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
Comparing Treatment With Versus Without Neoadjuvant Doxorubicin and Ifosfamide in Selected Patients With High-Risk Resectable Soft-Tissue Sarcoma
Study Overview
Status
Conditions
Intervention / Treatment
- Drug: Ifosfamide
- Other: Questionnaire Administration
- Procedure: Magnetic Resonance Imaging
- Procedure: Computed Tomography
- Biological: Pembrolizumab
- Procedure: Biospecimen Collection
- Radiation: Intensity-Modulated Radiation Therapy
- Drug: Doxorubicin
- Procedure: Multigated Acquisition Scan
- Procedure: Transthoracic Echocardiography Test
- Procedure: Surgical Procedure
Detailed Description
PRIMARY OBJECTIVE:
I. 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:
I. 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.
V. 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.
Study Type
Enrollment (Estimated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: The Ohio State University Comprehensive Cancer Center
- Phone Number: 800-293-5066
- Email: OSUCCCClinicaltrials@osumc.edu
Study Locations
-
-
Ohio
-
Columbus, Ohio, United States, 43210
- Ohio State University Comprehensive Cancer Center
-
Principal Investigator:
- David A. Liebner
-
Contact:
- David A. Liebner
- Phone Number: 614-366-6087
- Email: David.Liebner@osumc.edu
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Age ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
Histologically proven diagnosis of UPS or LPS originating in an extremity or trunk wall. Alternative terms for UPS include but are not limited to the following:
- Fibrosarcoma
- Malignant fibrous histiocytoma
- Myxofibrosarcoma
- Pleomorphic fibroblastic sarcoma
- Pleomorphic sarcoma with giant cells
- Pleomorphic sarcoma with prominent inflammation
- Pleomorphic spindle cell sarcoma
- Pleomorphic undifferentiated sarcoma
- Spindle cell sarcoma, not otherwise specified (NOS)
- Unclassified spindle cell sarcoma
Undifferentiated high-grade pleomorphic sarcoma
- Please contact the medical monitor or study principal investigator (PI) with any questions regarding potentially eligible histologies
- Tumor size ≥ 5 cm on anatomic imaging (computed tomography [CT] or magnetic resonance imaging [MRI])
- Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (G)3
- Eligible for definitive local management of soft-tissue sarcoma (STS) per established guidelines with wide oncologic resection as determined by a surgeon with expertise in STS management
- Must be a candidate for neoadjuvant radiation as part of local control plan as determined by a radiation oncologist with expertise in STS management
- Hemoglobin ≥ 9.0 g/dL without transfusion within 7 days of enrollment
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
- Platelets ≥ 100 x 10^9/L
- Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN), or estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/m^2 (modification of diet in renal disease [MDRD] formula) for patients with serum creatinine > 1.5 x institutional ULN
- Bilirubin ≤ 1.5 x institutional ULN (in patients with a documented history of Gilbert's syndrome, bilirubin ≤ 3 x institutional ULN)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x institutional ULN
- In patients for whom prothrombin time (PT) and international normalized ratio (INR) testing is clinically indicated, PT or INR must be ≤ 1.5 x ULN in patients not on anticoagulation. In patients receiving anticoagulant therapy, PT and INR must be within therapeutic range for the given anticoagulant
- In patients for whom partial thromboplastin time (PTT) testing is clinically indicated, PTT must be ≤ 1.5 x ULN in patients not on anticoagulation. In patients receiving anticoagulant therapy, PTT must be within therapeutic range for the given anticoagulant
- Clinically normal cardiac function based on left ventricular ejection fraction (LVEF) ≥ 50%
- In patients for whom 12-lead electrocardiogram (ECG) is indicated, ECG without clinically significant abnormalities
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to randomization
- Subjects in both arms must agree to use highly effective birth control measures during the study treatment period and for at least 6 months after the last dose of chemotherapy or date of surgery, whichever is later
- Female subjects who are breastfeeding should discontinue nursing prior to the first day of study treatment and abstain from nursing until 6 months after the last study treatment
Exclusion Criteria:
Patients with evidence of nodal metastases or distant metastases (DM)
- Lung nodule(s) between 0.6-1.0 cm are permitted on study if stable on imaging for least 6 months or if fluorodeoxyglucose-positron emission tomography (FDG-PET) scan suggests that the nodule(s) are low-risk for metastatic disease
- Lung nodules > 1.0 cm should be considered metastatic unless proven otherwise by biopsy or resection or if nodules have stable appearance for at least 6 months on imaging
- Any prior surgery (apart from diagnostic biopsy), radiation therapy, or systemic therapy for management of present tumor. Patients with locally recurrent sarcoma after prior surgery alone are eligible for enrollment if other inclusion criteria are met
- Hypersensitivity to DOXOrubicin, ifosfamide, mesna, or pembrolizumab or their metabolites or excipients
- Prior treatment with DOXOrubicin (or other anthracyclines and anthracenediones)
Clinically significant cardiac disease, including, but not limited to:
- Symptomatic congestive heart failure
- Angina pectoris
- Acute inflammatory heart disease
- Myocardial infarction within 1 year before randomization
- Uncontrolled cardiac arrhythmia
- Active bleeding or clinically significant major bleeding episode within the last 4 weeks
- Other invasive malignancy within 2 years, with the exception of adequately treated nonmelanoma skin cancer, localized cervical cancer, or low-risk prostate cancer
