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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Soft Tissue Sarcoma
• Intervention / Treatment: Combination product: Combination Radiation, Immunotherapy, Surgery

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity: Number of subjects experiencing high-grade toxicity	Number of subjects experiencing high-grade toxicity	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
Histopathologic Response	Number of subjects with an excellent response on histopathologic examination of the surgically removed tumor	At time of surgery

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: AstraZeneca; West Penn Allegheny Health System; University of Arizona
• Investigators: Principal Investigator: Vincent Y. Ng, MD, University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center

Publications and helpful links

General Publications

• Vatner R, James CD, Sathiaseelan V, Bondra KM, Kalapurakal JA, Houghton PJ. Radiation therapy and molecular-targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges. Pediatr Blood Cancer. 2021 May;68 Suppl 2:e28439. doi: 10.1002/pbc.28439. Epub 2020 Aug 22.

Helpful Links

• The Bone Cancer and Soft Tissue Sarcoma Service at Greenebaum Comprehensive Cancer Center at the University of Maryland Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2017
• Primary Completion (Estimated): June 21, 2032
• Study Completion (Estimated): June 21, 2037

Study Registration Dates

• First Submitted: April 12, 2017
• First Submitted That Met QC Criteria: April 14, 2017
• First Posted (Actual): April 17, 2017

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Surgery; Immunotherapy; Checkpoint Inhibitor; Radiotherapy; Preoperative; Neoadjuvant; Durvalumab; Soft Tissue Sarcoma; Radiation; Tremelimumab; Combined; PD-1 (Programmed Cell Death Protein 1); PD-L1 (Programmed Death Ligand 1); CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4)
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Physiological Effects of Drugs; Immunologic Factors; Immunomodulating Agents
• Other Study ID Numbers: HP-00073356

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No