Clinical Trials /

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

NCT03217266

Description:

This phase Ib trial studies the side effects of MDM2 inhibitor AMG-232 (KRT-232) and radiation therapy in treating patients with soft tissue sarcoma. MDM2 inhibitor AMG-232 (KRT-232) may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving MDM2 inhibitor AMG-232 (KRT-232) and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MDM2 Inhibitor AMG-232 and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma
  • Official Title: A Phase Ib Trial of Neoadjuvant AMG-232 Concurrent With Preoperative Radiotherapy in Wild-Type P53 Soft Tissue Sarcoma (STS)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01234
  • SECONDARY ID: NCI-2017-01234
  • SECONDARY ID: NRG-DT001
  • SECONDARY ID: NRG-DT001
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03217266

Conditions

  • Soft Tissue Sarcoma

Interventions

DrugSynonymsArms
MDM2 Inhibitor AMG-232AMG 232, AMG-232Treatment (MDM2 inhibitor AMG-232, radiation therapy)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (MDM2 inhibitor AMG-232, radiation therapy)ExperimentalPatients 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.
  • MDM2 Inhibitor AMG-232

Eligibility 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). 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose/recommended phase 2 dosage
Time Frame:At 4 weeks after treatment completion
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Local failure
Time Frame:At 2 years
Safety Issue:
Description:Will be described by cumulative incidence plots or descriptive statistics.
Measure:Disease free survival
Time Frame:At 2 years
Safety Issue:
Description:Will be described with Kaplan-Meier plots.
Measure:Overall survival
Time Frame:At 2 years
Safety Issue:
Description:Will be described with Kaplan-Meier plots.
Measure:Tumor genetic mutations in cell-free circulating tumor deoxyribonucleic acid isolated from exosomes
Time Frame:Up to 2.5 years
Safety Issue:
Description:
Measure:Serial serum macrophage inhibitory cytokine-1 levels
Time Frame:Up to 2.5 years
Safety Issue:
Description:Will be tabulated and descriptive statistics and calculated for each dose level.
Measure:AMG 232 exposure-response relationships
Time Frame:Up to 2.5 years
Safety Issue:
Description:
Measure:Percent of necrosis in final surgical resection specimen
Time Frame:At 2 years
Safety Issue:
Description:Will be summarized using binomial proportions.
Measure:Pathologic complete response in final surgical resection specimen
Time Frame:At 2 years
Safety Issue:
Description:Will be summarized using binomial proportions.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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