- Diagnosis of immunodeficiency or treatment with systemic corticosteroids or any other form of systemic immunosuppressive therapy within 7 days prior to study treatment
History of autoimmune disease treated with systemic corticosteroids and/or other disease-modifying agents in the last 2 years
- Replacement endocrine therapy (thyroid hormone, insulin, corticosteroids) is not exclusionary
- Patients with a history of autoimmune disease previously treated with systemic corticosteroids and/or other disease-modifying agents > 2 years ago, who are not currently on systemic therapy, may be considered for enrollment on consultation with the medical monitor or study PI
- Clinically significant, active, or uncontrolled infection
- Known history of active tuberculosis
- Active human immunodeficiency virus (HIV) (confirmed by detectable viral load)
- Active hepatitis B (confirmed by detectable viral load)
- Active hepatitis C (confirmed by detectable viral load)
- Any medically significant comorbidity, which in the opinion of the investigator would preclude safe participation in the study
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
|
Given IV
Other Names:
Ancillary studies
Undergo MRI
Other Names:
Undergo CT
Other Names:
Given IV
Other Names:
Undergo blood sample collection
Other Names:
Undergo IMRT
Other Names:
Given IV
Other Names:
Undergo MUGA
Other Names:
Undergo TTE
Other Names:
Undergo oncologic resection
Other Names:
|
|
Active Comparator: Arm B (pembrolizumab, IMRT, surgery)
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 up to a total of 17 cycles 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. |
Ancillary studies
Undergo MRI
Other Names:
Undergo CT
Other Names:
Given IV
Other Names:
Undergo blood sample collection
Other Names:
Undergo IMRT
Other Names:
Undergo MUGA
Other Names:
Undergo TTE
Other Names:
Undergo oncologic resection
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Disease-free survival (DFS)
Time Frame: From randomization to disease recurrence of death, whichever occurs first, assessed up to 2 years
|
DFS will be estimated using the Kaplan-Meier method and compared between treatment groups using the stratified log-rank test.
In addition, a Cox proportional hazards model will be used to estimate the hazard ratio and 95% confidence interval, adjusting for relevant covariates.
|
From randomization to disease recurrence of death, whichever occurs first, assessed up to 2 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Patient-reported quality of life (QOL)
Time Frame: At baseline and at 1 and 2 years post-randomization
|
Will be evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30.
A linear mixed-effects model will be used to assess changes in QOL over time, including random intercepts and slopes.
The model will incorporate treatment group, time, baseline QOL score, and the treatment-by-time interaction as covariates.
|
At baseline and at 1 and 2 years post-randomization
|
|
Overall survival (OS)
Time Frame: From randomization to death from any cause, assessed up to 5 years
|
Will be estimated using the Kaplan-Meier method and compared between treatment groups using the log-rank test.
A Cox proportional hazards model will also be used to evaluate OS, adjusting for relevant covariates.
|
From randomization to death from any cause, assessed up to 5 years
|
|
Loco-regional DFS
Time Frame: Up to 5 years
|
Will be defined as clinical or biopsy-confirmed recurrence at the primary tumor site, regional nodal involvement, and loco-regional relapse.
Will be estimated using the Kaplan-Meier method and compared between treatment groups using the log-rank test.
A Cox proportional hazards model will also be used to evaluate loco-regional DFS, adjusting for relevant covariates.
|
Up to 5 years
|
|
Distant DFS
Time Frame: Up to 5 years
|
Will be defined as clinical or biopsy-confirmed recurrence at a distant site distinct from the primary tumor site.
Will be estimated using the Kaplan-Meier method and compared between treatment groups using the log-rank test.
A Cox proportional hazards model will also be used to evaluate distant DFS, adjusting for relevant covariates.
|
Up to 5 years
|
|
Incidence of treatment-related adverse events (TRAEs)
Time Frame: Up to 5 years
|
Will be measured using Common Terminology Criteria for Adverse Events version 6.
The rate of TRAEs will be calculated as the number of patients who develop TRAEs divided by the total number of eligible and evaluable patients.
The frequency and severity of TRAEs will be collected and summarized by descriptive statistics.
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
|
Up to 5 years
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: David A Liebner, Ohio State University Comprehensive Cancer Center
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Organic Chemicals
- Heterocyclic Compounds, 1-Ring
- Heterocyclic Compounds
- Investigative Techniques
- Therapeutics
- Clinical Laboratory Techniques
- Diagnostic Techniques and Procedures
- Diagnosis
- Hydrocarbons
- Hydrocarbons, Cyclic
- Carbohydrates
- Polycyclic Aromatic Hydrocarbons
- Hydrocarbons, Aromatic
- Polycyclic Compounds
- Glycosides
- Chemistry Techniques, Analytical
- Spectrum Analysis
- Phosphoramide Mustards
- Nitrogen Mustard Compounds
- Mustard Compounds
- Hydrocarbons, Halogenated
- Phosphoramides
- Organophosphorus Compounds
- Anthracyclines
- Naphthacenes
- Aminoglycosides
- Radiotherapy
- Daunorubicin
- Oxazines
- Radiotherapy, Conformal
- Radiotherapy, Computer-Assisted
- Cyclophosphamide
- Doxorubicin
- Ifosfamide
- Specimen Handling
- pembrolizumab
- Magnetic Resonance Spectroscopy
- Surgical Procedures, Operative
- Radiotherapy, Intensity-Modulated
Other Study ID Numbers
- OSU-26068
- NCI-2026-06505 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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