positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:
* A stable regimen of highly active anti-retroviral therapy (HAART)
* No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
* A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based test
* HIV testing is not required
* Treatment with medications known to cause corrected QT (QTc) interval prolongation within 7 days of study day 1 is not permitted unless approved by the sponsor; use of ondansetron is permitted for treatment of nausea and vomiting
Exclusion Criteria
* Definitive clinical or radiologic evidence of metastatic disease; indeterminant lung nodules less than 8 mm are acceptable
* The patient has history of another primary malignancy, with the exception of
* Curatively treated non-melanomatous skin cancer;
* Curatively treated cervical carcinoma in situ;
* Non-metastatic prostate cancer
* Other primary non-hematologic malignancies or solid tumor treated with curative intent, no known active disease, and no treatment administered during the last 3 years prior to registration
* The patient has a serious cardiac condition, such as congestive heart failure; New York Heart Association class II/ III/IV heart disease; unstable angina pectoris, cardiac stenting within 6 months of enrollment; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatment
* Females who are pregnant or breastfeeding
* Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
18 Years
ALL
No
Sponsors
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NRG Oncology
OTHER
National Cancer Institute (NCI)
NIH
Responsible Party
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Principal Investigators
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Meng X Welliver
Role: PRINCIPAL_INVESTIGATOR
NRG Oncology
Locations
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CTCA at Western Regional Medical Center
Goodyear, Arizona, United States
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
Poudre Valley Hospital
Fort Collins, Colorado, United States
Emory University Hospital Midtown
Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
Northside Hospital
Atlanta, Georgia, United States
CTCA at Southeastern Regional Medical Center
Newnan, Georgia, United States
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, United States
Northwestern University
Chicago, Illinois, United States
Rush University Medical Center
Chicago, Illinois, United States
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, United States
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Siteman Cancer Center-South County
St Louis, Missouri, United States
Benefis Sletten Cancer Institute
Great Falls, Montana, United States
Logan Health Medical Center
Kalispell, Montana, United States
Nebraska Methodist Hospital
Omaha, Nebraska, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Eastern Regional Medical Center
Philadelphia, Pennsylvania, United States
UPMC-Shadyside Hospital
Pittsburgh, Pennsylvania, United States
Parkland Memorial Hospital
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, United States
Aurora Cancer Care-Southern Lakes VLCC
Burlington, Wisconsin, United States
Aurora Health Center-Fond du Lac
Fond du Lac, Wisconsin, United States
Aurora Health Care Germantown Health Center
Germantown, Wisconsin, United States
Aurora Cancer Care-Grafton
Grafton, Wisconsin, United States
Aurora BayCare Medical Center
Green Bay, Wisconsin, United States
Aurora Cancer Care-Kenosha South
Kenosha, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, United States
Aurora Bay Area Medical Group-Marinette
Marinette, Wisconsin, United States
Aurora Cancer Care-Milwaukee
Milwaukee, Wisconsin, United States
Aurora Saint Luke's Medical Center
Milwaukee, Wisconsin, United States
Aurora Sinai Medical Center
Milwaukee, Wisconsin, United States
Vince Lombardi Cancer Clinic - Oshkosh
Oshkosh, Wisconsin, United States
Aurora Cancer Care-Racine
Racine, Wisconsin, United States
Vince Lombardi Cancer Clinic-Sheboygan
Sheboygan, Wisconsin, United States
Aurora Medical Center in Summit
Summit, Wisconsin, United States
Vince Lombardi Cancer Clinic-Two Rivers
Two Rivers, Wisconsin, United States
Aurora Cancer Care-Milwaukee West
Wauwatosa, Wisconsin, United States
Aurora West Allis Medical Center
West Allis, Wisconsin, United States
Countries
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References
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Vatner R, James CD, Sathiaseelan V, Bondra KM, Kalapurakal JA, Houghton PJ. Radiation therapy and molecular-targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges. Pediatr Blood Cancer. 2021 May;68 Suppl 2:e28439. doi: 10.1002/pbc.28439. Epub 2020 Aug 22.
Elzanowska J, Semira C, Costa-Silva B. DNA in extracellular vesicles: biological and clinical aspects. Mol Oncol. 2021 Jun;15(6):1701-1714. doi: 10.1002/1878-0261.12777. Epub 2020 Aug 19.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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NCI-2017-01234
Identifier Type: REGISTRY
Identifier Source: secondary_id
NRG-DT001
Identifier Type: OTHER
Identifier Source: secondary_id
NRG-DT001
Identifier Type: OTHER
Identifier Source: secondary_id
NCI-2017-01234
Identifier Type: -
Identifier Source: org_study_id
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