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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 : February 5, 2020
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 13, 2017
First Posted Date  ICMJE July 14, 2017
Last Update Posted Date February 5, 2020
Actual Study Start Date  ICMJE November 3, 2017
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 1, 2018)
Maximum tolerated dose/recommended phase 2 dosage [ Time Frame: At 4 weeks after treatment completion ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 13, 2017)
Maximum tolerated dose/recommended phase 2 dosage [ Time Frame: At 4 weeks after treatment completion ]
Will be observed.
Change History Complete list of historical versions of study NCT03217266 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2018)
  • Local failure [ Time Frame: At 2 years ]
    Will be described by cumulative incidence plots or descriptive statistics.
  • Disease free survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.
  • Overall survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.
  • Tumor genetic mutations in cell-free circulating tumor deoxyribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
  • 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.
  • AMG 232 exposure-response relationships [ Time Frame: Up to 2.5 years ]
  • Percent of necrosis in final surgical resection specimen [ Time Frame: At 2 years ]
    Will be summarized using binomial proportions.
  • Pathologic complete response in final surgical resection specimen [ Time Frame: At 2 years ]
    Will be summarized using binomial proportions.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 13, 2017)
  • AMG 232 exposure-response relationships [ Time Frame: Up to 2.5 years ]
    Will be observed.
  • Disease free survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.
  • Distant disease free survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.
  • Local failure [ Time Frame: At 2 years ]
    Will be described by cumulative incidence plots or descriptive statistics.
  • Overall survival [ Time Frame: At 2 years ]
    Will be described with Kaplan-Meier plots.
  • Pathologic complete response in final surgical resection specimen [ Time Frame: At 2 years ]
    Will be summarized using binomial proportions.
  • Percent of necrosis in final surgical resection specimen [ Time Frame: At 2 years ]
    Will be summarized using binomial proportions.
  • 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.
  • Tumor genetic mutations in cell-free circulating tumor deoxyribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
    Will be observed.
Current Other Pre-specified Outcome Measures
 (submitted: March 2, 2018)
  • Tumor volume changes [ Time Frame: Up to 2.5 years ]
    Will be compared by paired t test.
  • Clinical outcomes by genomic biomarkers [ Time Frame: Up to 2.5 years ]
  • mdm2/4 expression [ Time Frame: Up to 2.5 years ]
    Will be correlated with protein levels and assessed using Pearson's correlation.
  • Tumor genetic mutations in deoxyribonucleic acid ribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
Original Other Pre-specified Outcome Measures
 (submitted: July 13, 2017)
  • Clinical outcomes by genomic biomarkers [ Time Frame: Up to 2.5 years ]
    Will be observed.
  • mdm2/4 expression [ Time Frame: Up to 2.5 years ]
    Will be correlated with protein levels and assessed using Pearson's correlation.
  • Tumor genetic mutations in deoxyribonucleic acid ribonucleic acid isolated from exosomes [ Time Frame: Up to 2.5 years ]
    Will be observed.
  • Tumor volume changes [ Time Frame: Up to 2.5 years ]
    Will be compared by paired t test.
 
Descriptive Information
Brief Title  ICMJE MDM2 Inhibitor AMG-232 and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma
Official Title  ICMJE A Phase Ib Trial of Neoadjuvant AMG-232 Concurrent With Preoperative Radiotherapy in Wild-Type P53 Soft Tissue Sarcoma (STS)
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.
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).

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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Soft Tissue Sarcoma
Intervention  ICMJE
  • Drug: MDM2 Inhibitor AMG-232
    Given PO
    Other Names:
    • AMG 232
    • AMG-232
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • irradiated
    • irradiation
    • RADIATION
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
Study Arms  ICMJE 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.
Interventions:
  • Drug: MDM2 Inhibitor AMG-232
  • Radiation: Radiation Therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 27, 2019)
46
Original Estimated Enrollment  ICMJE
 (submitted: July 13, 2017)
80
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03217266
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: "NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Meng X Welliver NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP