A Phase 1/2a, Multicenter, Open-label Trial of TBio-6517, an Oncolytic Vaccinia Virus, Administered Alone and in Combination With Pembrolizumab, in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 27
- 试验地点
- 9
- 主要终点
- Incidence of adverse events when TBio-6517 administered by direct injection into tumor(s) alone at each dose level
研究概览
简要总结
To determine the recommended Phase 2 dose (RP2D) of TBio-6517 when administered by direct injection into tumor(s) or intravenously and when combined with pembrolizumab in patients with solid tumors (RIVAL-01).
详细描述
This is a Phase 1/2a dose escalation study with TBio-6517 administered by direct injection into tumor(s) or by intravenous infusion. The Phase 1 portion has 4 arms; the first arm (Arm A) will determine the RP2D of TBio-6517 alone when directly injected into tumor(s), and the second arm (Arm B) will determine the RP2D of TBio-6517 when combined with pembrolizumab. The third and fourth arms will determine the RP2D of TBio-6517 when given intravenously alone and with pembrolizumab, respectively.
In the Phase 2a portion, the clinical benefit of TBio-6517 combined with pembrolizumab will be further explored in patients with Microsatellite Stable Colorectal Cancer (MSS-CRC), Cholangiocarcinoma (CCA), Cutaneous Melanoma, and Cutaneous Squamous Cell Carcinoma of the Skin (cSCC), as assessed by overall response rate (ORR) from central radiology review.
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
- •Have a histologically or pathologically documented, locally-advanced or metastatic solid tumor for which standard curative measures do not exist or are no longer effective
- •Measurable disease as per RECIST 1.1 criteria
- •At least one tumor amenable to safe ITu injections and biopsies
- •ECOG performance status 0 or 1
- •Demonstrate adequate organ function
- •Must be willing to comply with all protocol procedures and adhere to post-treatment care instructions
- •Additional Inclusion criteria exist
- •For patients in phase 2 only: Have a histologically or cytologically confirmed advanced (metastatic and/or unresectable) solid tumor listed below, that is incurable and for which prior standard treatment has failed:
- •Advanced (unresectable) or metastatic, intra or extra hepatic adenocarcinoma originating from the bile duct, CCA (Cohort 1) having progressed on at least 1 line of systemic therapy (including targeted therapy if eligible)
- •Locally advanced or metastatic cutaneous melanoma (Cohort 2) that has failed anti-PD-1 or anti-PDL1 therapy (+/- anti-CTLA-4 therapy) and if BRAF+, having failed a BRAF/ +/-MEK inhibitor
- •Locally advanced or metastatic cSCC (Cohort 3) that has not received systemic therapy (e.g., local resection or local topical therapy is permitted).
- •Locally advanced or metastatic MSS-CRC (Cohort 4) patients that have progressed on at least 2 prior lines of systemic therapy which should include irinotecan and oxaliplatin +/- targeted therapy if warranted.
排除标准
- •Prior systemic therapy, including experimental, surgery or radiation therapy within 4 weeks and must have recovered from acute toxicity.
- •Prior treatment with any oncolytic virus.
- •Requires use of anti-platelet or anti-coagulant therapy that cannot be safely suspended for per protocol biopsies or intra-tumoral injections.
- •CNS metastases and/or carcinomatous meningitis that have not been completely resected or completely irradiated.
- •Prior history of myocarditis
- •Symptomatic or asymptomatic cardiovascular disease
- •Known HIV/AIDS, active HBV or HCV infection.
- •Received immunosuppressive medication within 4 weeks. (>10mg/day prednisone)
- •Known intolerance to anti-PD-1 or anti-PD-L1 antibody therapy
- •Additional Exclusion criteria exist
研究组 & 干预措施
Arm A: TBio-6517 alone
Dose escalation of TBio-6517 alone administered by direct injection into tumor(s) x 4. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: TBio-6517 (Biological)
Arm B: TBio-6517 and Pembrolizumab
Dose escalation of TBio-6517 administered in combination with pembrolizumab. TBio-6517 will be directly injected into tumor(s) x 4. Booster injections of TBio-6517 are permitted for up to 24 months. Pembrolizumab will be administered beginning at Day 9 via intravenous (IV) infusion every 3 weeks for up to 24 months.
干预措施: TBio-6517 (Biological)
Arm B: TBio-6517 and Pembrolizumab
Dose escalation of TBio-6517 administered in combination with pembrolizumab. TBio-6517 will be directly injected into tumor(s) x 4. Booster injections of TBio-6517 are permitted for up to 24 months. Pembrolizumab will be administered beginning at Day 9 via intravenous (IV) infusion every 3 weeks for up to 24 months.
