A Modular, Phase II, Open-Label, Multicentre Study to Assess the Preliminary Efficacy and Safety of RXC004, in Patients With Advanced Solid Tumours That Have Progressed Following Therapy With Current Standard of Care
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 13
- 主要终点
- Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months
研究概览
简要总结
This study is to evaluate the preliminary efficacy and safety of RXC004 monotherapy and in combination with pembrolizumab in advanced solid tumours that have progressed following SoC treatment.
详细描述
This Phase II, modular, open label, multicentre study initially opened with ring finger protein 43 (RNF43) loss of function (LoF) mutation-positive pancreatic ductal adenocarcinoma (PDAC) (Module 1) and molecularly unselected biliary tract cancer (BTC) (Module 2) modules. Module 3 will investigate RXC004 in combination with pembrolizumab in BTC. Modules 1 and 2 are monotherapies and Module 3 is the combination therapy.
The primary objective of the study is to assess the preliminary efficacy of RXC004 in each module. This will be evaluated in terms of progression free survival (PFS) at 6 months in Modules 1 and 2, and in terms of Objective response rate (ORR) in Module 3. Following radiological progression, patients will be followed-up for survival.
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
- •At least one lesion that is measurable by RECIST 1.1 at baseline (within 6 weeks prior to start of study treatment).
- •Mandatory paired biopsies; Patients must have at least one lesion suitable for biopsy at screening
- •Adequate organ and marrow function
- •Female patients of childbearing potential must have a negative pregnancy test prior to start of dosing
- •Female patients of childbearing potential and male patients with female partners of childbearing potential must agree to use a highly effective method of contraception during the study from the time of treatment initiation, and for at least 5 months after the last dose of study drug.
- •Module 1 (PDAC) Specific Inclusion Criteria
- •Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) PDAC, with documented loss of function tumour mutation in RNF43
- •Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic PDAC (Stage III/IV), with clear evidence of radiological disease progression
- •Patients must be enrolled and receive first dose of study treatment within 6 weeks of radiologically confirmed progression
- •Karnofsky performance status ≥
- •Module 2 and Module 3 (BTC) Specific Inclusion Criteria
- •Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) BTC (intrahepatic or extrahepatic cholangiocarcinoma, ampulla of Vater, or gallbladder cancer)
- •Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic BTC, with clear evidence of radiological disease progression
- •Patients must be enrolled and receive first dose of study treatment within 6 weeks of radiologically confirmed progression
- •ECOG status 0 or
排除标准
- •Prior therapy with a compound of the same mechanism of action as RXC004
- •Patients at higher risk of bone fractures
- •Any known uncontrolled inter-current illness or persistent clinically significant toxicity related to prior anti-cancer treatment
- •Patients who have any history of an active (requiring treatment) other malignancy within 2 years of study entry
- •Patients with known or suspected brain metastases
- •Use of anti-neoplastic agents
- •Patients with a known hypersensitivity to any RXC004 excipients
- •Patients with a contra-indication for denosumab treatment
- •Patients who are pregnant or breast-feeding
- •Known active human immunodeficiency viruses (HIV), hepatitis B (HBV), or hepatitis C (HCV) infections
- •Use of any live or live-attenuated vaccines against infectious diseases (e.g., influenza nasal spray, varicella) within 4 weeks (28 days) of initiation of study treatment
- •Mean resting corrected QTcF >470 ms, obtained from triplicate ECGs performed at screening.
- •There are no exclusion criteria specific to Modules 1 and
- •Module 3 Specific Exclusion Criteria:
- •Patients with any contraindication to the use of pembrolizumab as per approved label
- •Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor, and was discontinued from that treatment due to a Grade 3 or higher AE
- •Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of pembrolizumab in this study
- •Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
- •Has an active autoimmune disease that has required systemic treatment in past 2 years
- •Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease
- •Has an active infection requiring systemic therapy
- •Patients with a history of allogeneic tissue/solid organ transplant
- •Patients with active infections, including tuberculosis, HIV, HBV, or HCV
研究组 & 干预措施
Module 1 - RNF43 Mutated Advanced (unresectable)/Metastatic Pancreatic Cancer (Stage III/IV)
Patients (Karnofsky performance status ≥70) will be recruited and dosed with RXC004 (2 mg once daily [QD], orally) within 6 weeks of progression following 1st line SoC treatment.
