Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

NCT03217266 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2017-01234NRG-DT001U10CA180868
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 53

Brief Summary

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.

Conditions

Resectable Soft Tissue Sarcoma; Soft Tissue Sarcoma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dosage for Each Cohort

  Dose was determined separately for each cohort using the classic 3+3 design to determine the safety of each dose level from the number of participants with dose limiting toxicities (DLTs), starting with dose level 1. If dose level 1 were considered unsafe, a lower dose level of twice/week would be tested. The highest dose level deemed safe is considered the MTD. Five additional patients were accrued to the MTD to ensure safety. A DLT is defined as any grade 4-5 adverse event (AE) using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) that was definitely, probably, or possibly (DPP) related to navtemadlin or combined navtemadlin+RT ≤ 4 weeks after completing navtemadlin. Any grade 3 AE DPP related to navtemadlin/navtemadlin+RT was also considered a DLT if due to the grade 3 AE there was a delay of \>2 weeks or if there were ≥ 2 dose reductions. CTCAE 5.0 Grade 3 is a severe AE, Grade 4 is a life-threatening or disabling AE, and Grade 5 results in death.

  Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total)

• Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)

  A DLT is defined as any grade 4-5 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) that was definitely, probably, or possibly related to navtemadlin or combined navtemadlin+RT up to 4 weeks after the completion of navtemadlin. Any grade 3 AE definitely, probably, or possibly related to navtemadlin or combined navtemadlin+RT was also considered DLT if any of the 2 following situations occurred: a delay of \>2 weeks due to the grade 3 AE, or ≥ 2 dose reductions due to the grade 3 AE. CTCAE 5.0 Grade 3 is a severe AE, Grade 4 is a life-threatening or disabling AE, and Grade 5 results in death.

  Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total)

Secondary Outcomes (7)

• Percent of Necrosis in Final Surgical Resection Specimen

  At time of surgery (approximately 11 to 14 weeks)

• Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen

  At time of surgery (approximately 11 to 14 weeks)

• Number of Participants With Local Failure

  Baseline to the date of failure or last known follow-up, up to 2.5 years from end of RT (six weeks).

• Number of Participants With Disease or Death From Any Cause

  Baseline to the date of disease, death, or last known follow-up, up to 2.5 years from end of RT (six weeks).

• Number of Participants Who Died

  Baseline to the date of death or last known follow-up, up to 2.5 years from end of RT (six weeks).

Other Outcomes (4)

• Tumor Volume Changes

  Up to 2.5 years

• Clinical Outcomes by Genomic Biomarkers

  Up to 2.5 years

• mdm2/4 Expression

  Up to 2.5 years

Study Arms (3)

Step 1 (tumor tissue testing, navtemadlin)

EXPERIMENTAL

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.

Drug: Navtemadlin; Radiation: Radiation Therapy

Step 2, Group I (navtemadlin, radiation therapy, surgery)

EXPERIMENTAL

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.

Drug: Navtemadlin; Radiation: Radiation Therapy; Procedure: Surgical Procedure

Step 2, Group II (radiation therapy, surgery)

EXPERIMENTAL

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: Radiation Therapy; Procedure: Surgical Procedure

Interventions

Navtemadlin DRUG

Given PO

Also known as: (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-2-methyl-1-(((1-methylethyl)sulfonyl)methyl)propyl)-2-oxo-3-piperidineacetic Acid, AMG 232, AMG-232, KRT 232, KRT-232, KRT232, MDM2 Inhibitor KRT-232

Step 1 (tumor tissue testing, navtemadlin); Step 2, Group I (navtemadlin, radiation therapy, surgery)

Radiation Therapy RADIATION

Undergo radiation therapy

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Step 1 (tumor tissue testing, navtemadlin); Step 2, Group I (navtemadlin, radiation therapy, surgery); Step 2, Group II (radiation therapy, surgery)

Surgical Procedure PROCEDURE

Undergo surgery

Also known as: Operation, Surgery, Surgery Type, Surgery, NOS, Surgical, Surgical Intervention, Surgical Interventions, Surgical Procedures, Type of Surgery

Step 2, Group I (navtemadlin, radiation therapy, surgery); Step 2, Group II (radiation therapy, surgery)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• 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)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• NRG Oncology: collaborator

Study Sites (53)

