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

This study is currently recruiting participants.
Verified June 2017 by Vincent Ng, University of Maryland
Sponsor:
ClinicalTrials.gov Identifier:
NCT03116529
First Posted: April 17, 2017
Last Update Posted: June 23, 2017
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.
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Vincent Ng, University of Maryland
  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.

Condition Intervention Phase
Soft Tissue Sarcoma Combination Product: Combination Radiation, Immunotherapy, Surgery Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Anti-PD-L1 (Durvalumab/MEDI4736) Plus Anti-CTLA-4 (Tremelimumab) and Radiation for High Risk Soft-Tissue Sarcoma

Resource links provided by NLM:


Further study details as provided by Vincent Ng, University of Maryland:

Primary Outcome Measures:
  • 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 ]
    Number of subjects experiencing high-grade toxicity

  • Histopathologic Response [ Time Frame: At time of surgery ]
    Number of subjects with an excellent response on histopathologic examination of the surgically removed tumor


Secondary Outcome Measures:
  • Overall Survival Rate [ Time Frame: Two years after start of treatment ]
    Percentage of patients still alive

  • Overall Survival Rate [ Time Frame: Five years after start of treatment ]
    Percentage of patients still alive

  • Disease-Specific Survival Rate [ Time Frame: Two years after start of treatment ]
    Percentage of patients who have not died from soft tissue sarcoma

  • Disease-Specific Survival Rate [ Time Frame: Five years after start of treatment ]
    Percentage of patients who have not died from soft tissue sarcoma

  • Relapse-Free Survival Rate [ Time Frame: Two years after start of treatment ]
    Percentage of patients who have not had a documented relapse of local or distant disease

  • Relapse-Free Survival Rate [ Time Frame: Five years after start of treatment ]
    Percentage of patients who have not had a documented relapse of local or distant disease

  • Radiologic Response To Treatment [ Time Frame: At time of surgery ]
    Best overall response to Neoadjuvant Radiation and Immunotherapy using Response Evaluation Criteria in Solid Tumors (RECIST)

  • Radiologic Response To Treatment [ Time Frame: At time of surgery ]
    Best overall response to Neoadjuvant Radiation and Immunotherapy using immune-related response criteria (irRC)


Estimated Enrollment: 35
Actual Study Start Date: June 21, 2017
Estimated Study Completion Date: June 2022
Estimated Primary Completion Date: June 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment
Neoadjuvant Radiation plus Durvalumab and Tremelimumab Wide Surgical Resection Adjuvant Durvalumab
Combination Product: Combination Radiation, Immunotherapy, Surgery

Three doses of Durvalumab (1500 mg) and Tremelimumab (75 mg) given intravenously once every four weeks during radiotherapy prior to surgery.

Radiation therapy delivered with a minimum dose of 50 Gy and 1.8-2 Gy per fraction. Bulky sarcomas, defined as >10 cms in greatest dimension, receive a single 15 Gy fraction of high-dose spatially fractionated (GRID) radiation therapy within 1-3 days prior to radiation therapy

Surgical resection is performed at least 5-8 weeks after cessation of radiotherapy and 4 weeks after completion of neoadjuvant immunotherapy.

Patients with no evidence of disease following surgical resection receive four additional doses and patients with evidence of disease receive nine additional doses of Durvalumab (1500 mg IV) once every four weeks unless there is clear progression of disease.


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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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): NCT03116529


Contacts
Contact: Study Coordinator 410-328-6465 Navid.Saeidi@umm.edu
Contact: Vincent Y. Ng, MD 443-462-5903 vng@umoa.umm.edu

Locations
United States, Maryland
University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Navid Saeidi    410-328-6465    Navid.Saeidi@umm.edu   
Sub-Investigator: Ed Sausville, MD         
Sub-Investigator: William Regine, MD         
Sub-Investigator: Daniel Lerman, MD         
Sub-Investigator: Paul Staats, MD         
Sub-Investigator: Eduardo Davila, PhD         
Sponsors and Collaborators
University of Maryland
AstraZeneca
Investigators
Principal Investigator: Vincent Y. Ng, MD University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center
  More Information

Additional Information:
Responsible Party: Vincent Ng, Assistant Professor, University of Maryland
ClinicalTrials.gov Identifier: NCT03116529     History of Changes
Other Study ID Numbers: HP-00073356
First Submitted: April 12, 2017
First Posted: April 17, 2017
Last Update Posted: June 23, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Vincent Ng, University of Maryland:
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

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Antibodies, Monoclonal
Tremelimumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents