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Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Recruiting
CT.gov ID
NCT03217266
Collaborator
NRG Oncology (Other)
46
Enrollment
53
Locations
3
Arms
61.9
Anticipated Duration (Months)
0.9
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

PRIMARY OBJECTIVES:

  1. 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).

  2. 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:

  1. To observe and record anti-tumor activity. II. To determine percentage (%) necrosis and pathologic complete response (pCR) in final surgical resection specimen.

  2. To determine % local failure (LF), disease free survival (DFS) and overall survival (OS) at 2 years.

  3. To determine pharmacodynamics (PD) effects of AMG 232 (KRT-232) when combined with radiotherapy by assessing serial serum macrophage inhibitory cytokine (MIC)-1 levels.

  4. To determine AMG 232 (KRT-232) exposure (pharmacokinetics)-response relationships (PD, toxicity, and efficacy).

EXPLORATORY OBJECTIVES:

  1. To determine tumor volume changes determined by magnetic resonance imaging (MRI) or computed tomography (CT) with and without contrast pre- and post-radiotherapy.

  2. To characterize clinical outcomes in patients treated with AMG 232 (KRT-232) by genomic biomarkers.

  3. To determine the correlation between mdm2/4 expression determined by next-generation sequencing (NGS) and the protein levels by immunohistochemistry (IHC).

  4. 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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
46 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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 :
Nov 3, 2017
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Step 1 (tumor tissue testing, navtemadlin)

Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin 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.

Drug: Navtemadlin
Given PO
Other Names:
  • (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

    • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

    		•
    Experimental: Step 2, Group I (navtemadlin, radiation therapy)

    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.

    Drug: Navtemadlin
    Given PO
    Other Names:
  • (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

    • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

    		•
    Experimental: Step 2, Group II (radiation therapy)

    Patients undergo radiation therapy daily on weeks 1-5 in the absence of disease progression or unacceptable toxicity.

    Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum tolerated dose/recommended phase 2 dosage [At 4 weeks after treatment completion]

    Secondary Outcome Measures

    1. Percent of necrosis in final surgical resection specimen [At 2 years]

      Will be summarized using binomial proportions.

    2. Pathologic complete response in final surgical resection specimen [At 2 years]

      Will be summarized using binomial proportions.

    3. Local failure [At 2 years]

      Will be described by cumulative incidence plots or descriptive statistics.

    4. Disease free survival [At 2 years]

      Will be described with Kaplan-Meier plots.

    5. Overall survival [At 2 years]

      Will be described with Kaplan-Meier plots.

    6. Serial serum macrophage inhibitory cytokine-1 levels [Up to 2.5 years]

      Will be tabulated and descriptive statistics and calculated for each dose level.

    7. AMG 232 (KRTI-232) exposure-response relationships [Up to 2.5 years]

    Other Outcome Measures

    1. Tumor volume changes [Up to 2.5 years]

      Will be compared by paired t test.

    2. Clinical outcomes by genomic biomarkers [Up to 2.5 years]

    3. mdm2/4 expression [Up to 2.5 years]

      Will be correlated with protein levels and assessed using Pearson's correlation.

    4. Tumor genetic mutations in deoxyribonucleic acid ribonucleic acid isolated from exosomes [Up to 2.5 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 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

