Randomized Phase 2 Study of Cabozantinib, Ipilimumab, and Nivolumab in Patients With Soft Tissue Sarcoma
概览
- 阶段
- 2 期
- 干预措施
- Nivolumab
- 疾病 / 适应症
- 未指定
- 发起方
- National Cancer Institute LAO
- 入组人数
- 66
- 试验地点
- 54
- 主要终点
- Progression-free survival (PFS)
- 状态
- 进行中（未招募）
- 最后更新
- 11天前
概览
简要总结
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.
详细描述
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 urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. 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 urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. After completion of study treatment, patients are followed for 30 days.
研究者
入排标准
入选标准
- •Patients must have histologically or cytologically confirmed metastatic STS, specifically undifferentiated pleomorphic sarcoma (UPS), extraskeletal myxoid chondrosarcoma (EMC), liposarcoma (LPS) or non-uterine leiomyosarcoma (LMS) that are locally advanced and surgically unresectable
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) by chest x-ray or as \>= 10 mm (\>= 1 cm) with CT scan, MRI, or calipers by clinical exam. Disease will be measured by RECISTv1.1
- •Patients with prior treatment with MET or VEGFR inhibitors are allowed. However, prior cabozantinib-treated patients will not be allowed. Prior ipilimumab in combination with nivolumab-treated patients will not be allowed
- •Age \>= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Absolute neutrophil count \>= 1,000/mcL
- •Platelets \>= 75,000/mcL
- •Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN
- •Creatinine =\< 1.5 x institutional ULN OR glomerular filtration rate (GFR) \>= 50 mL/min/1.73 m\^2
排除标准
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia, stable hyperthyroidism on replacement therapy, type-1 diabetes, well-controlled on insulin, and non-clinically significant toxicities at the discretion of the study Principal Investigator
- •Patients who are receiving any other investigational agents
- •Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity of cabozantinib will be determined following review of their cases by the Principal Investigator. Patients who are taking enzyme-inducing anticonvulsant agents are not eligible
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, or ipilimumab
- •Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) are not allowed for this study. Because the lists of these agents are constantly changing, frequently updated lists available at http://medicine.iupui.edu/clinpharm/ddis/table.asp or other reliable resources will be consulted. Patients who need to come off CYP3A4 inhibitors/inducers should adhere to a washout period of at least 5 times the half-life of the CYP3A4 inhibitors and 14 days of CYP3A4 inducers
- •Patients with any other significant condition(s) that would make this protocol unreasonably hazardous are ineligible. Patients with uncontrolled intercurrent illness or clinical evidence of an active infection at the time of enrollment are ineligible
- •Pregnant women are excluded from this study because cabozantinib is a receptor kinase inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib in combination with nivolumab and ipilimumab, breastfeeding should be discontinued if the mother is treated with cabozantinib. These potential risks may also apply to other immunotherapeutic agents (ipilimumab and nivolumab) used in this study
- •Patients with any of the following within 12 weeks prior to the first dose of cabozantinib: gastrointestinal bleeding, hemoptysis or pulmonary hemorrhage, radiographic evidence of cavitating pulmonary lesion(s), evidence of tumor invasion of the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum, or anus), or any evidence of endotracheal or endobronchial tumor or encasement of any major blood vessels are ineligible
- •The patient is unable to swallow tablets
- •The patient has a corrected QT interval calculated by the Fridericia formula (QTcF) \>= 470 ms within 28 days before enrollment
研究组 & 干预措施
Arm A (nivolumab, ipilimumab)
Patients receive nivolumab 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 CT or MRI scans, tumor biopsies, and collection of urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. Patients can crossover from Arm A to Arm B at the time of disease progression.
干预措施: Nivolumab
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Magnetic Resonance Imaging
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Nivolumab
Arm A (nivolumab, ipilimumab)
Patients receive nivolumab 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 CT or MRI scans, tumor biopsies, and collection of urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. Patients can crossover from Arm A to Arm B at the time of disease progression.
干预措施: Biopsy Procedure
Arm A (nivolumab, ipilimumab)
Patients receive nivolumab 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 CT or MRI scans, tumor biopsies, and collection of urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. Patients can crossover from Arm A to Arm B at the time of disease progression.
干预措施: Biospecimen Collection
Arm A (nivolumab, ipilimumab)
Patients receive nivolumab 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 CT or MRI scans, tumor biopsies, and collection of urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. Patients can crossover from Arm A to Arm B at the time of disease progression.
干预措施: Computed Tomography
Arm A (nivolumab, ipilimumab)
Patients receive nivolumab 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 CT or MRI scans, tumor biopsies, and collection of urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. Patients can crossover from Arm A to Arm B at the time of disease progression.
干预措施: Magnetic Resonance Imaging
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Biopsy Procedure
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Biospecimen Collection
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Computed Tomography
Arm A (nivolumab, ipilimumab)
Patients receive nivolumab 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 CT or MRI scans, tumor biopsies, and collection of urine samples throughout the trial. Patients may also optionally undergo collection of blood samples at baseline. Patients can crossover from Arm A to Arm B at the time of disease progression.
干预措施: Ipilimumab
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Cabozantinib
Arm B (cabozantinib, nivolumab, ipilimumab)
See Detailed Description.
干预措施: Ipilimumab
结局指标
主要结局
Progression-free survival (PFS)
时间窗: Up to 30 days after completion of study treatment
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 or once all patients have gone off trial, whichever comes first. 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).
次要结局
- Objective response rate(Up to 30 days after completion of study treatment)
- Number of tumor-infiltrating CD8+ T cells(Baseline and pre-cycle 3)