干预措施: Pembrolizumab (Biological)
TBio-6517 and Pembrolizumab in MSS-CRC
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 9 given every 3 weeks for up to 24 months in patients with microsatellite stable colorectal carcinoma (MSS-CRC). Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: TBio-6517 (Biological)
TBio-6517 and Pembrolizumab in MSS-CRC
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 9 given every 3 weeks for up to 24 months in patients with microsatellite stable colorectal carcinoma (MSS-CRC). Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: Pembrolizumab (Biological)
TBio-6517 and Pembrolizumab in cutaneous melanoma
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 9 given every 3 weeks for up to 24 months in patients with malignant melanoma of the skin. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: TBio-6517 (Biological)
TBio-6517 and Pembrolizumab in cutaneous melanoma
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 9 given every 3 weeks for up to 24 months in patients with malignant melanoma of the skin. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: Pembrolizumab (Biological)
TBio-6517 and Pembrolizumab in cutaneous squamous cell carcinoma of the skin
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 8 given every 3 weeks for up to 24 months in patients with cSCC. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: TBio-6517 (Biological)
TBio-6517 and Pembrolizumab in cutaneous squamous cell carcinoma of the skin
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 8 given every 3 weeks for up to 24 months in patients with cSCC. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: Pembrolizumab (Biological)
TBio-6517 and Pembrolizumab in HPV positive head and neck cancer
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 9 given every 3 weeks for up to 24 months in patients with HPV associated oropharyngeal cancer. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: TBio-6517 (Biological)
TBio-6517 and Pembrolizumab in HPV positive head and neck cancer
Doses of TBio-6517 will be administered by direct injection into tumor(s) x 4 in combination with pembrolizumab beginning at Day 9 given every 3 weeks for up to 24 months in patients with HPV associated oropharyngeal cancer. Booster injections of TBio-6517 are permitted for up to 24 months.
干预措施: Pembrolizumab (Biological)
Arm C: TBio-6517 intravenous
Dose escalation of TBio-6517 alone administered by intravenous infusion x 4. Booster infusions of TBio-6517 are permitted for up to 24 months.
干预措施: TBio-6517 (Biological)
Arm D: TBio-6517 intravenous and Pembrolizumab
Dose escalation of TBio-6517 administered in combination with pembrolizumab. Dose escalation of TBio-6517 alone administered by intravenous infusion x 4. Booster infusions of TBio-6517 are permitted for up to 24 months. Pembrolizumab will be administered beginning at Day 9 via intravenous (IV) infusion every 3 weeks for up to 24 months.
干预措施: TBio-6517 (Biological)
Arm D: TBio-6517 intravenous and Pembrolizumab
Dose escalation of TBio-6517 administered in combination with pembrolizumab. Dose escalation of TBio-6517 alone administered by intravenous infusion x 4. Booster infusions of TBio-6517 are permitted for up to 24 months. Pembrolizumab will be administered beginning at Day 9 via intravenous (IV) infusion every 3 weeks for up to 24 months.
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Incidence of adverse events when TBio-6517 administered by direct injection into tumor(s) alone at each dose level
时间窗: 25 months
Percentage of patients with adverse events by grade as determined by NCI CTCAE v5.0
Maximum tolerated dose (MTD) or Maximum feasible dose (MFD) and determination of the recommended Phase 2 dose (RP2D) of TBio-6517 alone and in combination with pembrolizumab.
时间窗: 4 weeks
The highest dose of TBio-6517 that can be administered where fewer than 2 patients have a dose-limiting safety event alone or when combined with pembrolizumab as assessed by NCI CTCAE v.5.0 during the Phase 1 dose escalation
Percentage of overall response rate (ORR) by RECIST 1.1 at the RP2D
时间窗: 25 months
Percentage of patients treated at the RP2D in combination with pembrolizumab with a partial response or complete response by RECIST 1.1 following central radiologist review
Percentage of overall response rate (ORR) by immunotherapy RECIST (iRECIST) at the RP2D
时间窗: 25 months
Percentage of patients treated at the RP2D with pembrolizumab with a partial response (PR) or complete response (CR) by iRECIST following central radiologist review
Incidence of adverse events when TBio-6517 administered by direct injection into tumor(s) when combined with pembrolizumab
时间窗: 25 months
Percentage of patients with adverse events by severity as determined by NCI CTCAE v5.0
次要结局
- Time to tumor progression (TTP)(25 months)
- Number and severity of adverse events at the RP2D(25 months)
- Proportion of patients with a response (ORR)(25 months)
- Median Disease Control Rate (DCR)(25 months)
- Median progression free survival(25 months)
- Median overall survival (OS)(48 months)
- Median Duration of Response (DoR)(25 months)