This phase II trial compares the effect of immunotherapy with ipilimumab and nivolumab alone to their combination with cabozantinib in treating patients with soft tissue sarcoma that has spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply and may also prevent the growth of new blood vessels that tumors need to grow. By these actions it may help slow or stop the spread of cancer cells. Adding cabozantinib to the combination of ipilimumab and nivolumab may be better in stopping or slowing the growth of tumor compared to ipilimumab and nivolumab alone in patients with advanced soft tissue sarcoma.
PRIMARY OBJECTIVE: I. Assess progression free survival (PFS) of ipilimumab + nivolumab versus (vs.) the cabozantinib + nivolumab + ipilimumab combination in patients with metastatic, or locally advanced, surgically unresectable soft tissue sarcoma (STS) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. SECONDARY OBJECTIVES: I. Evaluate the response rate (complete response \[CR\]+partial response \[PR\]) of ipilimumab + nivolumab vs. the cabozantinib + nivolumab + ipilimumab combination. II. Evaluate the response rate (CR+PR) of cabozantinib + ipilimumab + nivolumab in (crossover) patients whose disease has progressed on ipilimumab + nivolumab therapy. III. Assess the number of tumor-infiltrating CD8+ T cells in tumor biopsies before and after treatment. EXPLORATORY OBJECTIVES: I. Measure tumor-infiltrating CD3+ T cells and CD68+ macrophages in biopsy specimens. II. Evaluate genomic alterations in circulating tumor DNA (ctDNA) and their potential association with therapy response or resistance. III. Investigate whether response is associated with genetic aberrations and/or tumor mutational burden. IV. Analyze total MET and activated MET (p1235-MET) in biopsy specimens before and after study treatment and evaluate molecular target engagement by cabozantinib (as shown by a lower phosphorylated \[p\]MET/MET ratio). V. Evaluate the objective response rate in patients treated with ipilimumab + nivolumab or the cabozantinib + nivolumab + ipilimumab combination using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST). OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive nivolumab intravenously (IV) over 30-60 minutes and ipilimumab IV over 60-90 minutes on day 1 of each cycle. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV over 30 minutes on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans, tumor biopsies, and collection of blood and urine samples throughout the trial. Patients can crossover from Arm A to Arm B at the time of disease progression. ARM B: Patients receive cabozantinib orally (PO) once daily (QD) or every other day (QOD), nivolumab IV over 30-60 minutes on day 1, and ipilimumab IV over 60-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV over 30 minutes on day 1 and cabozantinib PO QD or QOD of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients crossing over after ≥ 4 ipilimumab + nivolumab (Arm A) cycles will receive cabozantinib and nivolumab only on Arm B; patients that cross over after \< 4 ipilimumab + nivolumab (Arm A) cycles will receive the remaining cycles of ipilimumab (totaling 4 doses) plus nivolumab in combination with cabozantinib. Patients who crossover will start with the every 3 weeks cycle 1 treatment even if they will not be receiving ipilimumab. Patients also undergo CT or MRI scans, tumor biopsies, and collection of blood and urine samples throughout the trial. After completion of study treatment, patients are followed for 30 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
66
Undergo biopsy
Undergo collection of blood and urine sample
Given PO
Undergo CT
Given IV
Undergo MRI
Given IV
City of Hope Comprehensive Cancer Center
Duarte, California, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
Keck Medicine of USC Koreatown
Los Angeles, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Progression-free survival (PFS)
Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. The primary analysis will be a logrank test and will be performed once 52 PFS events have been observed. For Arm A (ipilimumab + nivolumab), a within-arm interim futility analysis will be performed; if at least one partial response, complete response, or stable disease (SD) (SD with duration of at least 6 months) is observed among the first 14 patients enrolled to this arm. In addition, a single interim futility analysis (Wieand rule) will be performed at 50% information (26 PFS events).
Time frame: Up to 30 days after completion of study treatment
Objective response rate
Defined as complete response or partial response by RECIST v1.1. Response rates within the two study arms will be (separately) reported and will be directly compared using a two-sample test of proportions. In addition, will report the rate of objective response to cabozantinib + ipilimumab + nivolumab triplet therapy in patients who have crossed over after their disease progressed on ipilimumab + nivolumab doublet.
Time frame: Up to 30 days after completion of study treatment
Number of tumor-infiltrating CD8+ T cells
Will be evaluated in tumor biopsies before and after treatment. Changes between paired samples will be interpreted as being likely treatment-induced if they exceed the sampling, biological, and technical variabilities determined for the assay. Unpaired baseline and post-treatment measurements may also be assessed for correlation with response, which will shed light on possible CD8+ T cell density or infiltration requirements that could inform future trial designs.
Time frame: Baseline and pre-cycle 3
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, United States
...and 17 more locations