Maintenance Ipilimumab + Nivolumab Post Induction Chemotherapy + SBRT for First Line
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Objective tumor response rate1 (ORR1) in study patients, assessed by RECIST v1.1
研究概览
简要总结
In this study we aim to test the efficacy of a combined and novel approach including induction chemotherapy (per standard of care) followed by SBRT and maintenance ipililumab + nivolumab in the first line setting of stage IV PDAC.
Study Hypothesis:
Cytotoxic chemotherapy followed by hypofractionated radiotherapy will sensitize pancreatic cancer to immunotherapy consisting of combined PD-1 and CTLA4 blockade. We hypothesize that direct targeting of the pancreatic cancer cells by chemotherapy and hypofractionated radiotherapy is necessary for initial anti-tumor response. Furthermore, the combination of immunotherapy as a maintenance strategy will have profound anti-tumor efficacy in this setting.
Implications of hypothesis:
- Improved response rate above historical controls
- Lengthened progression-free survival
- Improved overall-survival
Exploratory Hypothesis:
We hypothesize that baseline markers of immune activation such as Tumor Infiltrating Lymphocytes and CD8+ lymphocytes will correlate with response to ipililumab + nivolumab and that responders will have distinct tumor immune phenotype as determined by immunohistochemistry and gene expression profiling compared to nonresponders.
详细描述
This is a single arm, single institution study, which aims to evaluate the efficacy and safety of combination therapy with radiosurgery nivolumab and ipilimumab as a maintenance regimen following first line induction chemotherapy in patients with metastatic pancreatic cancer.
Chemotherapy will be administrated for a minimum of 4 cycles. Patients who have not progressed on chemotherapy will receive SBRT to one primary/metastatic tumor, followed by ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks). After a further 8 weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab until disease progression, non-responders will receive very low dose radiation to metastatic sites (this will only be allowed once) prior to continuing ipilimumab + nivolumab until disease progression. Immunotherapy will be continued until disease progression or up to 24 months in the absence of disease progression or unacceptable toxicity.
Study rationale Overall rational in Brief Although there is evidence for that the immune system plays an active role in pancreatic cancer, until now checkpoint inhibitors have yet to demonstrate efficacy in this population. We hypothesize that combining irradiation along with checkpoint inhibition in a patient population demonstrating stable disease in a first line setting will be a novel approach towards the treatment of pancreatic cancer.
Rationale for Combining Nivolumab and Ipilimumab The roles of CTLA-4 and PD-1 in inhibiting antitumor responses are largely distinct. Whereas CTLA-4 is thought to regulate T-cell proliferation early in the immune response, primarily in lymph nodes, PD-1 suppresses T cells at a later stage in the immune response, primarily in peripheral tissues.
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may improve antitumor activity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Provide written informed consent and be between the ages of 18 and up.
- •Metastatic histology proven adenocarcinoma of the pancreas. If patient has primary resected tumor, tumor recurrence needs to >12 months after last adjuvant chemotherapy.
- •ECOG performance status 0-
- •Life expectancy of >= 3 months.
- •If female and of child-bearing potential, have a negative serum pregnancy test during screening.
- •Agree to use of a barrier method of contraception if sexually active (both men and women) from the time of administration of the first treatment and for at least 5 months after treatment.
- •Have PT - INR < 1.5, WBC > 2000/μL absolute neutrophil count (ANC) > 1500 x 103 cells/ μL, platelets ≥ 100,000/ μL, and hemoglobin >= 9 mg/dL Serum creatinine < 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockroft-Gault formula) AST/ALT: < 3.0 x ULN Total bilirubin < 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0x ULN).
- •A disease lesion, including primary pancreas lung/liver/peritoneal/bone /lynph nodes, that is suitable for SBRT as deemed by the investigator.
- •Screening procedures completed within 4 weeks of starting treatment.
- •Availability of at least 1 measurable lesion not previously irradiated that is not planned to be irradiated with SBRT during the study and measurable as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.
