An Open-Label, Multi-Center Trial of INO-5401 + INO-9012 in Combination With Atezolizumab in Subjects With Locally Advanced Unresectable or Metastatic/Recurrent Urothelial Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 22
- 主要终点
- Antigen-Specific Cellular Immune Response
研究概览
简要总结
This was a Phase I/IIA, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical efficacy of INO-5401 + INO-9012 delivered by intramuscular (IM) injection followed by electroporation (EP), in combination with atezolizumab in participants with locally advanced unresectable or metastatic/recurrent Urothelial Carcinoma (UCa). The trial population was divided into two cohorts: Cohort A: participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti-programmed death receptor-1/programmed death receptor ligand-1 (anti-PD-1/PD-L1) therapy; Cohort B: participants with locally advanced unresectable or metastatic/recurrent UCa, who were treatment naïve and ineligible for cisplatin-based chemotherapy. A safety run-in was performed using a modified rolling six design, enrolling up to 6 participants (safety analysis participants) from Cohort A.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Sign an Informed Consent Form (ICF);
- •Have histologically or cytologically documented locally advanced unresectable or metastatic/recurrent urothelial carcinoma (including renal pelvis, ureters, urinary bladder, and urethra);
- •For Cohort A: Participants who have radiographically confirmed disease progression during or following treatment with an anti-PD-1/PD-L1 based therapy;
- •For Cohort B: No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UCa and ineligible ("unfit") for cisplatin-based chemotherapy;
- •Have measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1;
- •Have a performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) Performance Scale;
- •Have life expectancy of >/= 3 months;
- •Be willing to provide a tissue sample for pre-treatment intra-tumoral assessment of proinflammatory and immunosuppressive factors;
- •Have electrocardiogram (ECG) with no clinically significant findings as assessed by the investigator performed within 28 days prior to first dose;
- •Demonstrate adequate hematological, renal, hepatic, and coagulation function;
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study treatment;
- •For male participants: agreement not to father a child. Participants must be surgically sterile (e.g, vasectomy) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study treatment.
排除标准
- •Any approved anti-cancer therapy including chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks prior to trial Day 0 as well as current participation or recipient of treatment on a clinical trial within 28 days prior to Day 0;
- •Documented active or untreated central nervous system (CNS) metastases and/or carcinomatous meningitis;
- •Malignancies other than UCa within 3 years prior to Day 0, with the exception of those with negligible risk of metastasis or death treated with expected curative outcome;
- •Prior treatment with CD137 agonists or immune checkpoint blockade therapies;
- •Treatment with systemic immunostimulatory agents;
- •Treatment with systemic immunosuppressive medication;
- •History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins;
- •Known hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the PD-1/PD-L1 inhibitor formulation;
- •Active or history of autoimmune disease or immune deficiency;
- •History or any evidence of interstitial lung disease;
- •History of human immunodeficiency virus (HIV);
- •Active hepatitis B or active hepatitis C;
- •Severe infections within 4 weeks prior to enrollment;
- •Received therapeutic oral or IV antibiotics within 2 weeks prior to Day 0;
- •History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial; interfere with the participant's participation for the full duration of the trial, or is negatively impacted by EP treatment, or is not in the best interest of the participant to participate in the opinion of the treating investigator;
- •Prior allogeneic stem cell or solid organ transplant;
- •Uncontrolled tumor-related pain; pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures; or, hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
研究组 & 干预措施
Cohort A: Prior Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti- programmed death receptor-1/ programmed cell death-ligand 1 (PD-1/PD-L1) therapy received INO-5401 9 milligrams (mg) and INO-9012 1 mg, intramuscular (IM) injection, followed by electroporation (EP) by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, intravenous (IV) infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: CELLECTRA® 2000 (Device)
Cohort B: Naïve Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa who are treatment naïve and ineligible for cisplatin-based chemotherapy received INO-5401 9 mg and INO-9012 1 mg, IM injection, followed by EP by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, IV infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: CELLECTRA® 2000 (Device)
Cohort B: Naïve Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa who are treatment naïve and ineligible for cisplatin-based chemotherapy received INO-5401 9 mg and INO-9012 1 mg, IM injection, followed by EP by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, IV infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: Atezolizumab (Drug)
Cohort A: Prior Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti- programmed death receptor-1/ programmed cell death-ligand 1 (PD-1/PD-L1) therapy received INO-5401 9 milligrams (mg) and INO-9012 1 mg, intramuscular (IM) injection, followed by electroporation (EP) by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, intravenous (IV) infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: Atezolizumab (Drug)
Cohort A: Prior Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti- programmed death receptor-1/ programmed cell death-ligand 1 (PD-1/PD-L1) therapy received INO-5401 9 milligrams (mg) and INO-9012 1 mg, intramuscular (IM) injection, followed by electroporation (EP) by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, intravenous (IV) infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: INO-9012 (Biological)
Cohort B: Naïve Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa who are treatment naïve and ineligible for cisplatin-based chemotherapy received INO-5401 9 mg and INO-9012 1 mg, IM injection, followed by EP by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, IV infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: INO-5401 (Biological)
Cohort A: Prior Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti- programmed death receptor-1/ programmed cell death-ligand 1 (PD-1/PD-L1) therapy received INO-5401 9 milligrams (mg) and INO-9012 1 mg, intramuscular (IM) injection, followed by electroporation (EP) by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, intravenous (IV) infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: INO-5401 (Biological)
Cohort B: Naïve Anti-PD-1/PD-L1
Participants with locally advanced unresectable or metastatic/recurrent UCa who are treatment naïve and ineligible for cisplatin-based chemotherapy received INO-5401 9 mg and INO-9012 1 mg, IM injection, followed by EP by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, IV infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.
