Pembrolizumab and Radiation Therapy With or Without Neoadjuvant Doxorubicin and Ifosfamide for the Treatment of High-Risk Resectable Undifferentiated Pleomorphic Sarcoma or Liposarcoma of the Extremity or Trunk Wall

PRIMARY OBJECTIVE:

1. Disease-free survival (DFS).

SECONDARY OBJECTIVES:

I.Patient-reported quality of life (QoL). II. Overall survival (OS). III. Loco-regional DFS. IV. Distant DFS. V. Treatment-related adverse events (TRAEs).

EXPLORATORY OBJECTIVES:

1. To evaluate DFS between study arms in patients stratified by estimated 10-year (yr) OS (< 60% versus [vs] ≥ 60%) as determined by SARCULATOR nomogram.

II. To characterize the immune micro-environment of UPS and LPS prior to treatment and after neoadjuvant treatment.

III. To identify factors associated with pathologic response to neoadjuvant therapy.

IV. To compare surgical outcomes between arms, including percentage of patients who successfully undergo protocol-defined surgical resection, rate of R0 vs ≥ R1 resection, rate of re-resection, and surgical complication rates.

1. To identify factors associated with DFS. VI. To identify circulating biomarkers associated with response to treatment and risk of recurrence.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A:

NEOADJUVANT: Patients receive doxorubicin intravenously (IV) within 72 hours on day 1 and ifosfamide IV on days 1-3 or on days 1-5 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Starting 21 days after completing neoadjuvant chemotherapy with AIM, patients receive standard of care pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Starting 4 weeks after beginning last cycle of AIM, patients also undergo IMRT once daily (QD) on Monday-Friday (5 days per week) for up to 25 fractions (5 weeks) per standard of care. Starting 4-6 weeks after completing radiation therapy, patients undergo oncologic resection per standard of care.

POST-SURGERY: Starting 1-4 weeks after surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle per standard of care. Cycles repeat every 21 days for cycles 4-17 in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo transthoracic echocardiography (TTE) or multigated acquisition scan (MUGA) at screening, and blood sample collection, computed tomography (CT) and magnetic resonance imaging (MRI) throughout the study.

ARM B:

NEOADJUVANT: Patients receive standard of care pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Starting on day 8, patients undergo radiation therapy, patients undergo IMRT QD on Monday-Friday (5 days per week) for up to 25 fractions (5 weeks) per standard of care. Starting 4-6 weeks after completing radiation therapy, patients undergo oncologic resection per standard of care.

POST-SURGERY: Starting 1-4 weeks after surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle per standard of care. Cycles repeat every 21 days for cycles 4-17 in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo TTE or MUGA at screening, and blood sample collection, CT and MRI throughout the study.

After completion of study treatment, patients are followed every 12 weeks (3 months) for 2 years then every 24 weeks (about every 6 months) through year 5.