干预措施: RXC004 (Drug)
Module 1 - RNF43 Mutated Advanced (unresectable)/Metastatic Pancreatic Cancer (Stage III/IV)
Patients (Karnofsky performance status ≥70) will be recruited and dosed with RXC004 (2 mg once daily [QD], orally) within 6 weeks of progression following 1st line SoC treatment.
干预措施: Denosumab (Biological)
Module 2 -Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV)
Patients (Eastern Cooperative Oncology Group [ECOG] performance status 0-1) will be recruited and dosed with RXC004 within 6 weeks of progression, following 1st line SoC treatment.
干预措施: RXC004 (Drug)
Module 2 -Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV)
Patients (Eastern Cooperative Oncology Group [ECOG] performance status 0-1) will be recruited and dosed with RXC004 within 6 weeks of progression, following 1st line SoC treatment.
干预措施: Denosumab (Biological)
Module 3-Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy
Patients (ECOG performance status 0-1) will be recruited and dosed with RXC004 (1.5 mg QD, orally) in combination with pembrolizumab 400 mg IV infusion every 6 weeks (q6w) within 6 weeks of progression, following 1st line Soc treatment.
干预措施: RXC004 (Drug)
Module 3-Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy
Patients (ECOG performance status 0-1) will be recruited and dosed with RXC004 (1.5 mg QD, orally) in combination with pembrolizumab 400 mg IV infusion every 6 weeks (q6w) within 6 weeks of progression, following 1st line Soc treatment.
干预措施: Denosumab (Biological)
Module 3-Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy
Patients (ECOG performance status 0-1) will be recruited and dosed with RXC004 (1.5 mg QD, orally) in combination with pembrolizumab 400 mg IV infusion every 6 weeks (q6w) within 6 weeks of progression, following 1st line Soc treatment.
干预措施: pembrolizumab (Biological)
结局指标
主要结局
Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months
时间窗: At 6 months
The anti-tumour activity of RXC004 was assessed. Progression free survival rate at 6 months was defined as the percentage of patients who remained alive and free of progression at 6 months according to Kaplan-Meier estimates.
Combination Therapy (Module 3): Objective Response Rate (ORR)
时间窗: Up to 23 months
The anti-tumour activity of RXC004 as a combination therapy was assessed. ORR was defined as the percentage of patients with a best overall response of complete response or partial response based on local investigator assessment as defined in RECIST 1.1.
次要结局
- Monotherapy (Modules 1 and 2): ORR(Up to 23 months)
- Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR)(Up to 23 months)
- Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS(Up to 23 months)
- Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size(Up to 23 months)
- Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS)(Up to 23 months)
- Maximum Observed Plasma Concentration (Cmax)(At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length))
- Time to Cmax (Tmax)(At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length))
- Minimum Observed Concentration Across the Dosing Interval (Cmin)(At Cycle 1 Day 15 (The cycle was 21 days in length) (Up to 23 months))
- Terminal Rate Constant (λz)(At Cycle 0 Day 1 (The cycle was 21 days in length))
- Terminal Half-life (t½)(At Cycle 0 Day 1(The cycle was 21 days in length))
- Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)(At Cycle 0 Day 1 (The cycle was 21 days in length))
- Total Plasma Clearance After Oral Administration (CL/F)(At Cycle 0 Day 1 (The cycle was 21 days in length))
- Apparent Volume of Distribution After Oral Administration (Vz/F)(At Cycle 0 Day 1 (The cycle was 21 days in length))
- Number of Patients With Adverse Events (AEs)(From time of signature of main study informed consent form throughout the treatment period and until the 30 days after last dose of RXC004 (Up to 23 months))