A Phase 1b/2a Dose-escalation and Safety/Efficacy Evaluation Study of Pexa-Vec (Thymidine Kinase-Deactivated Vaccinia Virus Plus GM-CSF) in Combination With Cemiplimab (REGN2810; Anti-PD-1) in Patients With Metastatic or Unresectable Renal Cell Carcinoma (RCC)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 95
- 试验地点
- 39
- 主要终点
- Maximum tolerated dose(MTD) / Maximum feasible dose (MFD)
研究概览
简要总结
This is a Phase 1b/2a, open-label, multi-center, dose-escalation and safety/efficacy evaluation trial of Pexa-Vec plus Cemiplimab in patients with metastatic or unresectable renal cell carcinoma (RCC). The trial consists of a dose-escalation stage, where the maximum feasible dose of Pexa-Vec in combination with Cemiplimab will be determined, followed by an expansion stage. During the expansion patients will receive Cemiplimab alone or in combination with Pexa-Vec, which will be administered either through intravenous (IV) or intratumoral (IT) injection.
详细描述
For Pexa-Vec IV infusions (Part 1 / Part 2: Arm C and Arm D): Day -7, 1, 8, and 15), patients allocated to Part 1 or Part 2: Arm C or Arm D will receive an IV infusion of Pexa-Vec in approximately 250 mL buffered saline.
For Pexa-Vec IT Injections (Part 2 Arm A + Arm B), patients in Part 2, Arm A (and those in Arm B who progress on Cemiplimab monotherapy) will receive an IT injection of Pexa-Vec in a volume of buffered saline dependent on size of tumor(s).
For administration of Cemiplimab, Cemiplimab will be administered at a dose of 350 mg IV infusion over 30 minutes (±10 minutes) every 3 weeks per manufactures guidelines.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Histologically or cytologically confirmed metastatic or unresectable clear cell renal cell carcinoma (ccRCC)
- •Part 2 Arm D ONLY: Patients must be refractory to anti PD-1 or anti-PD-L1 (either as monotherapy or in-combination with other approved checkpoint inhibitors or targeted therapies according to their approved label) and patients must meet all of the following criteria:
- •Received treatment of approved anti PD-1 or anti-PD-L1 (dosed per label of the country providing the clinical site) for at least 6 weeks. History of anti-PD-L1 only is not allowed.
- •Progressive disease after anti PD-1 or anti-PD-L1 will be defined according to RECIST v1.
- •The initial evidence of progressive disease is to be confirmed by a second assessment, no less than 4 weeks from the date of the first documented progressive disease, in the absence of rapid clinical progression. (This determination is made by the Investigator; the Sponsor will collect imaging scans for retrospective analysis. Once progressive disease is confirmed, the initial date of progressive disease documentation will be considered the date of disease progression).
- •Documented disease progression within 12 weeks of the last dose of anti PD-1 or anti-PD-L
- •Patients who were re-treated or on maintenance with anti-PD-1 or anti-PD-L1 will be allowed to enter the study as long as there is documented progressive disease within 12 weeks of the last treatment date.
- •Naive to systemic therapy for RCC or have progressed after, or were intolerant of, prior systemic therapy.
- •Measurable disease based on RECIST v1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
- •Karnofsky performance status of 70-100
- •Age ≥20 years old (or appropriate age of consent for the region)
- •Adequate hematological, hepatic, and renal function
排除标准
- •Known significant immunodeficiency due to underlying illness (e.g., human immunodeficiency virus [HIV] / acquired immune deficiency syndrome [AIDS]) and/or immune-suppressive medication including high-dose corticosteroids
- •Part 2 only: Arm A,B,C: Prior treatment with any anti-cancer immunotherapy, including therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (prior IL-2 or interferon allowed) . For Part 1: patients are excluded if they were intolerant to anti-PD-1 or anti-PD-L1 targeted therapies
- •Major surgery within 4 weeks of study treatment (minor surgical procedures are allowed)
- •Ongoing severe inflammatory skin condition requiring prior medical treatment
- •History of eczema requiring prior medical treatment
- •Tumor(s) invading a major vascular structure (e.g., carotid artery) or other key anatomical structure (e.g., pulmonary airway) OR viable central nervous system malignancy
- •Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions.
