Treatment of Pyroptosis-inducible Newcasstle Disease Oncolytic Virus (PIN) Plus Sintilimab (Anti-PD1 Antibody) for Patients With Advanced pMMR/ MSS Colorectal Cancer With Hepatic Metastases:an Open-Label, Randomized,Phase I Study.
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Incidence of treatment-related AEs.
研究概览
简要总结
In this single-center,open-label, phase I study, the safety and efficacy of PIN in combination with anti-programmed cell death -1 (anti-PD1) antibody therapeutic regimen (sintilimab) will be evaluated in patients with advanced proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) with hepatic metastases . A total of 25 to 30 patients are planned to be enrolled and receive PIN plus sintilimab combined treatment. It aims to:
1).assess the safety and antitumor effects of the above combined treatment regimen. 2).detect the dynamic changes and molecular characteristics of PIN induced CD8+ T cells with special phenotype in peripheral blood (PB) and transformation of tumor microenvironment (TME) after the treatment with PIN. 3).evaluate the immunological or clinical predictive biomarkers for toxicity and efficacy.
详细描述
Over 40% of CRC patients experience liver metastasis during the course of the disease, and up to 50% present with unresectable disease. Without surgical intervention or in cases of postoperative recurrence, survival for patients treated with systemic therapies alone is dismal,especially those with pMMR/MSS (who are almost unresponsive to anti-PD1 antibody treatment).
Several clinical studies have found that oncolytic viruses (OVs) can provide clinical benefits to patients with various malignant tumors, including primary and metastatic liver tumors.In recent years, new generations of OVs developed or in clinical stages have shown better safety and stronger anti-tumor capabilities. Through genetic engineering, OVs can express target genes that have anti-tumor effects, such as granulocyte-macrophage colonystimulating factor (GM-CSF), interleukin-12(IL-12),etc, further enhancing their anti-tumor effects. Despite these advances, how to obtain a more durable antitumor immune response and long-term benefits is still an urgent clinical issue.
Previous studies have confirmed that the newcastle disease oncolytic virus (NDV) can selectively infect tumor cells while sparing normal cells, demonstrating an acceptable safety profile. In this study, investigators have developed a nove PIN . Preclinical studies and clinical studies conducted in patients with refractory advanced primary hepatocellular carcinoma have both shown that combining PIN with anti-PD1antibody therapy can reverse the immunosuppressive microenvironment and transform "cold" tumors into "hot" tumors, thereby triggering local and systemic anti-tumor immune responses and significantly improving the efficacy of the immune checkpoint inhibitor(ICI). Based on these findings, investigators are conducting this clinical trial to evaluate the safety and anti tumor activity of the PIN and sintilimab combination therapy in patients with advanced pMMR/ MSS CRC with hepatic metastases.
In this study, 25 to 30 subjects with advanced pMMR/ MSS CRC with hepatic metastases will be enrolled. The initial dose for the first cycle will be determined as 4e9 or 8e9 viral particles based on the number of injectable lesions, their longest diameter, and the tumor volume capacity.
Following the first cycle of treatment, the subsequent dose and injection sites of PIN will be adjusted based on the permissible volume of the injected tumor mass, according to the following principles:
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-75 (inclusive).
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Estimated life expectancy of more than 3 months.
- •Histologically confirmed diagnosis of unresectable locally advanced, recurrent or metastatic CRC with hepatic metastases have failed at least two lines of prior treatment.
- •Tumor tissues were identified as pMMR by immunohistochemistry (IHC) method or MSS by polymerase chain reaction (PCR).
- •At least one measurable lesion at baseline according to investigators Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1).
- •Patients with injectable lesions (those suitable for direct injection or injection with the assistance of medical imaging) in the liver metastatic lesions, defined as follows: at least one injectable lesion in the skin, mucous membrane, subcutaneous tissue, lymph node or visceral organ with a longest diameter ≥10 mm.
- •Subjects are willing to accept tumor rebiopsy in the process of this study.
- •Adequate organ function as defined by the following criteria:
- •Absolute neutrophil count (ANC) ≥ 1 x 10^9/L, Platelet count ≥50 x 10^9/ L, hemoglobin (Hgb) ≥ 80g/L ;
- •Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥60 mL/min;
- •Serum aspartate amino transferase (AST) and alanine aminotransferase (ALT), ≤5 x ULN ; Total serum bilirubin ≤3 x ULN);
- •Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings;
- •International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN;
- •Baseline oxygen saturation >91% on room air.
- •Previous treatments must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to <= grade 1 toxicity (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
- •Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
- •Voluntarily participate in this clinical trial and sign an informed consent form.
排除标准
- •Participants with DNA mismatch repair-deficient or microsatellite instability-high (dMMR /MSI-H) CRC.
- •Advanced CRC without hepatic metastases.
- •Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
- •Active central nervous system disease involvement (but allow patients with prior brain metastases treated at least 4 weeks prior to enrollment that are clinically stable and do not require intervention), or prior history of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 drug-related Central Nervous System (CNS) toxicity.
- •Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
- •Any serious underlying medical (eg, pulmonary, renal, hepatic,gastrointestinal, or neurological) or psychiatric condition or any issue that would limit compliance with study requirements.
- •Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
- •Received cytotoxic chemicals, monoclonal antibodies, immunotherapy or other intervene within 4 weeks or 5 half-lives before enrollment.
- •Received radiotherapy within 3 months before enrollment.
- •Patients with primary immunodeficiency or autoimmune diseases requiring immunosuppressive therapy.
- •The presence of uncontrollable serous membrane fluid, such as massive pleural effusion or ascites.
- •Previous or concurrent cancer within 3 years prior to treatment start except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
- •Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
- •Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation.
- •History of allergy or intolerance to study drug components.
- •Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
- •Being participating any other trials or withdraw within 4 weeks.
- •Researchers believe that other reasons are not suitable for clinical trials.
研究组 & 干预措施
PIN+sintilimab
- Initial treatment phase:
The combined treatment of PIN and sintilimab will be administered for 8 cycles; Unless PD or serious intolerable AEs. 2. Maintenance treatment phase:
For patients who completed 8 cycles treatment and obtained effective disease control, if residual tumor lesions are still accessible for local injection, combination therapy will be continued. If no injectable lesion, sintilimab will be administrated per 3 weeks till 2 years unless PD or serious intolerable AEs. 3. Salvage treatment phase:
For patients who experience disease recurrence or progression 16 weeks after ceasing PIN injection, if there are accessible lesions available for PIN injection, combination therapy will be resumed.
If specific T cells induced by PIN can be detected in PB when there is no injectable lesion, then the specific T cells are amplified and transfused for salvage therapy.
干预措施: PIN+sintilimab (Biological)
结局指标
主要结局
Incidence of treatment-related AEs.
时间窗: Up to 12 months since the initiation of treatment.
Treatment-related AEs are defined as any adverse medical events occurring since the initiation of treatment and grading these toxicities by Common Terminology Criteria for Adverse Events (CTCAE) V5.0.
次要结局
- DCR(Up to 2 years since the initiation of treatment.)
- ORR(Up to 2 years since the initiation of treatment.)
- DOR(Up to 5 years since the initiation of treatment.)
- PFS(Up to 5 years since the initiation of treatment.)
- OS(Up to 5 years since the initiation of treatment.)
- Quality of Life Assessment.(Every 6 weeks up to 2 years since the initiation of treatment.)
研究者
Han weidong
Director of Biotherapeutic Department
Chinese PLA General Hospital