    • 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 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 CTCA at Western Regional Medical Center Goodyear Arizona United States 85338
    2 Mayo Clinic Hospital in Arizona Phoenix Arizona United States 85054
    3 Mayo Clinic in Arizona Scottsdale Arizona United States 85259
    4 University of Arizona Cancer Center-Orange Grove Campus Tucson Arizona United States 85704
    5 University of Arizona Cancer Center-North Campus Tucson Arizona United States 85719
    6 University of Colorado Hospital Aurora Colorado United States 80045
    7 Poudre Valley Hospital Fort Collins Colorado United States 80524
    8 Emory University Hospital Midtown Atlanta Georgia United States 30308
    9 Emory University Hospital/Winship Cancer Institute Atlanta Georgia United States 30322
    10 Northside Hospital Atlanta Georgia United States 30342
    11 CTCA at Southeastern Regional Medical Center Newnan Georgia United States 30265
    12 Saint Alphonsus Cancer Care Center-Boise Boise Idaho United States 83706
    13 Northwestern University Chicago Illinois United States 60611
    14 Rush University Medical Center Chicago Illinois United States 60612
    15 University of Kansas Cancer Center-Overland Park Overland Park Kansas United States 66210
    16 The James Graham Brown Cancer Center at University of Louisville Louisville Kentucky United States 40202
    17 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    18 Siteman Cancer Center at West County Hospital Creve Coeur Missouri United States 63141
    19 Washington University School of Medicine Saint Louis Missouri United States 63110
    20 Siteman Cancer Center-South County Saint Louis Missouri United States 63129
    21 Benefis Healthcare- Sletten Cancer Institute Great Falls Montana United States 59405
    22 Kalispell Regional Medical Center Kalispell Montana United States 59901
    23 Nebraska Methodist Hospital Omaha Nebraska United States 68114
    24 Rutgers Cancer Institute of New Jersey New Brunswick New Jersey United States 08903
    25 Roswell Park Cancer Institute Buffalo New York United States 14263
    26 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    27 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    28 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    29 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    30 Thomas Jefferson University Hospital Philadelphia Pennsylvania United States 19107
    31 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111
    32 Eastern Regional Medical Center Philadelphia Pennsylvania United States 19124
    33 UPMC-Shadyside Hospital Pittsburgh Pennsylvania United States 15232
    34 Parkland Memorial Hospital Dallas Texas United States 75235
    35 UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas United States 75390
    36 Aurora Cancer Care-Southern Lakes VLCC Burlington Wisconsin United States 53105
    37 Aurora Health Center-Fond du Lac Fond Du Lac Wisconsin United States 54937
    38 Aurora Health Care Germantown Health Center Germantown Wisconsin United States 53022
    39 Aurora Cancer Care-Grafton Grafton Wisconsin United States 53024
    40 Aurora BayCare Medical Center Green Bay Wisconsin United States 54311
    41 Aurora Cancer Care-Kenosha South Kenosha Wisconsin United States 53142
    42 University of Wisconsin Carbone Cancer Center Madison Wisconsin United States 53792
    43 Aurora Bay Area Medical Group-Marinette Marinette Wisconsin United States 54143
    44 Aurora Cancer Care-Milwaukee Milwaukee Wisconsin United States 53209
    45 Aurora Saint Luke's Medical Center Milwaukee Wisconsin United States 53215
    46 Aurora Sinai Medical Center Milwaukee Wisconsin United States 53233
    47 Vince Lombardi Cancer Clinic - Oshkosh Oshkosh Wisconsin United States 54904
    48 Aurora Cancer Care-Racine Racine Wisconsin United States 53406
    49 Vince Lombardi Cancer Clinic-Sheboygan Sheboygan Wisconsin United States 53081
    50 Aurora Medical Center in Summit Summit Wisconsin United States 53066
    51 Vince Lombardi Cancer Clinic-Two Rivers Two Rivers Wisconsin United States 54241
    52 Aurora Cancer Care-Milwaukee West Wauwatosa Wisconsin United States 53226
    53 Aurora West Allis Medical Center West Allis Wisconsin United States 53227

    Sponsors and Collaborators

    • National Cancer Institute (NCI)
    • NRG Oncology

    Investigators

    • Principal Investigator: Meng X Welliver, NRG Oncology

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03217266
    Other Study ID Numbers:
    • NCI-2017-01234
    • NCI-2017-01234
    • NRG-DT001
    • NRG-DT001
    • U10CA180868
    First Posted:
    Jul 14, 2017
    Last Update Posted:
    Aug 25, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Sarcoma

    Study Results

    No Results Posted as of Aug 25, 2022