- •Symptomatic cardiovascular disease, including but not limited to significant coronary artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months.
- •Asymptomatic cardiovascular disease (current or past history) unless cardiology consultation and clearance has been obtained for study participation.
- •Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after all Pexa-Vec treatments
- •Use of interferon/pegylated interferon (PEG-IFN) or ribavirin that cannot be discontinued within 14 days prior to any Pexa-Vec dose
- •Known active Hepatitis B or Hepatitis C
研究组 & 干预措施
Part 2-Arm A, Pexa-Vec (IT) and Cemiplimab
Pexa-Vec will be administered via IT (intratumoral) injection every 2 weeks for 3 treatments.
Cemiplimab will be administered via IV infusion every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Cemiplimab (Biological)
Part 2-Arm A, Pexa-Vec (IT) and Cemiplimab
Pexa-Vec will be administered via IT (intratumoral) injection every 2 weeks for 3 treatments.
Cemiplimab will be administered via IV infusion every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Pexastimogene Devacirepvec (Pexa-Vec) (Biological)
Part 2-Arm B, Cemiplimab
Cemiplimab will be administered via IV infusion every 3 weeks.
At disease progression, Pexa-Vec will be administered via IT (intratumoral) injection every 2 weeks for 3 treatments. Cemiplimab will continue every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Pexastimogene Devacirepvec (Pexa-Vec) (Biological)
Part 2-Arm B, Cemiplimab
Cemiplimab will be administered via IV infusion every 3 weeks.
At disease progression, Pexa-Vec will be administered via IT (intratumoral) injection every 2 weeks for 3 treatments. Cemiplimab will continue every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Cemiplimab (Biological)
Part 2-Arm C, Pexa-Vec (IV) and Cemiplimab
Pexa-Vec will be administered via IV infusion once per week for 4 treatments.
Cemiplimab will be administered via IV infusion every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Pexastimogene Devacirepvec (Pexa-Vec) (Biological)
Part 2-Arm C, Pexa-Vec (IV) and Cemiplimab
Pexa-Vec will be administered via IV infusion once per week for 4 treatments.
Cemiplimab will be administered via IV infusion every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Cemiplimab (Biological)
Part 2-Arm D, Pexa-Vec (IV) and Cemiplimab
Pexa-Vec will be administered via IV infusion once per week for 4 treatments.
Cemiplimab will be administered via IV infusion every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Cemiplimab (Biological)
Part 2-Arm D, Pexa-Vec (IV) and Cemiplimab
Pexa-Vec will be administered via IV infusion once per week for 4 treatments.
Cemiplimab will be administered via IV infusion every 3 weeks.
Pexastimogene Devacirepvec (Pexa-Vec): Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
Cemiplimab: Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
干预措施: Pexastimogene Devacirepvec (Pexa-Vec) (Biological)
结局指标
主要结局
Maximum tolerated dose(MTD) / Maximum feasible dose (MFD)
时间窗: 36 days after first treatment
MTD/MFD of Pexa-Vec administered by IV infusion in combination with Cemiplimab
Severity and frequency of adverse events to determine safety of Pexa-Vec administered by IV infusions or IT injections in combination with IV Cemiplimab
时间窗: From date of first treatment until 28 days after last treatment
Safety will be determined by assessing the severity and frequency of adverse events and laboratory toxicity using CTCAE v4.03
Overall response rate
时间窗: Every 9 weeks, then every 12 weeks after 1 year until date of first documented progression, up to 72 months
Evaluate anti-tumor activity and efficacy of IV or IT Pexa-Vec combined with IV Cemiplimab with respect to overall response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
次要结局
- Progression free survival(Every 9 weeks, then every 12 weeks after 1 year until date of first documented progression, up to 72 months)
- Disease control rate(Every 9 weeks, then every 12 weeks after 1 year until date of first documented progression, up to 72 months)
- Best radiographic response(Every 9 weeks, then every 12 weeks after 1 year until date of first documented progression, up to 72 months)
- Overall survival(Every 9 weeks, then every 12 weeks after 1 year until date of death from any cause, up to 72 months)