A Randomized Phase III Trial of Doxorubicin + Pembrolizumab Versus Doxorubicin Alone for the Treatment of Dedifferentiated Liposarcoma (DDLPS), Undifferentiated Pleomorphic Sarcoma (UPS) and Related Poorly Differentiated Sarcomas
Overview
- Phase
- Phase 3
- Intervention
- Echocardiography Test
- Conditions
- Metastatic Dedifferentiated Liposarcoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 365
- Locations
- 458
- Primary Endpoint
- Progression free survival (PFS)
- Status
- Recruiting
- Last Updated
- yesterday
Overview
Brief Summary
This phase III trial compares the effect of immunotherapy (pembrolizumab) plus chemotherapy (doxorubicin) to chemotherapy (doxorubicin) alone in treating patients with dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS) or a related poorly differentiated sarcoma that has spread from where it first started (primary site) to other places in the body (metastatic) or that cannot be removed by surgery (unresectable). Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's deoxyribonucleic acid (DNA) and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding immunotherapy (pembrolizumab) to the standard chemotherapy (doxorubicin) may help patients with metastatic or unresectable DDLPS, UPS or a related poorly differentiated sarcoma live longer without having disease progression.
Detailed Description
PRIMARY OBJECTIVES: I. To assess whether the combination of doxorubicin and pembrolizumab will improve progression free survival (PFS) in UPS and related poorly differentiated sarcomas relative to doxorubicin alone. II. To assess whether the combination of doxorubicin and pembrolizumab will improve PFS in DDLPS relative to doxorubicin alone. KEY SECONDARY OBJECTIVE: I. To assess whether the combination of doxorubicin and pembrolizumab versus (vs) the re-introduction of pembrolizumab in the doxorubicin alone arm at disease progression (i.e., upfront pembrolizumab vs second line pembrolizumab) improves overall survival (OS) in DDLPS and the UPS family of diseases. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability in each treatment arm. II. To quantify overall response rate (ORR) and durability of response (DOR) in each treatment. EXPLORATORY OBJECTIVES: I. To evaluate the agreement between the central review and local Response Evaluation Criteria in Solid Tumors (RECIST) assessments for patients identified for central imaging review. II. To compare PFS, OS, ORR and DOR of doxorubicin with or without pembrolizumab for all patients, combining the UPS and DDLPS patients together. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive doxorubicin intravenously (IV) over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients in both arms also undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan, standard imaging scans and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months in years 2-10.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient must be \>= 18 years of age
- •Patient must have a confirmed histopathologic diagnosis of dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS) or a related poorly differentiated sarcoma. Because UPS can sometimes exist in a spectrum among related diagnoses, the following additional diagnostic will be allowed, but not limited to:
- •Pleomorphic sarcoma with inflammation or with limited areas of differentiation
- •Pleomorphic sarcoma with giant cells
- •Malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory subtypes)
- •Myxofibrosarcoma
- •Poorly differentiated sarcoma not otherwise specified (NOS)
- •Undifferentiated spindle cell sarcoma
- •Poorly differentiated spindle cell sarcoma NOS Any of these subtypes may have areas of focal myogenic differentiation
- •Patient must have metastatic or unresectable sarcoma
Exclusion Criteria
- Not provided
Arms & Interventions
Arm B (doxorubicin)
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Echocardiography Test
Arm B (doxorubicin)
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Multigated Acquisition Scan
Arm A (doxorubicin and pembrolizumab
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm A (doxorubicin and pembrolizumab
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Echocardiography Test
Arm A (doxorubicin and pembrolizumab
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Multigated Acquisition Scan
Arm B (doxorubicin)
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm B (doxorubicin)
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Diagnostic Imaging Testing
Arm A (doxorubicin and pembrolizumab
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Doxorubicin
Arm A (doxorubicin and pembrolizumab
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Pembrolizumab
Arm B (doxorubicin)
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Doxorubicin
Arm A (doxorubicin and pembrolizumab
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Intervention: Diagnostic Imaging Testing
Outcomes
Primary Outcomes
Progression free survival (PFS)
Time Frame: From randomization to documented progression (per Response Evaluation Criteria in Solid Tumors version 1.1) or death from any cause without prior progression, up to 5 years
Will be compared between the treatment arms (doxorubicin + pembrolizumab versus \[vs\] doxorubicin alone). The comparison of PFS between treatment arms will be done using a stratified (on Eastern Cooperative Oncology group performance status \[0 vs 1\]) log-rank test with a 2.5% type I error (1-sided). Will be analyzed separately for the undifferentiated pleomorphic sarcoma and related malignancies and for the dedifferentiated liposarcoma.
Progression free survival (PFS)
Time Frame: From randomization to documented progression (per Response Evaluation Criteria in Solid Tumors version 1.1) or death from any cause without prior progression, up to 5 years
Will be compared between the treatment arms (doxorubicin + pembrolizumab versus \[vs\] doxorubicin alone). The comparison of PFS between treatment arms will be done using a stratified (on Eastern Cooperative Oncology group performance status \[0 vs 1\]) log-rank test with a 2.5% type I error (1-sided). Will be analyzed separately for the undifferentiated pleomorphic sarcoma and related malignancies and for the dedifferentiated liposarcoma.
Secondary Outcomes
- Overall survival(From randomization to death, up to 5 years)