CTCA at Western Regional Medical Center

Goodyear, Arizona, 85338, United States

Location

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic in Arizona

Scottsdale, Arizona, 85259, United States

Location

University of Arizona Cancer Center-Orange Grove Campus

Tucson, Arizona, 85704, United States

Location

University of Arizona Cancer Center-North Campus

Tucson, Arizona, 85719, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Poudre Valley Hospital

Fort Collins, Colorado, 80524, United States

Location

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Northside Hospital

Atlanta, Georgia, 30342, United States

Location

CTCA at Southeastern Regional Medical Center

Newnan, Georgia, 30265, United States

Location

Saint Alphonsus Cancer Care Center-Boise

Boise, Idaho, 83706, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, 66210, United States

Location

The James Graham Brown Cancer Center at University of Louisville

Louisville, Kentucky, 40202, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, 63141, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Siteman Cancer Center-South County

St Louis, Missouri, 63129, United States

Location

Benefis Sletten Cancer Institute

Great Falls, Montana, 59405, United States

Location

Logan Health Medical Center

Kalispell, Montana, 59901, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, 10032, United States

Location

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Eastern Regional Medical Center

Philadelphia, Pennsylvania, 19124, United States

Location

UPMC-Shadyside Hospital

Pittsburgh, Pennsylvania, 15232, United States

Location

Parkland Memorial Hospital

Dallas, Texas, 75235, United States

Location

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, 75390, United States

Location

Aurora Cancer Care-Southern Lakes VLCC

Burlington, Wisconsin, 53105, United States

Location

Aurora Health Center-Fond du Lac

Fond du Lac, Wisconsin, 54937, United States

Location

Aurora Health Care Germantown Health Center

Germantown, Wisconsin, 53022, United States

Location

Aurora Cancer Care-Grafton

Grafton, Wisconsin, 53024, United States

Location

Aurora BayCare Medical Center

Green Bay, Wisconsin, 54311, United States

Location

Aurora Cancer Care-Kenosha South

Kenosha, Wisconsin, 53142, United States

Location

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, 53792, United States

Location

Aurora Bay Area Medical Group-Marinette

Marinette, Wisconsin, 54143, United States

Location

Aurora Cancer Care-Milwaukee

Milwaukee, Wisconsin, 53209, United States

Location

Aurora Saint Luke's Medical Center

Milwaukee, Wisconsin, 53215, United States

Location

Aurora Sinai Medical Center

Milwaukee, Wisconsin, 53233, United States

Location

Vince Lombardi Cancer Clinic - Oshkosh

Oshkosh, Wisconsin, 54904, United States

Location

Aurora Cancer Care-Racine

Racine, Wisconsin, 53406, United States

Location

Vince Lombardi Cancer Clinic-Sheboygan

Sheboygan, Wisconsin, 53081, United States

Location

Aurora Medical Center in Summit

Summit, Wisconsin, 53066, United States

Location

Vince Lombardi Cancer Clinic-Two Rivers

Two Rivers, Wisconsin, 54241, United States

Location

Aurora Cancer Care-Milwaukee West

Wauwatosa, Wisconsin, 53226, United States

Location

Aurora West Allis Medical Center

West Allis, Wisconsin, 53227, United States

Location

Related Publications (2)

• 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.

  PMID: 32827353 DERIVED

• 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.

  PMID: 32767659 DERIVED

MeSH Terms

Conditions

Sarcoma

Interventions

navtemadlin; 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; 2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; Radiotherapy; Radiation; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Therapeutics; Physical Phenomena

Limitations and Caveats

Dose escalates independently in each cohort (extremity/body wall; abdomen/pelvis/retroperitoneum). All participants begin one week of treatment at Step 1 while p53 determination takes place. At Step 2, participants with wild-type p53 continue study drug for purpose of study analysis. The rest discontinue study drug and are not included in study analysis; only collected AEs are reported. Study accrual stopped early due to poor accrual, therefore the third dose level did not open for Cohort B.

Results Point of Contact

• Title: Wendy Seiferheld
• Organization: NRG Oncology

seiferheldw@nrgoncology.org

215-574-3208

Study Officials

• Meng X Welliver

  NRG Oncology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2017
• First Posted: July 14, 2017
• Study Start: June 20, 2018
• Primary Completion: August 27, 2023
• Study Completion: September 4, 2025
• Last Updated: September 23, 2025
• Results First Posted: November 8, 2024

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

US (53)