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

NCT03116529 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: HP-00073356
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Soft Tissue Sarcoma

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (8)

• Overall Survival Rate

  Two years after start of treatment

• Overall Survival Rate

  Five years after start of treatment

• Disease-Specific Survival Rate

  Two years after start of treatment

• Disease-Specific Survival Rate

  Five years after start of treatment

• Relapse-Free Survival Rate

  Two years after start of treatment

Study Arms (1)

Treatment

EXPERIMENTAL

Neoadjuvant Radiation plus Durvalumab and Tremelimumab Wide Surgical Resection Adjuvant Durvalumab

Combination Product: Combination Radiation, Immunotherapy, Surgery

Interventions

Combination Radiation, Immunotherapy, Surgery COMBINATION_PRODUCT

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.

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead
• AstraZeneca: collaborator
• University of Arizona: collaborator
• West Penn Allegheny Health System: collaborator

Study Sites (3)

University of Arizona

Tucson, Arizona, 85724, United States

Location

University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

Related Publications (2)

• Ng VY, Sahlani MN, Fogel JD, Chiu AK, Kallen ME, Davis D, Snider J, Regine W, Bentzen SM, Sausville E. Results of an Integrated Phase I/II Prospective Clinical Trial (NEXIS) for Neoadjuvant Anti-PD-L1 (Durvalumab) and Anti-CTLA-4 (Tremelimumab) With Radiation for High-Risk Soft-Tissue Sarcoma of the Trunk and Extremities. Cureus. 2024 Oct 22;16(10):e72119. doi: 10.7759/cureus.72119. eCollection 2024 Oct.

  PMID: 39575028 DERIVED

• 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.

  PMID: 32827353 DERIVED

Related Links

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

MeSH Terms

Conditions

Sarcoma; Parkinson Disease 4, Autosomal Dominant Lewy Body; Diabetes Mellitus, Insulin-Dependent, 12

Interventions

Immunotherapy; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Immunomodulation; Biological Therapy; Therapeutics

Study Officials

• Vincent Y. Ng, MD

  University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: April 17, 2017
• Study Start: June 21, 2017
• Primary Completion: June 21, 2024
• Study Completion: June 21, 2024
• Last Updated: November 4, 2024

Record last verified: 2024-10

Locations

US (3)