A Randomized Trial of Pembrolizumab & Radiotherapy Versus Radiotherapy in High-Risk Soft Tissue Sarcoma of the Extremity (SU2C-SARC032)

SU2C-SARC032: A Phase II Randomized Controlled Trial of Neoadjuvant Pembrolizumab With Radiotherapy and Adjuvant Pembrolizumab in Patients With High-Risk, Localized Soft Tissue Sarcoma of the Extremity

This is an open-label, multi-institutional phase II randomized study comparing neoadjuvant radiotherapy followed by surgical resection to neoadjuvant pembrolizumab with concurrent radiotherapy, followed by surgical resection and adjuvant pembrolizumab. The total duration of pembrolizumab will be one year in the experimental arm.

Study Overview

• Status: Active, not recruiting
• Conditions: Soft Tissue Sarcoma of the Extremity
• Intervention / Treatment: Drug: Pembrolizumab

Detailed Description

This is a multicenter, randomized phase II trial with an initial safety run-in to test the safety and efficacy of neoadjuvant pembrolizumab with image-guided radiotherapy and adjuvant pembrolizumab compared to radiation therapy alone in patients with clinically localized extremity soft tissue sarcoma at high risk for developing metastatic disease (tumor size > 5 cm, intermediate- to high-grade; approximately 50% risk for distant disease at 2 years). Histologies will be limited to undifferentiated pleomorphic sarcoma and dedifferentiated/pleomorphic liposarcoma based on preliminary data from SARC028. Other terms for undifferentiated pleomorphic sarcoma may include, but are not limited to. pleomorphic undifferentiated sarcoma, unclassified spindle cell sarcoma, spindle cell sarcoma not otherwise specified, pleomorphic spindle cell sarcoma, pleomorphic fibroblastic sarcoma, undifferentiated high-grade pleomorphic sarcoma, pleomorphicsarcoma with prominent inflammation, pleomorphic sarcoma with giant cells, malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory subtypes), fibrosarcoma, and myxofibrosarcoma (located deep to the fascia in muscle). Radiation therapy with three cycles of pembrolizumab will be administered as neoadjuvant therapy for patients randomized to the experimental arm. These patients will also receive up to fourteen cycles of adjuvant pembrolizumab after surgical resection. Patients in the standard of care arm will receive neoadjuvant radiotherapy (50 Gy in 25 fractions) followed by surgical resection as in RTOG 0630.

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Chris O'Brien Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic- Florida
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • University of Pennsylvania- Abramson Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh (UPMC Hillman Cancer Center)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 12 years
• Histologically confirmed diagnosis of grade 2 or 3 out of 3 UPS or dedifferentiated/pleomorphic LPS of the extremity (including limb girdle, i.e. shoulder or hip) that measures greater than 5 cm in any direction as assessed by imaging
• Patients with non-melanomatous skin cancer, in situ carcinoma, or low-risk prostate cancer can be enrolled.
• ECOG Performance Status of 0 or 1
• Resectable primary tumor with no evidence of metastatic disease by imaging.
• Adequate organ function within 10 days of Day 1
• Written, voluntary informed consent
• Fertile men and women of childbearing potential must agree to use an effective method of birth control from Day 1 of study and for 120 days after last pembrolizumab administration in both sexes. Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test ≤ 72 hours prior to Day 1 of study.

Exclusion Criteria:

• Prior chemotherapy, targeted small molecule therapy, or radiation therapy for current diagnosis of sarcoma
• Prior radiation therapy in excess of 20 Gy to the site of the current diagnosis of sarcoma. No overlap with prior radiation fields in excess of 20 Gy is allowed.
• Concurrent, clinically significant, active malignancies within two years of study enrollment.
• Patients with locally recurrent sarcoma after surgery alone are eligible for enrollment if other inclusion criteria are met.
• Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol
• Major surgery within four weeks prior to Day 1 of study or who have not recovered adequately from prior surgery.
• Currently receiving a study therapy or if they had an investigational agent within 4 weeks at the time of enrollment.
• Women who are pregnant or nursing/breastfeeding, or expecting to conceive or men who are expecting to father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of pembrolizumab.
• Inability to comply with protocol required procedures
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy by oral or IV routes within 7 days prior to the first dose of trial treatment
• Known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Metastatic disease or regional lymph node involvement. Chest CT will be mandatory prior to enrollment to evaluate for the presence of metastatic disease. Pulmonary nodule(s) < 5 mm without a histological diagnosis may not be the basis for study exclusion given the lack of specificity of chest CT. If pulmonary nodule(s) measuring 6 - 10 mm are noted on chest CT but appear stable relative to prior chest imaging of at least 6 months duration or if 18FDG-PET scan indicates that the nodule(s) are unlikely to be metastatic disease, then this is permitted. Pulmonary nodules >10 mm should be considered metastatic unless proven otherwise by biopsy/resection or stable appearance for at least 6 months on imaging.
• Unresectable disease or medically inoperable
• Planned to receive neoadjuvant or adjuvant chemotherapy for current diagnosis of localized soft tissue sarcoma
• Active autoimmune disease that has required systemic treatment in the past two years (i.e. with use of disease modifying agents, systemic corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis.
• Active infection requiring systemic therapy
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
• Known active Hepatitis B (e.g., HBsAg reactive, confirmed by detectable viral load) or Hepatitis C (e.g., HCV RNA [qualitative] detected)
• Received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Diagnosis of scleroderma.
• Diagnosis of inflammatory bowel disease (Crohn's disease or Ulcerative Colitis).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Neoadjuvant pembrolizumab with concurrent radiotherapy, followed by surgical resection and adjuvant pembrolizumab.	Drug: Pembrolizumab; Pembrolizumab will be administered at 200 mg intravenously every 3 weeks for patients on the treatment arm.; Other Names: KEYTRUDA®
No Intervention: Standard of Care; Neoadjuvant radiotherapy followed by surgical resection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	Disease recurrence is defined as clinically diagnosed or biopsy-confirmed recurrent sarcoma at a site distant to the primary tumor, including nodal metastasis, loco-regional recurrence, and death without documented recurrence.	2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Loco-regional disease-free survival	The length of time after treatment ends without any locoregional recurrence of sarcoma.	5 years
Distant disease free survival	The length of time after treatment ends that the patient survives without any signs or symptoms of sarcoma	5 years
Overall survival	The length of time from the start of treatment that patients diagnosed with sarcoma are still alive.	5 years
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Test the safety of neoadjuvant pembrolizumab administered with conventionally fractionated radiotherapy targeting soft tissue sarcoma of the extremity.	5 years

Collaborators and Investigators

• Sponsor: Sarcoma Alliance for Research through Collaboration
• Collaborators: Merck Sharp & Dohme LLC; Stand Up To Cancer
• Investigators: Principal Investigator: David Kirsch, MD, PhD, Princess Margaret Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2017
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: March 15, 2017
• First Submitted That Met QC Criteria: March 20, 2017
• First Posted (Actual): March 27, 2017

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: SU2C-SARC032

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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