An Open-label, Multicenter Phase Ib/II Clinical Study: Aim to Valuate the Efficacy and Safety of XS-03 Comination With FOLFOX or FOLFIRI and Bevacizumab in Metastatic Colorectal Cancer Patients With RAS Mutation
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 102
- 试验地点
- 2
- 主要终点
- Phase 1b: Number of participants with Dose-limiting Toxicities (DLTs) in experimental arm of XS-03 in combination with FOLFOX or FOLFIRI and Bevacizumab
研究概览
简要总结
XS-03 in combination with FOLFOX or FOLFIRI and Bevacizumab for treatment of metastatic colorectal cancer patients with RAS mutation
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntarily participate in the clinical trial and sign the informed consent form.
- •Age ≥18 and ≤ 75 years. No gender restrictions.
- •Patients with histologically and/or cytologically confirmed metastatic colorectal cancer who are not suitable for surgical treatment.
- •Advanced or metastatic colorectal cancer: Stage Ib patients must have received at least one prior systemic therapy; Stage II patients have no prior systemic therapy. For patients with previously neoadjuvant/adjuvant therapy, disease progression must occur no less than 6 months after the end of therapy to be eligible for inclusion.
- •Documentation of RAS mutation. The previously gene test report issued by qualified testing institution is acceptable. BRAF status is not restricted.
- •Consent to provide tumor tissue samples and peripheral blood for biomarker analysis.
- •Has measurable extracranial lesion according to RECIST v1.1 criteria, defined as at least one lesion that has not received radiotherapy. For previously radiotherapy lesion, there must be imaging evidence of progression after radiotherapy.
- •Eastern Cooperative Oncology Group (ECOG) performance status score 0-
- •Expected life expectancy ≥ 6 months.
- •The patient has adequate hepatic, renal and bone marrow function.
- •For a woman of child-bearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Woman of child-bearing potential and fertile men must agree to use adequate contraception for the duration of study participation and for 6 months after the last dose.
排除标准
- •Patients with known high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) primary or metastatic colorectal cancer and suitable for immune checkpoint inhibitor treatment assessed by investigators.
- •Previously received bevacizumab and its biosimilar therapy. (Only for phase II)
- •Central nervous system metastases which are symptomatic or require therapy.
- •Imaging shows major blood vessel invasion (such as the aorta, pulmonary artery, pulmonary vein, vena cava, etc.).
- •Adverse events and/or complications that caused by previous antitumor therapy have not recovered to baseline level or ≤ CTCAE grade
- •Baseline level or ≤ Grade
- •However, any grade of alopecia, pigmentation, or ≤ Grade 2 peripheral sensory neuropathy, or other conditions assessed by the investigator as having become chronic and not affecting the safety of the study medication are allowed for inclusion.
- •With a history of other malignancies within 5 years or with other malignancies currently prior to screening, except colorectal cancer. Exception: curatively treated early-stage malignancies (in situ carcinoma or stage I tumors), such as adequately treated basal cell or squamous cell skin cancer or in situ cancer of the cervix.
- •Patients have a significant risk of bleeding.
- •Patients have a significant risk of thrombus.
- •Patients have severe cardiovascular disease, including but not limited to: Ischemic heart disease within the past 6 months prior to screening; coronary artery disease post-surgery or stent implantation within 6 months; New York Heart Association (NYHA) functional classification ≥ Class II within 6 months prior to screening; or known left ventricular insufficiency (LVEF <50%)；transient ischemic attack or cerebrovascular accident within 6 months prior to screening; uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) despite standard treatment, or history of hypertensive crisis or hypertensive encephalopathy;severe arrhythmia requiring clinical intervention; any other cardiovascular disease that researchers regard the patient unsuitable for participation in the study.
- •Patients with a significantly increased risk of QTc prolongation.
- •Patients unable to swallow drugs or have severe diseases that significantly affect drug absorption.
- •Patients have one of the following viral active infections: active hepatitis B or C; human immunodeficiency virus (HIV) infection; active syphilis
- •During screening, the presence of interstitial lung disease, interstitial pneumonia, pulmonary interstitial fibrosis requiring therapy, or a history of pneumonia caused by tyrosine kinase inhibitors.
- •Patients received radiotherapy within the past 4 weeks prior to the first first dose of study drug.
- •Patients received therapeutic surgeries (excluding diagnosis, biopsy, or drainage procedures) within the past 4 weeks prior to the first dose of study drug, including local treatments such as radiofrequency ablation for liver metastases, or are expected to have major surgeries during the study period.
