An Open-Label, Phase 1b/2 Study to Evaluate the Safety and Efficacy of Fruquintinib in Combination With Tislelizumab in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Hutchmed
- 入组人数
- 52
- 试验地点
- 16
- 主要终点
- Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is an open-label, multi-center, non-randomized, Phase 1b/2 study to assess the safety and efficacy of fruquintinib in combination with tislelizumab in patients with locally advanced or metastatic solid tumors. This study will be conducted in 2 parts; a Safety Lead-in Phase (Part 1) and a Dose Expansion Phase (Part 2).
The Safety Lead-in Phase, open to any-comer solid tumors, will determine the RP2D. The RP2D will be administered to 3 cohorts of patients in the Dose Expansion Phase.
- Cohort A: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-treated)
- Cohort B: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-Naïve)
- Cohort C: Advanced or Metastatic Endometrial Cancer (EC) (IO-Naïve)
- Cohort D: Advanced or Metastatic Colorectal Cancer (mCRC) (IO-Naïve)
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
- •Willing and able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines;
- •Age ≥18 years;
- •Histologically or cytologically documented, advanced or metastatic Triple Negative Breast Cancer, histologically or cytologically documented, advanced or metastatic endometrial carcinoma, histologically or cytologically confirmed advanced or metastatic, unresectable adenocarcinoma of the colon or rectum.
- •Tumor tissue (archival or fresh tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for central laboratory assessment.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤
- •At least 1 measurable lesion as defined by RECIST v1.1.
排除标准
- •Has at screening any central nervous system metastasis and/or leptomeningeal disease.
- •Except for Cohort A, Prior therapy targeting CTLA-4, PD-1, PD-L1 or programmed cell death protein ligand-2 (PD-L2) or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways.
- •Prior treatment with a VEGFR-TKI or anti-VEGFR antibody (eg, ramucirumab).
- •Except for Cohort D, prior treatment with an anti-VEGFR antibody (eg, bevacizumab).
- •Tumor tissue (archival or fresh tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for central laboratory assessment.
- •Active autoimmune diseases or history of autoimmune diseases that may relapse, or history of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including but not limited to pulmonary fibrosis, acute lung diseases, etc.
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply
研究组 & 干预措施
Part 1
Approximately 6-12 patients with locally advanced or metastatic solid tumors will be enrolled to receive fruquintinib in combination with tislelizumab and assessed for DLTs during the 28-day DLT observation period
干预措施: Fruquintinib (Drug)
Part 1
Approximately 6-12 patients with locally advanced or metastatic solid tumors will be enrolled to receive fruquintinib in combination with tislelizumab and assessed for DLTs during the 28-day DLT observation period
干预措施: Tislelizumab (Drug)
Part 2
Patients will be enrolled to one of the following expansion cohorts:
- Cohort A: TNBC (immuno-oncology [IO]-treated in the metastatic setting)
- Cohort B: TNBC (IO-Naïve in the metastatic setting)
- Cohort C: EC
- Cohort D: MSS CRC
干预措施: Fruquintinib (Drug)
Part 2
Patients will be enrolled to one of the following expansion cohorts:
- Cohort A: TNBC (immuno-oncology [IO]-treated in the metastatic setting)
- Cohort B: TNBC (IO-Naïve in the metastatic setting)
- Cohort C: EC
- Cohort D: MSS CRC
干预措施: Tislelizumab (Drug)
结局指标
主要结局
Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs)
时间窗: From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks)
According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) v5.0, DLT was defined as any 1 of following toxicities during DLT assessment window and considered by Investigator to be related to 1 or more study treatments:a)Hematologic: grade(G) 4 neutropenia lasting \>7 days, G ≥3 febrile neutropenia, G 3 thrombocytopenia with clinically significant bleeding, G 4 thrombocytopenia, G ≥4 anemia.b) Non-hematologic:all G ≥3 non-hematologic toxicities except:G 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolved to G ≤1 within 7 days, G 3 nausea/vomiting or diarrhea for \<72 hours with antiemetic and supportive care, G 3 fatigue for \<1 week, G ≥3 electrolyte abnormality lasting up to 72 hours and resolving with treatment, G 3 rash returning to baseline or G ≤1 within 7 days with treatment,G ≥3 amylase or lipase elevation without symptoms of pancreatitis,G 3 hypertension returning to baseline or G≤1 within 7 days with treatment.
Part 1: Recommended Phase 2 Dose (RP2D) of Fruquintinib in Combination With Tislelizumab
时间窗: From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks)
The RP2D of fruquintinib in combination with tislelizumab based on the safety and tolerability assessments in Part 1 patients.
Part 2: Objective Response Rate (ORR)
时间窗: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
The ORR was defined as the percentage of patients with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 millimeters (mm). The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
次要结局
- Parts 1 and 2: Progression-free Survival (PFS)(Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months)
- Parts 1 and 2: Disease Control Rate (DCR)(Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months)
- Parts 1 and 2: Clinical Benefit Rate (CBR)(Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months)
- Part 1: Objective Response Rate(Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months)
- Parts 1 and 2: Duration of Response (DoR)(Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months)
- Parts 1 and 2: Overall Survival (OS)(From the first dose of study treatment (Day 1) up to date of death due to any cause, up to a maximum of approximately 34 months)
- Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11(Pre-dose on Days 1, 8, 15, 21 of Cycle 1 and on Day 1 of Cycles 2, 4, 7, 13; 2 to 4 hours post-dose on Days 1 and 21 of Cycle 1 (cycle duration: 4 weeks))
- Parts 1 and 2: Serum Concentrations of Tislelizumab(Pre-infusion on Day 1 of Cycles 1, 2, 4, 7, 13; at end of infusion on Day 1 of Cycles 1 and 4; on Days 8, 15, and 21 of Cycle 1 (cycle duration: 4 weeks))
- Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab(From the first dose of study treatment (Day 1) up to end of treatment, up to approximately 17 months for Part 1 and 20 months for Part 2)
- Part 2: Change From Baseline in Programmed Death-Ligand 1 (PD-L1) Expression(Baseline (Day 1) up to end of treatment, up to approximately 20 months)
- Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation(From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 21 months)