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

NCT ID: NCT03092323

Last Updated: 2023-11-18

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 126 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-19
• Study Completion Date: 2028-09-01

Brief Summary

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.

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.

Conditions

Soft Tissue Sarcoma of the Extremity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment

Neoadjuvant pembrolizumab with concurrent radiotherapy, followed by surgical resection and adjuvant pembrolizumab.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab will be administered at 200 mg intravenously every 3 weeks for patients on the treatment arm.

Standard of Care

Neoadjuvant radiotherapy followed by surgical resection.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Pembrolizumab

Pembrolizumab will be administered at 200 mg intravenously every 3 weeks for patients on the treatment arm.

Intervention Type: DRUG

Other Intervention Names

KEYTRUDA®

Eligibility Criteria

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.

• 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).

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.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stand Up To Cancer

OTHER

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Sarcoma Alliance for Research through Collaboration

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Kirsch, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Princess Margaret Cancer Center

Locations

University of California Los Angeles

Los Angeles, California, United States

Mayo Clinic- Florida

Jacksonville, Florida, United States

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Washington University

St Louis, Missouri, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Duke University

Durham, North Carolina, United States

The Ohio State University

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

University of Pennsylvania- Abramson Cancer Center

Philadelphia, Pennsylvania, United States

University of Pittsburgh (UPMC Hillman Cancer Center)

Pittsburgh, Pennsylvania, United States

Chris O'Brien Hospital

Camperdown, New South Wales, Australia

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

McGill University Health Centre

Montreal, Quebec, Canada

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, MI, Italy

Countries

United States; Australia; Canada; Italy

References

Mowery YM, Ballman KV, Hong AM, Schuetze SM, Wagner AJ, Monga V, Heise RS, Attia S, Choy E, Burgess MA, Bae S, Pryor DI, Van Tine BA, Tinoco G, Chmielowski B, Freeman C, Gronchi A, Meyer CF, Dickson MA, Hartner L, Davis LE, Powers BC, Moding EJ, Weinhold KJ, van de Rijn M, Brigman BE, Riedel RF, Kirsch DG. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. Lancet. 2024 Nov 23;404(10467):2053-2064. doi: 10.1016/S0140-6736(24)01812-9. Epub 2024 Nov 12.

Reference Type: DERIVED

PMID: 39547252 (View on PubMed)

Other Identifiers

SU2C-SARC032

Identifier Type: -

Identifier Source: org_study_id