干预措施: INO-9012 (Biological)
结局指标
主要结局
Antigen-Specific Cellular Immune Response
时间窗: At baseline, Weeks 3, 6, 9, 12 and every 12 weeks thereafter up to end of study (up to approximately 2 years)
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by Investigator Review in Cohort A
时间窗: From Baseline to disease progression or death, whichever occurs first (up to approximately 2 years)
Number of Adverse Events
时间窗: From baseline up to 90 days after last dose of study medication (up to approximately 2 years and 3 months)
Number of Participants With Clinically Significant Changes in Serum Chemistry Parameters
时间窗: Up to approximately 71 months
Clinically significant changes in serum chemistry parameters were determined based on the investigator's discretion.
Number of Participants With Clinically Significant Changes in Urinalysis Parameters
时间窗: At baseline, Weeks 3, 6, 9, then every 6 weeks thereafter, up to 71 months
Clinically significant changes in urinalysis parameters were determined based on the investigator's discretion.
Antigen-Specific Immune Response
时间窗: Up to approximately 71 months
Blood and tissue samples were collected to evaluate the antigen-specific immune response to INO-5401 + INO-9012 in combination with atezolizumab. Planned assessments included: Enzyme Linked Immunosorbent Spot-forming (ELISpot) Assay, Flow cytometry, T cell receptor (TCR) sequencing, ELISA and/or gene expression analysis.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs) Treatment
时间窗: Up to approximately 71 months
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as any AEs that occurred on or after Day 0. AESIs were toxicities and immune-mediated AEs that may have occurred up to 90 days after the last dose of trial treatment. AESIs were reported by the investigator to the Sponsor within 24 hours after learning of the event.
Number of Participants With Clinically Significant Changes in Hematological Parameters
时间窗: Up to approximately 71 months
Clinically significant changes in hematological parameters were determined based on the investigator's discretion.
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Review in Cohort A
时间窗: From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months
ORR was defined as the percentage of participants who had a confirmed complete response (CR) or a partial response (PR). CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters) per RECIST 1.1.
次要结局
- ORR by Immune RECIST (iRECIST)(From Baseline to disease progression or death, whichever occurs first (up to approximately 2 years))
- Duration of Response (DoR)(From Baseline to disease progression or death, whichever occurs first (up to approximately 2 years))
- ORR by RECIST version 1.1 by Investigator Review in Cohort B(From Baseline to disease progression or death, whichever occurs first (up to approximately 2 years))
- Progression Free Survival (PFS) as Assessed by RECIST version 1.1 and iRECIST(From Baseline to disease progression or death, whichever occurs first (up to approximately 2 years))
- Overall Survival (OS)(: From Baseline to the time of death from any cause (up to approximately 2 years))
- ORR as Assessed by RECIST Version 1.1 by Investigator Review in Cohort B(From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months)
- Percentage of Participants With ORR by Immune Response Evaluation Criteria in Solid Tumors (iRECIST)(From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months)
- Duration of Response (DoR)(From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (approximately 71 months))
- Progression-Free Survival (PFS) Per RECIST Version 1.1(From the first dose of study drug to date of PD or death, whichever occurred first (up to approximately 71 months))
- PFS Per Immune RECIST (iRECIST)(From Baseline to disease progression or death, whichever occurs first (up to approximately 71 months))
- Overall Survival (OS)(From date of first dose of study drug up to death from any cause, (approximately 71 months))