Comparing Treatment With Versus Without Neoadjuvant Doxorubicin and Ifosfamide in Selected Patients With High-Risk Resectable Soft-Tissue Sarcoma
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 228
- 试验地点
- 1
- 主要终点
- Disease-free survival (DFS)
研究概览
简要总结
This phase III trial compares the effect of adding doxorubicin and ifosfamide (AIM chemotherapy) before (neoadjuvant) receiving standard treatment with pembrolizumab, radiation therapy and surgery to standard of care treatment alone in treating patients with high-risk soft-tissue sarcomas, such as undifferentiated pleomorphic sarcoma (UPS) or liposarcoma (LPS), that originate in the arms, legs (extremity) or torso (trunk wall) and can be removed by surgery (resectable). Doxorubicin comes from the bacterium Streptomyces peucetius. It damages deoxyribonucleic acid (DNA) and may kill tumor cells. It is a type of anthracycline antitumor antibiotic. Ifosfamide attaches to DNA in cells and may kill tumor cells. It is a type of alkylating agent and a type of antimetabolite. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Intensity-modulated radiation therapy (IMRT)is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. Giving neoadjuvant doxorubicin and ifosfamide with standard of care pembrolizumab, radiation therapy and surgery may be safe, tolerable, and/or more effective than standard of care therapy alone in treating patients with high-risk resectable soft tissue sarcoma of the arms, legs, or torso.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Biospecimen Collection (Procedure)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Computed Tomography (Procedure)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Magnetic Resonance Imaging (Procedure)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Multigated Acquisition Scan (Procedure)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Questionnaire Administration (Other)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Surgical Procedure (Procedure)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Transthoracic Echocardiography Test (Procedure)
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.
干预措施: Biospecimen Collection (Procedure)
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.
干预措施: Computed Tomography (Procedure)
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.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
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.
干预措施: Multigated Acquisition Scan (Procedure)
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.
干预措施: Questionnaire Administration (Other)
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.
干预措施: Surgical Procedure (Procedure)
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.
干预措施: Transthoracic Echocardiography Test (Procedure)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Doxorubicin (Drug)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Pembrolizumab (Biological)
Arm A (AIM, pembrolizumab, IMRT, surgery)
See Detailed Description
干预措施: Ifosfamide (Drug)
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.
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Disease-free survival (DFS)
时间窗: 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.
次要结局
- Patient-reported quality of life (QOL)(At baseline and at 1 and 2 years post-randomization)
- Overall survival (OS)(From randomization to death from any cause, assessed up to 5 years)
- Loco-regional DFS(Up to 5 years)
- Distant DFS(Up to 5 years)
- Incidence of treatment-related adverse events (TRAEs)(Up to 5 years)
研究者
David Liebner, MD
Principal Investigator
Ohio State University Comprehensive Cancer Center