Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 5 of 5 for:    DT001

MDM2 Inhibitor AMG-232 and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03217266
Recruitment Status : Recruiting
First Posted : July 14, 2017
Last Update Posted : April 2, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase Ib trial studies the side effects of MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma. MDM2 inhibitor AMG-232 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving MDM2 inhibitor AMG-232 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
Soft Tissue Sarcoma Other: Laboratory Biomarker Analysis Drug: MDM2 Inhibitor AMG-232 Other: Pharmacological Study Radiation: Radiation Therapy Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of MDM2 inhibitor AMG-232 (AMG 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 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 when combined with radiotherapy by assessing serial serum macrophage inhibitory cytokine (MIC)-1 levels.

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

TERTIARY 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 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 AMG-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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Trial of Neoadjuvant AMG 232 Concurrent With Preoperative Radiotherapy in Wild-Type P53 Soft Tissue Sarcoma (STS)
Actual Study Start Date : November 3, 2017
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (MDM2 inhibitor AMG-232, radiation therapy)
Patients receive MDM2 inhibitor AMG-232 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.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: MDM2 Inhibitor AMG-232
Given PO
Other Names:
  • AMG 232
  • AMG-232

Other: Pharmacological Study
Correlative studies

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation




Primary Outcome Measures :
  1. Maximum tolerated dose/recommended phase 2 dosage [ Time Frame: At 4 weeks after treatment completion ]

Secondary Outcome Measures :
  1. Local failure [ Time Frame: At 2 years ]
    Will be described by cumulative incidence plots or descriptive statistics.

  2. Disease free survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.

  3. Overall survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.

  4. Tumor genetic mutations in cell-free circulating tumor deoxyribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
  5. Serial serum macrophage inhibitory cytokine-1 levels [ Time Frame: Up to 2.5 years ]
    Will be tabulated and descriptive statistics and calculated for each dose level.

  6. AMG 232 exposure-response relationships [ Time Frame: Up to 2.5 years ]
  7. Percent of necrosis in final surgical resection specimen [ Time Frame: At 2 years ]
    Will be summarized using binomial proportions.

  8. Pathologic complete response in final surgical resection specimen [ Time Frame: At 2 years ]
    Will be summarized using binomial proportions.


Other Outcome Measures:
  1. Tumor volume changes [ Time Frame: Up to 2.5 years ]
    Will be compared by paired t test.

  2. Clinical outcomes by genomic biomarkers [ Time Frame: Up to 2.5 years ]
  3. mdm2/4 expression [ Time Frame: 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 [ Time Frame: Up to 2.5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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); 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 and without contrast and/or positron emission tomography (PET)/CT within 60 days prior to registration;
    • Staging workup evaluated by chest CT and/or PET/CT showing no distant metastasis within 60 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: >= 8 g/dL (no transfusions within 7 days) 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 4.0 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 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
  • 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, and during the protocol AMG 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 and during protocol AMG 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 and during protocol AMG 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 and during the protocol AMG232 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03217266


Locations
Layout table for location information
United States, Arizona
Mayo Clinic Hospital Recruiting
Phoenix, Arizona, United States, 85054
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Scott H. Okuno         
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Scott H. Okuno         
University of Arizona Cancer Center-North Campus Recruiting
Tucson, Arizona, United States, 85719
Contact: Site Public Contact    800-327-2873      
Principal Investigator: Uma D. Goyal         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    720-848-0650      
Principal Investigator: Tracey E. Schefter         
Poudre Valley Hospital Recruiting
Fort Collins, Colorado, United States, 80524
Contact: Site Public Contact    970-297-6150      
Principal Investigator: Tracey E. Schefter         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Site Public Contact    312-942-5498    clinical_trials@rush.edu   
Principal Investigator: Dian Wang         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Scott H. Okuno         
United States, Missouri
Siteman Cancer Center at West County Hospital Recruiting
Creve Coeur, Missouri, United States, 63141
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Brian A. Van Tine         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Brian A. Van Tine         
Siteman Cancer Center-South County Recruiting
Saint Louis, Missouri, United States, 63129
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Brian A. Van Tine         
United States, Montana
Benefis Healthcare- Sletten Cancer Institute Recruiting
Great Falls, Montana, United States, 59405
Contact: Site Public Contact    406-969-6060    mccinfo@mtcancer.org   
Principal Investigator: Benjamin T. Marchello         
Kalispell Regional Medical Center Recruiting
Kalispell, Montana, United States, 59901
Contact: Site Public Contact    406-969-6060    mccinfo@mtcancer.org   
Principal Investigator: Benjamin T. Marchello         
United States, Nebraska
Nebraska Methodist Hospital Recruiting
Omaha, Nebraska, United States, 68114
Contact: Site Public Contact    402-354-5144      
Principal Investigator: Kirsten M. Leu         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Site Public Contact    800-767-9355    askroswell@roswellpark.org   
Principal Investigator: John M. Kane         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Thomas J. Scharschmidt         
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Site Public Contact    405-271-8777    ou-clinical-trials@ouhsc.edu   
Principal Investigator: Susanna V. Ulahannan         
United States, Pennsylvania
Thomas Jefferson University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Site Public Contact    215-955-6084      
Principal Investigator: Atrayee B. Mallick         
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Site Public Contact    215-728-4790      
Principal Investigator: Krisha J. Howell         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Meng X Welliver NRG Oncology

Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03217266     History of Changes
Other Study ID Numbers: NCI-2017-01234
NCI-2017-01234 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-DT001 ( Other Identifier: NRG Oncology )
NRG-DT001 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: July 14, 2017    Key Record Dates
Last Update Posted: April 2, 2019
Last Verified: November 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms