Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

  • End date
    Dec 31, 2022
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 24 July 2022
ct scan
platelet count
neutrophil count
tumor cells
cancer chemotherapy
soft tissue sarcoma


This phase Ib trial studies the side effects of navtemadlin and radiation therapy in treating patients with soft tissue sarcoma. Navtemadlin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving navtemadlin 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 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.


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).


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.

Condition Resectable Soft Tissue Sarcoma, Soft Tissue Sarcoma
Treatment radiation therapy, laboratory biomarker analysis, pharmacological study, MDM2 Inhibitor AMG-232, MDM2 Inhibitor KRT-232, Navtemadlin
Clinical Study IdentifierNCT03217266
SponsorNational Cancer Institute (NCI)
Last Modified on24 July 2022


Yes No Not Sure

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 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
TP53 sequencing by NGS performed by central pathology lab
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

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
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
The patient has a serious cardiac condition, such as congestive heart failure; New
York Heart Association class II/ III/IV heart disease; unstable angina
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)
pectoris, cardiac stenting within 6 months of enrollment; myocardial
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)
infarction within the last 3 months; valvulopathy that is severe, moderate, or
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
deemed clinically significant; or arrhythmias that are symptomatic or require
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
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
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
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