- •Patient received minimum of 4 cycles of first-line chemotherapy of induction chemotherapy per investigator's decision without progression.
- •Adjuvant treatment is allowed if ≥ 12 months has passed since last adjuvant treatment.
- •Fresh biopsy specimens are required unless biopsy deemed unsafe by investigator.
排除标准
- •Clinically significant pancreatitis within 8 weeks of treatment.
- •Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 5 months after the study are excluded.
- •A medical condition or any intercurrent medical illness or other medical condition that would in the judgment of the investigator compromise patient safety or the objectives of the study.
- •Have participated in any therapeutic research study within the last 4 weeks.
- •Known medical condition that predisposes to radiation toxicity (e.g. scleroderma)
- •Has a known MSI-H phenotype or a known MMR deficiency.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with type I diabetes mellitus, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects that require intermittent use of bronchodilators or local steroids, e.g., inhaled or topical steroids, at a dose of less than the equivalent of 10mg prednisone daily, would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
- •Has evidence of interstitial lung disease or active, non-infectious pneumonitis
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- •Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial (chronic pain management medications should not exclude study participation).
研究组 & 干预措施
study arm
Study treatments include SBRT (Stereotactic radiation therapy) to one primary/metastatic tumor (3 fractions of 8Gy) , and ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks) .
Every 8 weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab until disease progression, non-responders will receive very low dose radiation (2Gy single fraction to metastatic lesions of choice) prior to continuing ipilimumab + nivolumab .
干预措施: Nivolumab (Drug)
study arm
Study treatments include SBRT (Stereotactic radiation therapy) to one primary/metastatic tumor (3 fractions of 8Gy) , and ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks) .
Every 8 weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab until disease progression, non-responders will receive very low dose radiation (2Gy single fraction to metastatic lesions of choice) prior to continuing ipilimumab + nivolumab .
干预措施: ipilimumab (Drug)
study arm
Study treatments include SBRT (Stereotactic radiation therapy) to one primary/metastatic tumor (3 fractions of 8Gy) , and ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks) .
Every 8 weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab until disease progression, non-responders will receive very low dose radiation (2Gy single fraction to metastatic lesions of choice) prior to continuing ipilimumab + nivolumab .
干预措施: Stereotactic body radiation therapy (Radiation)
study arm
Study treatments include SBRT (Stereotactic radiation therapy) to one primary/metastatic tumor (3 fractions of 8Gy) , and ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks) .
Every 8 weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab until disease progression, non-responders will receive very low dose radiation (2Gy single fraction to metastatic lesions of choice) prior to continuing ipilimumab + nivolumab .
干预措施: Low dose irradiation (Radiation)
结局指标
主要结局
Objective tumor response rate1 (ORR1) in study patients, assessed by RECIST v1.1
时间窗: From first dose of SBRT until first progression, approximately 36 months.
Proportion of subjects showing best overall response of complete response (CR) or partial response (PR)
Objective tumor response rate 2 (ORR2) after first progression, assessed by RECIST v1.1
时间窗: From the date of low dose radiation until second progression, approximately 36 months
Proportion of subjects with best overall response of CR or PR, in progressors who continue to receive low dose radiation and re-challenge nivolumab and ipilimumab
次要结局
- Progression free survival 1 (PFS 1) in stage 4 PDAC, assessed by RECIST 1.1(From first dose of SBRT until first progression, approximately 36 months)
- Objective tumor progression free survival 2 (PFS 2) in progressors, assessed by RECIST v1.1(From the date of low dose radiation until second progression, approximately 36 months)
- Incidence of Treatment-Emergent Adverse Events, as assessed by CTCAE version 5.0(From day of subject's written consent until study termination, approximately 36 months)
- Median Overall survival (OS)(From documented metastatic disease until death (or date of last documentation of being alive), approximately 36 months)
研究者
Dr. Talia Golan
Medical diractor of phase 1 clinical trials unit and Sheba pancreatic cancer program
The Chaim Sheba Medical Center