Clinical Trials /

Neoadjuvant Durvalumab and Tremelimumab Plus Radiation for High Risk Soft-Tissue Sarcoma

NCT03116529

Description:

Chemotherapy is controversial for soft tissue sarcoma that has not yet metastasized. Surgery and radiation are effective for local control, but there are no highly effective interventions to prevent metastatic spread of soft tissue sarcoma. Immunotherapy has shown promise in other types of cancer. Combining two types of immunotherapy agents with preoperative radiation may help the immune system recognize the sarcoma and stimulate an anti-tumor immune response.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Durvalumab and Tremelimumab Plus Radiation for High Risk Soft-Tissue Sarcoma
  • Official Title: Neoadjuvant Anti-PD-L1 (Durvalumab/MEDI4736) Plus Anti-CTLA-4 (Tremelimumab) and Radiation for High Risk Soft-Tissue Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: HP-00073356
  • NCT ID: NCT03116529

Conditions

  • Soft Tissue Sarcoma

Purpose

Chemotherapy is controversial for soft tissue sarcoma that has not yet metastasized. Surgery and radiation are effective for local control, but there are no highly effective interventions to prevent metastatic spread of soft tissue sarcoma. Immunotherapy has shown promise in other types of cancer. Combining two types of immunotherapy agents with preoperative radiation may help the immune system recognize the sarcoma and stimulate an anti-tumor immune response.

Detailed Description

      The main purposes of this study are to evaluate the safety, tolerability, and efficacy of
      Durvalumab and Tremelimumab in combination with radiation prior to surgical resection of
      high-risk soft tissue sarcoma in the pelvis and extremities.

      Patients will receive the same radiation therapy and surgical care they would receive
      normally and with no change in timing or duration of each treatment. They will also receive
      two immunotherapy agents, Durvalumab and Tremelimumab, during radiation prior to surgery, and
      a single agent, Durvalumab, after surgery.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalNeoadjuvant Radiation plus Durvalumab and Tremelimumab Wide Surgical Resection Adjuvant Durvalumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Written informed consent
    
              -  Willingness and ability to comply with the protocol for the duration of the study
    
              -  Histologically confirmed intermediate or high grade adult-type soft tissue sarcoma
    
              -  Location of tumor is trunk (non-retroperitoneal) or extremities
    
              -  Tumor at least 5 cm in greatest dimension and deep to fascia, or locally recurrent, or
                 metastatic, or have had prior inadequate resections
    
              -  Judged as at least marginally resectable
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1
    
              -  Adequate normal organ and marrow function
    
              -  Female subjects must be either of non-reproductive potential (i.e., post-menopausal by
                 history: ≥60 years old and no menses for ≥1 year without an alternative medical cause;
                 OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
                 bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
    
              -  Females of childbearing potential who are sexually active with a non-sterilized male
                 partner and non-sterilized male subjects who are sexually active with a female partner
                 of childbearing potential must be willing to use 2 methods of effective contraception
                 from time of screening through 180 days after receipt of the final dose of Durvalumab
                 + Tremelimumab combination therapy or 90 days after receipt of the final dose of
                 Durvalumab Monotherapy, whichever is the longer time period.
    
            Exclusion Criteria:
    
              -  Primarily bone-based sarcomas that can occur in the soft tissue such as:
                 extra-skeletal Ewing sarcoma, extra-skeletal osteosarcoma, peripheral chordoma,
                 extra-skeletal myxoid chondrosarcoma, and mesenchymal chondrosarcoma
    
              -  Predominantly low-grade soft tissue sarcoma, such as solitary fibrous tumor /
                 hemangiopericytoma, well-differentiated liposarcoma, dermatofibrosarcoma protuberans,
                 Kaposi's sarcoma
    
              -  Pediatric-type soft tissue sarcoma, such as rhabdomyosarcoma
    
              -  Gastrointestinal stromal tumors (GIST)
    
              -  Retroperitoneal soft tissue sarcoma
    
              -  Patients with extra-pulmonary metastases aside from lymph node involvement
    
              -  Surgically unresectable primary lesion
    
              -  Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
                 of but not limited to surgery, radiation and/or corticosteroids.
    
              -  Any previous treatment with an anti-PD-1 (programmed cell death protein-1), anti-PD-L1
                 (programmed death ligand 1) or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein
                 4) therapy, including Durvalumab and Tremelimumab
    
              -  History of hypersensitivity to Durvalumab or any excipient
    
              -  History of hypersensitivity to Tremelimumab or any excipient
    
              -  History of hypersensitivity to the combination or comparator agent
    
              -  History or clinically confirmed pneumonitis or interstitial lung disease
    
              -  Receipt of the last dose of anti-cancer therapy (cytotoxic chemotherapy,
                 immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor
                 embolization, monoclonal antibodies, other investigational agent) ≤ 28 days prior to
                 the first dose of study drug (28 days prior to the first dose of study drug for
                 subjects who have received prior TKIs (tyrosine kinase inhibitors) [e.g., erlotinib,
                 gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C [If
                 sufficient wash-out time has not occurred due to the schedule or PK properties of an
                 agent, a longer wash-out period may be required])
    
              -  Current or prior use of immunosuppressive medication within 28 days before the first
                 dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled
                 corticosteroids or systemic corticosteroids at physiological doses, which are not to
                 exceed 10 mg/day of prednisone, or an equivalent corticosteroid
    
              -  Any unresolved toxicity (>grade 2) from previous anti-cancer therapy. NOTE: Subjects
                 with irreversible toxicity that is not reasonably expected to be exacerbated by the
                 investigational product may be included (e.g., hearing loss, peripherally neuropathy)
    
              -  Any prior immune-related adverse event (irAE) ≥ Grade 2 while receiving any previous
                 immunotherapy agent, or any unresolved irAE > Grade 1
    
              -  Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects
                 with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
                 the past 2 years) are not excluded.
    
