A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the Preliminary Efficacy of RXC004 in Monotherapy and in Combination With Nivolumab, in Patients With Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer Who Have Progressed Following Therapy With Current Standard of Care (PORCUPINE)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 22
- 主要终点
- RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1)
研究概览
简要总结
This is a Phase II, open label, multicentre, multi-arm, study to evaluate the preliminary efficacy and safety of RXC004 as monotherapy and in combination with nivolumab in patients with Ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, microsatellite stable (MSS), colorectal cancer (CRC), that have progressed following current standard of care treatment.
详细描述
The study is composed of two arms, RXC004 monotherapy (Arm A) and RXC004 in combination with nivolumab (Arm B). 20 evaluable patients will be enrolled in Arm A and 20 eligible patients in Arm B.
The study initially opened with Arm A; Arm B will be opened once a recommended Phase II dose (RP2D) for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470).
Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be randomised 2:1 to Arm B: Arm A in an open-label manner.
Patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease on the 8 week scan, as long as they are eligible for Arm B and have Sponsor approval.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Histological documentation of metastatic (Stage IV) Colorectal cancer (CRC) and
- •Documented tumour tissue aberration in RNF43 and/or RSPO
- •Documented confirmation of microsatellite stable (MSS) status
- •Patients must have had documented radiological progression following a minimum of 1 prior SOC treatment regimen for metastatic disease
- •Eastern Cooperative Oncology Group performance status 0 or 1
- •At least one lesion that is measurable by RECIST 1.1 at baseline
- •Patients must have at least one lesion suitable for biopsy at screening and be willing to provide mandatory tumour biopsy samples
- •Patients with adequate organ functions
- •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 and for at least 5 months after the last dose of study drug.
- •For patients on RXC004 monotherapy treatment (Arm A) the following inclusion criteria will also apply to enter the RXC004 + nivolumab treatment phase:
- •Patients must have had documented RECIST1.1 defined radiological progression on RXC004 monotherapy treatment on the first scheduled scan (week 8 +/- 1 week)
- •Patients must receive Cycle 1 Day 1 of combination study treatment within 28 days of the first scheduled scan (week 8 +/- 1 week).
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, immunosuppressants and other investigational drugs
- •Patients with a known hypersensitivity to any RXC004 excipients
- •Patients with a contra-indication for denosumab treatment
- •Patients who are pregnant or breast-feeding
- •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
- •Patients with a mean resting corrected QTcF >470 ms, obtained from triplicate electrocardiograms performed at screening
- •For patients on RXC004 + nivolumab combination treatment (Arm B or Arm A RXC004 + nivolumab treatment phase):
- •Patients with any contraindication to the use of nivolumab
- •Patients with active or prior documented autoimmune or inflammatory disorders within the past 5 years
- •Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus
- •Patients with a history of allogeneic organ transplant or active primary immunodeficiency
- •Patients with a known hypersensitivity to nivolumab or any of the excipients of the product
研究组 & 干预措施
Arm A: RXC004 monotherapy
Patients will receive RXC004 (2 mg once daily [QD], orally).
Patients in Arm A may crossover to Arm B treatment if they have progressive disease on the first Response Evaluation Criteria in Solid Tumours, (RECIST) scan (if Arm B is open at the time of progression).
干预措施: RXC004 (Drug)
Arm A: RXC004 monotherapy
Patients will receive RXC004 (2 mg once daily [QD], orally).
Patients in Arm A may crossover to Arm B treatment if they have progressive disease on the first Response Evaluation Criteria in Solid Tumours, (RECIST) scan (if Arm B is open at the time of progression).
干预措施: Denosumab (Biological)
Arm B: RXC004 + nivolumab
Patients will receive RXC004 (1.5 mg QD, orally) in combination with nivolumab (480 mg every 4 weeks [q4w], intravenous [IV] infusion).
Arm B will be opened once a RP2D for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470). RXC004 dose to be used in combination with nivolumab will be based on data from the phase 1 study (NCT03447470).
干预措施: RXC004 (Drug)
Arm B: RXC004 + nivolumab
Patients will receive RXC004 (1.5 mg QD, orally) in combination with nivolumab (480 mg every 4 weeks [q4w], intravenous [IV] infusion).
Arm B will be opened once a RP2D for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470). RXC004 dose to be used in combination with nivolumab will be based on data from the phase 1 study (NCT03447470).
干预措施: Nivolumab (Biological)
Arm B: RXC004 + nivolumab
Patients will receive RXC004 (1.5 mg QD, orally) in combination with nivolumab (480 mg every 4 weeks [q4w], intravenous [IV] infusion).
Arm B will be opened once a RP2D for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470). RXC004 dose to be used in combination with nivolumab will be based on data from the phase 1 study (NCT03447470).
干预措施: Denosumab (Biological)
结局指标
主要结局
RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1)
时间窗: Up to 28 months
The anti-tumour activity of RXC004 monotherapy was evaluated. DCR is defined as the percentage of patients with a BOR of either complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks post baseline.
RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1
时间窗: Up to 28 months
The anti-tumour activity as a combination therapy of RXC004 +nivolumab was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment, as defined in RECIST 1.1.
次要结局
- Overall Survival (OS)(Up to 28 months)
- Maximum Observed Plasma Concentration (Cmax)(On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length))
- Time to Maximum Plasma Concentration (Tmax)(On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length))
- Minimum Observed Concentration Across the Dosing Interval (Cmin)(On Cycle 1 Day 15 (28 days cycle in length))
- Terminal Rate Constant (λz)(On Cycle 0 Day 1 (3-7 days cycle in length))
- Terminal Half-life (t½)(On Cycle 0 Day 1 (3-7 days cycle in length))
- Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)(On Cycle 0 Day 1 (3-7 days cycle in length))
- Total Plasma Clearance After Oral Administration (CL/F)(On Cycle 0 Day 1 (3-7 days cycle in length))
- Apparent Volume of Distribution After Oral Administration (Vz/F)(On Cycle 0 Day 1 (3-7 days cycle in length))
- Number of Patients With Adverse Events (AEs)(From time of signature of informed consent form throughout the treatment period and until 30 days after the last dose of RXC004 (for RXC004 monotherapy only) or 90 days after the last dose of Nivolumab (for RXC004 + nivolumab) (up to 28 months))
- Best Percentage Change in Tumor Size(Up to 28 months)
- Progression Free Survival (PFS)(Up to 28 months)
- Duration of Response (DOR)(Up to 28 months)
- RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1(Up to 28 months)
- RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1(Up to 28 months)