Phase II Study of Neoadjuvant Checkpoint Blockade in Patients With Surgically Resectable Undifferentiated Pleomorphic Sarcoma and Dedifferentiated Liposarcoma
概览
- 阶段
- 2 期
- 干预措施
- Nivolumab
- 疾病 / 适应症
- Dedifferentiated Liposarcoma
- 发起方
- M.D. Anderson Cancer Center
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Pathologic response
- 状态
- 进行中（未招募）
- 最后更新
- 上个月
概览
简要总结
This phase II trial studies how well nivolumab with and without ipilimumab and radiation therapy when given before surgery works in treating patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab, ipilimumab, and radiation therapy may work better in treating patients with undifferentiated pleomorphic sarcoma.
详细描述
PRIMARY OBJECTIVES: I. To assess the pathologic response of nivolumab monotherapy and nivolumab and ipilimumab combination therapy administered in the neoadjuvant setting with and without radiation in patients with treatment-naive primary or locally recurrent resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. SECONDARY OBJECTIVES: I. To assess the change in percent viable tumor cells, percent hyalinization and necrosis, proliferation by phosphohistone H3 in biopsy specimens obtained at baseline and on treatment and surgical specimens. II. To assess the change in immune infiltrate in response to neoadjuvant nivolumab monotherapy and neoadjuvant nivolumab and ipilimumab combination therapy in patients with resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. III. To assess the objective response rate (ORR) of nivolumab monotherapy and nivolumab and ipilimumab combination therapy administered in the neoadjuvant setting as assessed by imaging (Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 and Immune Related Response Criteria \[irRC\]) in patients with resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. IV. To assess the 12- and 24-month recurrence-free survival (RFS) and overall survival (OS) of patients with resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma treated with neoadjuvant nivolumab monotherapy or nivolumab and ipilimumab combination therapy. V. To evaluate the safety of nivolumab monotherapy and combination ipilimumab and nivolumab in the neoadjuvant setting and peri-operatively by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. EXPLORATORY OBJECTIVES: I. To identify immunologic and genomic markers correlating with clinical response to nivolumab monotherapy and ipilimumab with nivolumab combination therapy. II. To assess the quality of life of patients with dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma undergoing neoadjuvant immunotherapy followed by surgical resection. III. To analyze the microbiome to determine the role of the microbiome on development and response to therapy. OUTLINE: Patients are randomized to 1 of 4 arms. ARM A: Patients receive nivolumab intravenously (IV) over 1 hour on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43. ARM B: Patients receive nivolumab as in Arm A. Patients also receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43. ARM C: Patients receive nivolumab IV over 1 hour on days 1, 15, 29, and 43. Patients also undergo radiation therapy (RT) once daily (QD) for 5 days during days 15-47 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71. ARM D: Patients receive nivolumab as in Arm C, ipilimumab as in Arm B, and RT as in Arm C in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71. After completion of study treatment, patients are followed up at 6 and 18 weeks and then every 3 months for up to 2 years.
研究者
入排标准
入选标准
- •Adult subjects with treatment naive primary or locally recurrent dedifferentiated liposarcoma (DDLPS) of the retroperitoneum or undifferentiated pleomorphic sarcoma (UPS) of the trunk or extremity will be eligible for inclusion in this study only if all of the following criteria apply.
- •Patients must be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •Patients must have disease determined to be surgically resectable and candidates for upfront surgery as agreed upon by a multidisciplinary consensus (Surgical Oncology, Medical Oncology, Radiation Oncology) after presentation at sarcoma multidisciplinary conference. Resectable tumors are defined as having no significant vascular, neural or bony involvement. Only cases where a complete surgical resection can safely be achieved are defined as resectable.
- •Patients will be evaluated by the anesthesia team prior to surgery.
- •Patient must have recent imaging (computed tomography \[CT\] or magnetic resonance imaging \[MRI\], as appropriate) within 4 weeks of trial enrollment, demonstrating measurable disease as defined by RECIST 1.
- •Patients must have at least one tumor amenable to serial biopsy in clinic or be willing to undergo serial biopsies through image-guided procedures during the neoadjuvant phase of the protocol. Patients must be willing to provide tumor samples at the time points.