              -  History of primary immunodeficiency
    
              -  History of allogeneic organ transplant (e.g. solid organ/bone marrow transplant
                 patients)
    
              -  Uncontrolled intercurrent illness including, but not limited to:
    
              -  Ongoing or active infections
    
              -  Cardiac conditions, such as:
    
              -  symptomatic congestive heart failure
    
              -  uncontrolled hypertension
    
              -  unstable angina pectoris
    
              -  cardiac arrhythmia
    
              -  Active peptic ulcer disease or gastritis
    
              -  History of inflammatory bowel disease, ulcerative colitis or Crohn's Disease
    
              -  Active bleeding diatheses
    
              -  Any subject known to have evidence of acute or chronic hepatitis B or hepatitis C
    
              -  Any subject known to have evidence of human immunodeficiency virus (HIV) or acquired
                 immune deficiency syndrome (AIDS)
    
              -  Uncontrolled seizures
    
              -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
                 electrocardiograms (ECGs) using Fredericia's Correction
    
              -  Known history of current or recent clinical diagnosis of tuberculosis (within three
                 months prior to enrollment)
    
              -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
                 ulcerative colitis)
    
              -  Any signs or symptoms of bowel obstruction within 28 days prior to study entry
    
              -  History of leptomeningeal carcinomatosis
    
              -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
                 30 days of receiving durvalumab or tremelimumab, or active infection
    
              -  History of psychiatric illness/social situations that would limit compliance with
                 study requirements or compromise the ability of the subject to give written informed
                 consent
    
              -  Any condition that, in the opinion of the investigator, would interfere with
                 evaluation of study treatment or interpretation of patient safety or study results
    
              -  Previously enrolled in the present study
    
              -  Participation in another clinical study with an investigational product during the
                 last 6 months
    
              -  Previously enrolled in the present study
    
              -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
                 staff and/or staff at the study site)
    
              -  Female patients who are pregnant or breastfeeding or male or female patients of
                 reproductive potential who are not willing to employ effective birth control from
                 screening to 180 days after the last dose of durvalumab + tremelimumab combination
                 therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the
                 longer time period
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Toxicity: Number of subjects experiencing high-grade toxicity
    Time Frame:90 days after receipt of final dose of Durvalumab monotherapy or 180 days after receipt of final dose of combination Durvalumab/Tremelimumab, whichever is longer
    Safety Issue:
    Description:Number of subjects experiencing high-grade toxicity

    Secondary Outcome Measures

    Measure:Overall Survival Rate
    Time Frame:Two years after start of treatment
    Safety Issue:
    Description:Percentage of patients still alive
    Measure:Overall Survival Rate
    Time Frame:Five years after start of treatment
    Safety Issue:
    Description:Percentage of patients still alive
    Measure:Disease-Specific Survival Rate
    Time Frame:Two years after start of treatment
    Safety Issue:
    Description:Percentage of patients who have not died from soft tissue sarcoma
    Measure:Disease-Specific Survival Rate
    Time Frame:Five years after start of treatment
    Safety Issue:
    Description:Percentage of patients who have not died from soft tissue sarcoma
    Measure:Relapse-Free Survival Rate
    Time Frame:Two years after start of treatment
    Safety Issue:
    Description:Percentage of patients who have not had a documented relapse of local or distant disease
    Measure:Relapse-Free Survival Rate
    Time Frame:Five years after start of treatment
    Safety Issue:
    Description:Percentage of patients who have not had a documented relapse of local or distant disease
    Measure:Radiologic Response To Treatment
    Time Frame:At time of surgery
    Safety Issue:
    Description:Best overall response to Neoadjuvant Radiation and Immunotherapy using Response Evaluation Criteria in Solid Tumors (RECIST)
    Measure:Radiologic Response To Treatment
    Time Frame:At time of surgery
    Safety Issue:
    Description:Best overall response to Neoadjuvant Radiation and Immunotherapy using immune-related response criteria (irRC)

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:University of Maryland

    Trial Keywords

    • Neoadjuvant
    • Soft Tissue Sarcoma
    • Immunotherapy
    • Checkpoint Inhibitor
    • PD-1 (Programmed Cell Death Protein 1)
    • PD-L1 (Programmed Death Ligand 1)
    • CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4)
    • Radiotherapy
    • Durvalumab
    • Tremelimumab
    • Surgery
    • Radiation
    • Combined
    • Preoperative

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