Phase 1/2 Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT7480 in Patients With Nectin-4 Associated Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 200
- 试验地点
- 9
- 主要终点
- Number of patients with treatment emergent adverse events in dose escalation phase
研究概览
简要总结
This clinical study is evaluating a drug called BT7480 alone and in combination with nivolumab in participants with advanced solid tumors associated with Nectin-4 expression.
The main goals of the study are to:
- Find the recommended dose of BT7480 that can be given safely to participants alone and in combination with nivolumab
- Learn about the side effects and effectiveness of BT7480 alone and in combination with nivolumab
- Learn about the effect BT7480 has on the body and how BT7480 is cleared by the body
- Learn about the side effects and effectiveness of BT7480 in patients with reduced kidney function
详细描述
BT7480 is a tumor targeted immune cell agonist consisting of three bicyclic peptides (Bicycle®) conjugated via a linker, one that binds selectively to Nectin-4 and two that bind to CD137.
This study is a Phase 1/2, multicenter, first-in-human, open-label study of BT7480 given as a single agent and in combination with nivolumab once weekly. There are five parts to the trial: 1) Phase 1 dose escalation in patients with select advanced solid tumors primarily to evaluate safety and tolerability of BT7480 as a monotherapy and determine a recommended Phase 2 dose (RP2D); 2) Phase 1 dose escalation in combination with nivolumab, once the monotherapy RP2D has been determined; 3) Phase 2 dose expansion as a monotherapy once the RP2D has been determined; 4) Phase 2 dose expansion in combination with nivolumab; 5) Phase 1 monotherapy dose confirmation in patients with renal insufficiency once the monotherapy RP2D has been determined
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Must have locally advanced or metastatic disease that is refractory to standard therapy, or for which no standard therapy is judged to be appropriate or provide clinical benefit, as judged by the Investigator
- •Must have a histologically or cytologically confirmed malignant solid tumor associated with Nectin-4 expression, including, but not limited to, urothelial (transitional cell) carcinoma; head and neck squamous cell carcinoma; non-small cell lung cancer; and ovarian, breast, gastric, or esophageal carcinoma
- •Must have ECOG performance status score 0 or 1 and acceptable organ and hematological function
- •Must have metastatic or locally advanced disease and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Life expectancy ≥12 weeks
- •Must submit fresh or archival tumor tissue
- •Must provide written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analysis
排除标准
- •Prior therapy with a cytotoxic, small molecule, or other systemic chemotherapy within 14 days of the first dose of study drug
- •Prior immunotherapy, including monoclonal antibodies, within 28 days or 5 half-lives of the first dose of study drug, whichever is shorter
- •Prior treatment with CD137 targeted therapy
- •Mean resting QTc (eg, QTcF) greater than 470 msec on triplicate electrocardiograms (ECGs) obtained at screening
- •Uncontrolled symptomatic brain metastases
- •Uncontrolled diabetes with glycosylated hemoglobin greater than or equal to 8%
- •Uncontrolled hypertension at screening or prior to initiation of study drug
- •History of autoimmune disease except well-controlled diabetes mellitus, alopecia, well controlled thyroid disease or vitiligo
研究组 & 干预措施
BT7480 monotherapy dose escalation
Participants will receive increasing doses of BT7480. It is expected that approximately 80 patients will participate in this dose escalation arm.
干预措施: BT7480 (Drug)
BT7480 and nivolumab dose escalation
Participants will receive increasing doses of BT7480 and standard dose of nivolumab. It is expected that approximately 12 patients will participate in this dose escalation arm.
干预措施: BT7480 (Drug)
BT7480 and nivolumab dose escalation
Participants will receive increasing doses of BT7480 and standard dose of nivolumab. It is expected that approximately 12 patients will participate in this dose escalation arm.
干预措施: Nivolumab (Drug)
BT7480 monotherapy dose expansion
Participants will receive a selected dose of BT7480. It is expected that approximately 45 patients will participate in this dose expansion arm in Phase 2.
干预措施: BT7480 (Drug)
BT7480 and nivolumab dose expansion
Participants will receive a selected dose of BT7480 and standard dose of nivolumab. It is expected that approximately 45 patients will participate in this dose expansion arm in Phase 2.
干预措施: BT7480 (Drug)
BT7480 and nivolumab dose expansion
Participants will receive a selected dose of BT7480 and standard dose of nivolumab. It is expected that approximately 45 patients will participate in this dose expansion arm in Phase 2.
干预措施: Nivolumab (Drug)
BT7480 monotherapy in patients with renal insufficiency
Participants will receive a selected dose of BT7480. It is expected that approximately 12 patients will participate in this dose confirmation arm.
干预措施: BT7480 (Drug)
结局指标
主要结局
Number of patients with treatment emergent adverse events in dose escalation phase
时间窗: From Cycle 1 Day 1 (each cycle is 28 days) until 125 (+/-5) days after the last dose of study drug
Incidence and severity of treatment emergent adverse events to assess safety and tolerability following treatment with BT7480 and in combination with nivolumab using NCI CTCAE v5.0 criteria
Confirmed response rate as measured by overall response rate (ORR) to demonstrate clinical activity following treatment with BT7480 in dose expansion phase
时间窗: From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months
Overall response rate (ORR) following treatment with BT7480 alone and in combination with nivolumab according to RECIST 1.1 criteria nivolumab according to RECIST 1.1 criteria
Confirmed response rate as measured by clinical benefit rate (CBR) to demonstrate clinical activity following treatment with BT7480 in dose expansion phase
时间窗: From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months
Clinical benefit rate (CBR) following treatment with BT7480 alone and in combination with nivolumab according to RECIST 1.1 criteria nivolumab according to RECIST 1.1 criteria
Number of patients with treatment emergent adverse events in dose escalation phase
时间窗: From Cycle 1 Day 1 (each cycle is 28 days) until 30 (+/-5) days after the last dose of study drug
Incidence and severity of treatment emergent adverse events to assess safety and tolerability following treatment with BT7480 alone and in patients with renal insufficiency using NCI CTCAE v5.0 criteria
次要结局
- Confirmed response rate as measured by overall response rate (ORR) to demonstrate clinical activity following treatment with BT7480 in dose escalation phase(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Confirmed response rate as measured by clinical benefit rate (CBR) to demonstrate clinical activity following treatment with BT7480 in dose escalation phase(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Number of patients with treatment emergent adverse events in dose expansion phase(From Cycle 1 Day 1 (each cycle is 28 days) until 125 (+/-5) days after the last dose of study drug)
- Progression free survival time in dose escalation and dose expansion phase(At 6 months)
- Maximum plasma concentration (Cmax) of BT7480(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Duration of response to assess clinical activity in dose escalation and dose expansion phase(From initial response to therapy to subsequent disease progression, an average of 6 months)
- Area under the plasma concentration-time curve (AUC) of BT7480(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Terminal half life (t1/2) of BT7480 in plasma(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Cumulative amount of BT7480 excreted in the urine(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Number of participants positive for anti-drug antibodies (ADA)(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Level of CD137 target engagement in all patients(From Cycle 1 Day 1 (each cycle is 28 days) through study completion, an average of 6 months)
- Number of patients with treatment emergent adverse events in dose expansion phase(From Cycle 1 Day 1 (each cycle is 28 days) until 30 (+/-5) days after the last dose of study drug)