Phase 1b/2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Anti-HER2 Bispecific Antibody ZW25 in Combination With Chemotherapy With/Without Tislelizumab in Patients With Advanced HER2-positive Breast Cancer or Gastric/Gastroesophageal Junction Adenocarcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 71
- 试验地点
- 42
- 主要终点
- Number of Participants experiencing Adverse Events (AEs)
研究概览
简要总结
The purpose of the study is to assess the safety, tolerability and preliminary antitumor activity of zanidatamab in combination with docetaxel in participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and zanidatamab in combination with tislelizumab and chemotherapy in participants with HER2-positive gastric/gastroesophageal Junction (GEJ) adenocarcinoma
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
- •Disease diagnosis and prior treatment:
- •Cohort 1 (the first-line breast cancer treatment cohort):
- •Female participants with histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic adenocarcinoma of the breast and candidate for chemotherapy. Locally recurrent disease must not be amenable to resection with curative intent.
- •Human epidermal growth factor receptor 2 (HER2) IHC 3+ or in situ hybridization positive on the archival tumor tissue or fresh biopsy sample.
- •Have not received previous systemic anticancer therapy for locally advanced unresectable or metastatic disease.
- •Cohort 2 (the first-line gastric/gastroesophageal junction adenocarcinoma treatment cohort):
- •Histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction
- •HER2 IHC 3+ or HER2 IHC 2+ together with in situ hybridization positive on the archival tumor tissue or fresh biopsy sample.
- •Have not received previous systemic anticancer therapy for locally advanced unresectable or metastatic disease, including any approved or investigational estimated glomerular filtration rate (EGFR) or anti-HER2 agents or vaccines, cytotoxic chemotherapy or checkpoint inhibitors
- •At least 1 measurable lesion as defined per RECIST Version 1.1
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
- •Adequate organ function
- •Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram or multigated acquisition scan (MUGA) (echocardiogram is the preferred method) within 28 days before the first dose of study drug
排除标准
- •Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- •History of approved or investigative tyrosine kinase/HER inhibitors in any treatment setting
- •a. except trastuzumab with or without pertuzumab used in neoadjuvant or adjuvant setting for Cohort 1
- •Active leptomeningeal disease, untreated or uncontrolled brain metastasis
- •Any active malignancy ≤ 2 years before the first dose of study drug, except for the specific cancer under investigation in this trial and any localized cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix)
- •Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study drug
- •Note: Participants who are currently or have previously been on any of the following steroid regimens are not excluded:
- •Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
- •Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption
- •Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen)
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Cohort 2A: Gastric/GEJC: Zanidatamab 30 mg/kg + Tislelizumab + CAPOX
Participants with HER2+ gastric / gastroesophageal junction cancer (GEJC) received zanidatamab 30 mg/kg IV and tislelizumab 200 mg IV once every 3 weeks until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Oxaliplatin (Drug)
Cohort 1A: Breast Cancer: Zanidatamab 30 mg/kg + Docetaxel
Participants with HER2+ breast cancer received zanidatamab 30 mg/kg intravenously (IV) and docetaxel 75 mg/m^2 IV once every 3 weeks (Q3W) for an initial period of up to six cycles. After cycle 6, continuation of docetaxel treatment was at the discretion of the investigator. Zanidatamab was administered until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met.
干预措施: Zanidatamab (Biological)
Cohort 2B: Gastric/GEJC : Zanidatamab 1800/2400 mg + Tislelizumab + CAPOX
Participants with HER2+ gastric / GEJC received zanidatamab 1800 mg (participants with body weight < 70 kg) or 2400 mg (participants with body weight ≥ 70 kg) IV and tislelizumab 200 mg IV Q3W until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Oxaliplatin (Drug)
Cohort 1A: Breast Cancer: Zanidatamab 30 mg/kg + Docetaxel
Participants with HER2+ breast cancer received zanidatamab 30 mg/kg intravenously (IV) and docetaxel 75 mg/m^2 IV once every 3 weeks (Q3W) for an initial period of up to six cycles. After cycle 6, continuation of docetaxel treatment was at the discretion of the investigator. Zanidatamab was administered until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met.
干预措施: Docetaxel (Drug)
Cohort 1B: Breast Cancer: Zanidatamab 1800 mg + Docetaxel
Participants with HER2+ breast cancer received zanidatamab 1800 mg/kg IV and docetaxel 75 mg/m^2 IV Q3W for an initial period of up to six cycles. After cycle 6, continuation of docetaxel treatment was at the discretion of the investigator. Zanidatamab was administered until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met.
干预措施: Zanidatamab (Biological)
Cohort 2B: Gastric/GEJC : Zanidatamab 1800/2400 mg + Tislelizumab + CAPOX
Participants with HER2+ gastric / GEJC received zanidatamab 1800 mg (participants with body weight < 70 kg) or 2400 mg (participants with body weight ≥ 70 kg) IV and tislelizumab 200 mg IV Q3W until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Capecitabine (Drug)
Cohort 1B: Breast Cancer: Zanidatamab 1800 mg + Docetaxel
Participants with HER2+ breast cancer received zanidatamab 1800 mg/kg IV and docetaxel 75 mg/m^2 IV Q3W for an initial period of up to six cycles. After cycle 6, continuation of docetaxel treatment was at the discretion of the investigator. Zanidatamab was administered until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met.