- •Severity infection need intravenous infusion of antibiotics, antiviral drugs, or hospitalisation within the past 2 weeks prior to the first dose of study drug.
- •Patients must use strong CYP3A4 inducers or inhibitors within the past 2 weeks prior to the first administration, or during the anticipated study period,
- •History of severe allergy, or known allergy to any active or inactive components of the study drug product.
- •Pregnancy or lactation.
- •Patients with severe diseases of any organs or systems, any clinical or laboratory test abnormalities, or other reasons that investigator assess them unsuitable to participate in this clinical study.
研究组 & 干预措施
Experimental arm 1: XS-03 + FOLFOX/FOLFIRI + Bevacizumab
Phase 1b: XS-03 escalating orally Day 1 through Day 5 and Day 15 through Day 19 of each 28-day cycle in combination with FOLFOX or FOLFIRI and bevacizumab.
FOLFOX (85 mg/m^2 oxaliplatin, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU) , 5 mg/kg bevacizumab FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU), 5 mg/kg bevacizumab
干预措施: Drug: XS-03, Biological: Bevacizumab, Drug: FOLFOX, Drug: FOLFIRI (Biological)
Experimental arm 2: XS-03 + FOLFOX/FOLFIRI + Bevacizumab
Phase 2: XS-03 Recommended Phase 2 Dose (RP2D) and selected one more dosage orally Day 1 through Day 5 and Day 15 through Day 19 of each 28-day cycle in combinationwith FOLFOX or FOLFIRI and bevacizumab.
FOLFOX (85 mg/m^2 oxaliplatin, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU) , 5 mg/kg bevacizumab FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU), 5 mg/kg bevacizumab
干预措施: Drug: XS-03 (Biological)
Comparator: FOLFOX/FOLFIRI + Bevacizumab
Phase 2: Comparator arm treat with FOLFOX or FOLFIRI + bevacizumab intravenously.
FOLFOX (85 mg/m^2 oxaliplatin, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU) , 5 mg/kg bevacizumab FOLFIRI (180 mg/m^2 irinotecan, 400 mg/m^2 leucovorin, 400 mg/m^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m^2 continuous intravenous infusion 5-FU), 5 mg/kg bevacizumab
干预措施: Biological: Bevacizumab, Drug: FOLFOX, Drug: FOLFIRI (Biological)
结局指标
主要结局
Phase 1b: Number of participants with Dose-limiting Toxicities (DLTs) in experimental arm of XS-03 in combination with FOLFOX or FOLFIRI and Bevacizumab
时间窗: up to day 28
Dose-limiting toxicities were defined as events related to XS-03 that were considered an adverse reaction or suspected adverse reaction during the first cycle of treatment
Phase 1b: Determine the Maximum Tolerated Dose (MTD) in experimental arm of XS-03 in combination with FOLFOX or FOLFIRI and Bevacizumab
时间窗: up to day 28
MTD is defined as at most 1 patient out of 6 experiencing DLT
Phase 2: Objective Response Rate (ORR) of two experimental arms and comparator arm
时间窗: up to 18 months after first dose of last patient
Defined as the percentage of participants that achieve a best overall response of complete response (CR) or partial response (PR) (per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria)
次要结局
- Number of Participants With Adverse Events (AEs) of treated participants(up to 28 days after last dose of study drug)
- Duration of response (DOR) of all treated participants(up to 18 months after first dose of last patient)
- Overall survival (OS) of treated participants(up to 18 months after first dose of last patient)
- Number of Participants With Clinically Significant Change From Baseline in safety monitoring(up to 28 days after last dose of study drug)
- Number of Participants With dose adjustment(up to 28 days after last dose of study drug)
- Area under the plasma concentration versus time curve from time zero to the last measurable concentration(AUC0-t)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- Elimination Half-life (T1/2)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- The volume of distribution(Vd/F)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- Phase 1b: Objective Response Rate (ORR) of all treated participants(up to 18 months after first dose of last patient)
- Progression-free survival (PFS) of treated participants(up to 18 months after first dose of last patient)
- Average concentration at steady state(Cavg,ss)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- Minimum observed concentration at steady state(Cmin,ss)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- Maximum Plasma Concentration(Cmax)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- Time to Reach Maximum Peak Plasma Concentration (Tmax)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))
- Systemic Clearance From Plasma Following Extravascular Administration (CL/F)(From pre-dose on day 1 of cycle 1 to day 5 of cycle 3 (28-day cycle length))