- •Patients must be medically fit to undergo surgery as determined by the treating medical and surgical oncology team and have Eastern Cooperative Oncology Group (ECOG) performance status 0-
- •Patients must have life expectancy \> 6 months.
- •Patients must be immunotherapy-naive. Those who have previously been treated with conventional chemotherapy for a prior history of sarcoma in the adjuvant setting may be included.
- •White blood cell count \> 3 K/uL.
排除标准
- •Disease that is considered surgically unresectable, including, but not limited to significant vascular, neural, or bone involvement, and in cases where a complete surgical resection cannot be safely performed.
- •Prior intra-abdominal surgery within 4 weeks of trial enrollment.
- •Prior chemotherapy or targeted small molecule therapy of the current sarcoma. In patients with locally recurrent disease, previous systemic chemotherapy of the primary tumor is allowed, as long as treatment was completed prior to study enrollment and patient has recovered (i.e., \< grade 1 or at baseline) from any adverse events due to previously administered agents.
- •Prior radiation therapy for sarcoma in the same area.
- •Active concurrent second malignancy.
- •Prior or concurrent immunotherapy, including treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody; tumor vaccines; interferon, or interleukins.
- •Prior malignancy active within the previous 2 years except for patient's prior diagnosis of sarcoma and locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast with local control measures (surgery, radiation).
- •Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks of trial enrollment.
- •Pregnant or lactating female.
- •Unwillingness or inability to follow the procedures required in the protocol.
研究组 & 干预措施
Arm A (nivolumab)
Patients receive nivolumab IV over 1 hour on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43.
干预措施: Nivolumab
Arm B (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm A. Patients also receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43.
干预措施: Ipilimumab
Arm B (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm A. Patients also receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43.
干预措施: Nivolumab
Arm C (nivolumab, RT)
Patients receive nivolumab IV over 1 hour on days 1, 15, 29, and 43. Patients also undergo RT QD for 5 days during days 15-47 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.
干预措施: Nivolumab
Arm C (nivolumab, RT)
Patients receive nivolumab IV over 1 hour on days 1, 15, 29, and 43. Patients also undergo RT QD for 5 days during days 15-47 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.
干预措施: Radiation Therapy
Arm D (nivolumab, ipilimumab, RT)
Patients receive nivolumab as in Arm C, ipilimumab as in Arm B, and RT as in Arm C in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.
干预措施: Ipilimumab
Arm D (nivolumab, ipilimumab, RT)
Patients receive nivolumab as in Arm C, ipilimumab as in Arm B, and RT as in Arm C in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.
干预措施: Nivolumab
Arm D (nivolumab, ipilimumab, RT)
Patients receive nivolumab as in Arm C, ipilimumab as in Arm B, and RT as in Arm C in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.
干预措施: Radiation Therapy
结局指标
主要结局
Pathologic response
时间窗: At day 43 (Arm A/B) or 71 (Arm C/D)
Pathologic response will be assessed at time of surgical resection by percentage hyalinization. The study will estimate the difference of the pathologic response between the treatment arms (A versus \[vs\] B, C vs D) along with the estimate of variation of the difference. Given the longitudinal nature of the data, linear mixed effect models for longitudinal measures will be employed to assess the change in the magnitude of the measures over time adjusting for multiple covariates including patient's characteristics, and tumor characteristics. Appropriate transformation of the outcome assessment values will be used to satisfy the normality assumption of linear mixed effect model.
次要结局
- Assessment of immunologic changes in the tumor microenvironment and blood(Up to 2 years)
- Overall survival (OS)(At 12 and 24 months)
- Recurrence-free survival (RFS)(At 12 and 24 months)
- Objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and Immune Related Response Criteria (irRC)(At days 43 and 71)
- Health status assessment(At baseline, day 15, and day 43 or 71)
- Change in Immune Infiltrate in Response to Neoadjuvant Nivolumab Monotherapy and Neoadjuvant Nivolumab and Ipilimumab Combination Therapy(Up to 2 years)
- Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0(Up to 100 days)