干预措施: Docetaxel (Drug)
Cohort 2A: Gastric/GEJC: Zanidatamab 30 mg/kg + Tislelizumab + CAPOX
Participants with HER2+ gastric / gastroesophageal junction cancer (GEJC) received zanidatamab 30 mg/kg IV and tislelizumab 200 mg IV once every 3 weeks until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Capecitabine (Drug)
Cohort 2A: Gastric/GEJC: Zanidatamab 30 mg/kg + Tislelizumab + CAPOX
Participants with HER2+ gastric / gastroesophageal junction cancer (GEJC) received zanidatamab 30 mg/kg IV and tislelizumab 200 mg IV once every 3 weeks until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Zanidatamab (Biological)
Cohort 2A: Gastric/GEJC: Zanidatamab 30 mg/kg + Tislelizumab + CAPOX
Participants with HER2+ gastric / gastroesophageal junction cancer (GEJC) received zanidatamab 30 mg/kg IV and tislelizumab 200 mg IV once every 3 weeks until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Tislelizumab (Biological)
Cohort 2B: Gastric/GEJC : Zanidatamab 1800/2400 mg + Tislelizumab + CAPOX
Participants with HER2+ gastric / GEJC received zanidatamab 1800 mg (participants with body weight < 70 kg) or 2400 mg (participants with body weight ≥ 70 kg) IV and tislelizumab 200 mg IV Q3W until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Zanidatamab (Biological)
Cohort 2B: Gastric/GEJC : Zanidatamab 1800/2400 mg + Tislelizumab + CAPOX
Participants with HER2+ gastric / GEJC received zanidatamab 1800 mg (participants with body weight < 70 kg) or 2400 mg (participants with body weight ≥ 70 kg) IV and tislelizumab 200 mg IV Q3W until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.
干预措施: Tislelizumab (Biological)
结局指标
主要结局
Number of Participants experiencing Adverse Events (AEs)
时间窗: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 41 months
Number of Participants experiencing Serious Adverse Events (SAEs) as assessed by the investigator.
时间窗: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 41 months
Objective response rate (ORR)
时间窗: From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 41 months
Defined as the percentage of participants who had a best overall response of complete response or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 42 months
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatments, whether considered related to study treatments or not. A serious AE (SAE) was any untoward medical occurrence that, at any dose - resulted in death, - was life threatening, - required hospitalization or prolongation of existing hospitalization, - resulted in disability/incapacity, - was a congenital anomaly/birth defect.
Objective Response Rate (ORR)
时间窗: Response was assessed every 6 weeks from cycle 1 day 1 for the first 36 weeks and then every 12 weeks thereafter; maximum time on study follow-up was 42months.
ORR is defined as the percentage of participants who had a best overall response of complete response or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
次要结局
- Duration of response (DOR)(From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 41 months)
- Time to response (TTR)(From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 41 months)
- Progression-free survival (PFS)(From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 41 months)
- Overall survival (OS)(From the start date of study treatment to the documented death date or the last known alive date, up to approximately 41 months)
- Serum concentration of zanidatamab as a function of time(Predose and immediately postdose)
- Observed maximum plasma concentration of zanidatamab during a sample interval (Cmax)(Predose and immediately postdose)
- Observed time to maximum plasma concentration of zanidatamab during a sampling interval (tmax)(Predose and immediately postdose)
- Terminal elimination half-life (t1/2) of zanidatamab(Predose and immediately postdose)
- Area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUC(0-t)) of zanidatamab(Predose and immediately postdose)
- Apparent clearance after oral administration (CL/F) of zanidatamab(Predose and immediately postdose)
- Presence of anti-zanidatamab-antibodies(Predose and immediately postdose)
- Presence of zanidatamab neutralizing antibodies(Predose and immediately postdose)
- Number of participants with AEs and SAEs who entered the long-term extension period(From the first dose of study drug(s) to 30 days after the last dose; up to approximately 51 months)
- Duration of Response (DOR)(From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 42 months)
- Time to Response (TTR)(From the start date of study treatment to the first documentation of response, whichever occurs first, up to approximately 42 months)
- Progression-free Survival (PFS)(From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 42 months)
- Disease Control Rate (DCR)(Response was assessed every 6 weeks from cycle 1 day 1 for the first 36 weeks and then every 12 weeks thereafter; maximum time on study follow-up was 42 months.)
- Overall Survival (OS)(From the start date of study treatment to the documented death date or the last known alive date, up to approximately 41 months)
- Serum Concentration of Zanidatamab as a Function of Time(Day 1 end of infusion of Cycle 1, 2, 5, 9, 17, 26 and 35. Each cycle is 21 days)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Timepoint (AUC(0-t)) of Zanidatamab(Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.)
- Observed Maximum Plasma Concentration of Zanidatamab During a Sample Interval (Cmax)(Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.)
- Observed Time to Maximum Plasma Concentration of Zanidatamab During a Sampling Interval (Tmax)(Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.)
- Terminal Elimination Half-life (t1/2) of Zanidatamab(Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.)
- Apparent Clearance After Oral Administration (CL/F) of Zanidatamab(Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose)
- Number of Participants With Anti-zanidatamab Antibodies(From the first dose of study drug(s) to 30 days after the last dose; up to approximately 42 months)
- Number of Participants With AEs and SAEs in Participants Who Entered the Long-term Extension Period(From the first dose of study drug(s) to 30 days after the last dose; up to approximately 51 months)