Skip to main content

MDM2 Inhibitor AMG-232 (KRT-232) and Radiation Therapy in Treating Patients with Soft Tissue Sarcoma

Trial Status: Active

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.

Inclusion Criteria

  • PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA
  • Patients with pathologically proven diagnosis of grade 2-3 (intermediate or high grade) soft tissue sarcoma with size >= 5 cm are eligible to enroll if the intention to treat is curative. They must have sufficient tissue to submit to central laboratory for review as well as for NGS sequencing (see submission requirement). Biopsy should be obtained within 180 days prior to registration. Availability of tumor tissue is mandatory for study eligibility. The patient must have consented to provide archived formalin-fixed paraffin-embedded tumor tissue for future central pathology review, NGS sequencing and/or translational research
  • 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 Cockroft-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
  • PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA
  • TP53 sequencing by NGS performed by central pathology lab

Exclusion Criteria

  • PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA
  • Well-differentiated liposarcoma or other low grade STS; Kaposi sarcoma, bone sarcomas, cartilage sarcomas and gastrointestinal stromal tumor (GIST)
  • 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 systemic chemotherapy for the study cancer (sarcoma); note that prior chemotherapy for a different cancer is allowable; however, unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible [defined as having been present and stable for > 6 months], such as ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor)
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Clinically significant bleeding within 4 weeks of screening, current use of warfarin, factor Xa inhibitors, and direct thrombin inhibitors unless these medications can be safely discontinued 14 days prior to AMG-232 (KRT-232) administration; Note: low molecular weight heparin and prophylactic low dose warfarin are permitted; PT/PTT must meet the inclusion criteria; subjects taking warfarin must have their INR followed closely
  • 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 terfanide; 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

Arizona

Goodyear
CTCA at Western Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 623-207-3000
Phoenix
Mayo Clinic Hospital in Arizona
Status: ACTIVE
Contact: Site Public Contact
Phone: 855-776-0015
Scottsdale
Mayo Clinic in Arizona
Status: ACTIVE
Contact: Site Public Contact
Phone: 855-776-0015
Tucson
University of Arizona Cancer Center-North Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-327-2873
University of Arizona Cancer Center-Orange Grove Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 520-694-8900

Colorado

Aurora
University of Colorado Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 720-848-0650
Fort Collins
Poudre Valley Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 970-297-6150

Georgia

Atlanta
Northside Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-303-3355
Newnan
CTCA at Southeastern Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 770-400-6629

Idaho

Boise
Saint Alphonsus Cancer Care Center-Boise
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-3671

Illinois

Chicago
Northwestern University
Status: ACTIVE
Contact: Site Public Contact
Phone: 312-695-1301
Rush University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 312-942-5498

Kansas

Overland Park
University of Kansas Cancer Center-Overland Park
Status: ACTIVE
Contact: Site Public Contact
Phone: 913-588-3671

Kentucky

Louisville
The James Graham Brown Cancer Center at University of Louisville
Status: ACTIVE
Contact: Site Public Contact
Phone: 502-562-3429

Minnesota

Rochester
Mayo Clinic in Rochester
Status: ACTIVE
Contact: Site Public Contact
Phone: 855-776-0015

Missouri

Creve Coeur
Siteman Cancer Center at West County Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606
Saint Louis
Siteman Cancer Center-South County
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606
Washington University School of Medicine
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606

Montana

Great Falls
Benefis Healthcare- Sletten Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 406-969-6060
Kalispell
Kalispell Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 406-969-6060

Nebraska

Omaha
Nebraska Methodist Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 402-354-5144

New Jersey

New Brunswick
Rutgers Cancer Institute of New Jersey
Status: ACTIVE
Contact: Site Public Contact
Phone: 732-235-8675

New York

Buffalo
Roswell Park Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-767-9355
New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-305-6361

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-668-0683

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-293-5066

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 405-271-8777

Pennsylvania

Philadelphia
Eastern Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-339-5294
Fox Chase Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 215-728-4790
Thomas Jefferson University Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 215-955-6084
Pittsburgh
UPMC-Shadyside Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-621-2334

Texas

Dallas
Parkland Memorial Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 214-590-5582
UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Site Public Contact
Phone: 214-648-7097

Wisconsin

Burlington
Aurora Cancer Care-Southern Lakes VLCC
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Fond Du Lac
Aurora Health Center-Fond du Lac
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Germantown
Aurora Health Care Germantown Health Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Grafton
Aurora Cancer Care-Grafton
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Green Bay
Aurora BayCare Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Kenosha
Aurora Cancer Care-Kenosha South
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Madison
University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-622-8922
Marinette
Aurora Bay Area Medical Group-Marinette
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Milwaukee
Aurora Cancer Care-Milwaukee
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Aurora Saint Luke's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Aurora Sinai Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Oshkosh
Vince Lombardi Cancer Clinic - Oshkosh
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Racine
Aurora Cancer Care-Racine
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Sheboygan
Vince Lombardi Cancer Clinic-Sheboygan
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Summit
Aurora Medical Center in Summit
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Two Rivers
Vince Lombardi Cancer Clinic-Two Rivers
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
Wauwatosa
Aurora Cancer Care-Milwaukee West
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304
West Allis
Aurora West Allis Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-302-2304

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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).

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.

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.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
NRG Oncology

Principal Investigator
Meng Xu Welliver

  • Primary ID NRG-DT001
  • Secondary IDs NCI-2017-01234
  • Clinicaltrials.gov ID NCT03217266