A Modular Multi-Arm, Phase 1, Adaptive Design Study to Evaluate the Safety and Tolerability of RXC004, Alone and in Combination With Anti-cancer Treatments, in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 5
- 主要终点
- Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:
研究概览
简要总结
The purpose of this study is to determine the safety and tolerability of RXC004 as monotherapy and in combination with Nivolumab in patients with advanced malignancies. In order to define the doses and schedules for further clinical evaluation.
详细描述
The study will consist of an ascending monotherapy dose, the doses are pre-defined.
The decision to escalate will be made upon the assessment of safety and tolerability data in the first cycle of treatment.
Module 1 will commence with a 3+3 dose escalation design up to a recommended Phase 2 monotherapy dose. Patients being monitored for dose limiting toxicities at each dose level.
Characterisation of the PK profile, MTD and/or recommended Phase 2 dose will be defined on the emerging data.
Module 2: RXC004 and Nivolumab - Follows a similar 3+3 dose escalation design using RXC004 plus Nivolumab. The MTD and/or Phase 2 dose will be defined based on the PK profile, emerging safety and the appearance of any dose limiting toxicities.
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
盲法说明
Open label design
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
- •Written informed consent
- •Aged at least 18 years
- •Histological or cytological confirmation of advanced malignancy not considered to be appropriate for further conventional treatment
- •Patients must use adequate contraception measures for the duration of the study and for 6 months after the study
- •Patients must have adequate organ functions
- •Ability to swallow and retain oral medication
排除标准
- •Prior treatment with a compound of the same mechanism of action as RXC004
- •No other anti-cancer therapy or investigational product throughout the study
- •Patients with persistent grade 2 or higher diarrhoea
- •Patients at high risk of bone fractures
- •QTc prolongation
- •Known uncontrolled intercurrent illness
- •Known severe allergies to any active or inactive ingredients
- •In addition for Module 2
- •Patients with any contraindication/hypersensitivity to Nivolumab of excipients
- •Patients with active or prior documented autoimmune of inflammatory disorders within the past 5 years
- •Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus
- •Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of initiation of study treatment
- •Patients with body weight <40kg
- •Patients with a history of allogeneic organ transplant or active primary immunodeficiency
- •In addition to Module 3
- •Patients with Wnt ligand-dependent solid tumours, defined as:
- •Biliary tract cancers
- •Thymus cancers (thymic and thymoma WHO classification)
- •Any solid tumour with documented aberration in RNF43 and/or RSPO from central pre-screening or from a recognised panel approved by the Sponsor
- •Patients willing to have mandatory skin biopsies at baseline and on one occasion while on study treatment.
研究组 & 干预措施
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)
Patients were given 0.5 mg RXC004 and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 2 Arm 1 - RXC004 (1.0 mg) plus Nivolumab
Patients were given 1.0 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 2 Arm 1 - RXC004 (1.0 mg) plus Nivolumab
Patients were given 1.0 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
干预措施: Nivolumab (Drug)
Module 3 - Intermittent schedules of monotherapy RXC004
Patients were given 2.0 mg RXC004. The patients were treated for 2 weeks at the same dose, followed by 1 week off for a 21 day cycle.
干预措施: RXC004 (Drug)
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)
Patients were given 1.0 mg RXC004 and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)
Patients were given 1.5 mg RXC004 and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)
Patients were given 2.0 mg RXC004 and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)
Patients were given 3.0 mg RXC004 and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)
Patients were given 10.0 mg RXC004 and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 2 Arm 2 - RXC004 (1.5 mg) plus Nivolumab
Patients were given 1.5 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
干预措施: RXC004 (Drug)
Module 2 Arm 2 - RXC004 (1.5 mg) plus Nivolumab
Patients were given 1.5 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
干预措施: Nivolumab (Drug)
结局指标
主要结局
Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:
时间窗: AE data was collected after each cycle and until 30-day follow-up visit after study exit. The DLT period were assessed from the first dose until the end of 21 days of continuous dosing in each cycle until a Maximum Tolerated Dose (MTD) was identified.
A DLT was defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 or higher for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days.
Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.
时间窗: The DLT period will be assessed from the first dose until the end of 28 days of continuous dosing. This will be completed for each dose level until a Maximum Tolerated Dose (MTD) is identified. Estimated time 12 Months in total
A DLT is defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 or higher for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days. Any grade 3 or higher immune-related adverse events
Module 3 - Safety and Tolerability of RXC004 at Intermittent Dosing Schedule.
时间窗: The assessment period will be from the first dose until the end of 21 days of intermittent dosing or within 7 days of IP discontinuation.
Haematological toxicity of CTCAE grade 4 or higher present for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days. Any grade 3 or higher immune-related adverse events.
次要结局
- Module 2 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 3 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 2 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 2 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 2 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 3 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 3 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)(Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.)
- Module 3 - PK Profile - Half-life on Cycle 0 Day 1 (C0D1)(Cycle 0 Day 1)