A Prospective,Open-label, Dose Escalation Phase 1 Study to Investigate the Safety, and Tolerability and to Determine the Maximum Tolerated Dose and Recommended Phase 2 Dose of a HLX07, in Patients With Advanced Solid Cancers.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Henlix, Inc
- 入组人数
- 19
- 试验地点
- 2
- 主要终点
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
研究概览
简要总结
This study is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of humanized anti-EGFR monoclonal antibody, HLX07, in patients with epithelial cancer who have failed standard therapy and deemed unamenable by conventional therapy. This study will also evaluate the pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor effect of HLX07 and explore the potential prognostic and predictive biomarkers.
详细描述
The role of EGFR in carcinogenesis led to the development and extensive evaluation of EGFR-blocking agents for cancer treatment. Two EGFR-targeted approaches have been explored: (a) small-molecule tyrosine kinase inhibitors targeting the intracellular EGFR tyrosine kinase domain and (b). mAbs targeting the EGFR extra-cellular domain.
Small-molecule tyrosine kinase inhibitors have been widely used in lung cancer with EGFR mutations. However, the results of using small molecule inhibitors for cancer with overexpressed wildtype EGFR have been unsatisfactory.
The best-studied of the anti-EGFR mAbs in cancer is cetuximab (Erbitux®), and panitumumab (Vectibix®). Necitumumab, another humanized anti-EGFR mAb is currently under investigation is multiple cancers. Both cetuximab and panitumumab have been approved in colorectal cancer and head/neck cancer.
Cetuximab is chimeric human-murine IgG1 mAb, and blocks ligand binding to EGFR, thereby diminishing receptor dimerization and autophosphorylation and inducing EGFR downregulation. The immunoglobulin IgG1 isotype of cetuximab may also engage hose immune functions such as antibody-dependent cellular cytotoxicity (ADCC). Cetuximab is approved to be used in combination with chemotherapy and has been shown to improve the survival of patients with advanced colorectal cancer. Cetuximab, when used in combination with radiotherapy has also improved response rate in patients with locally advanced head/neck cancer. However, the use of cetuximab has been associated with rare anaphylactic reactions, which is likely to be related to the specific glycosylation in the molecules and possibly its mouse/human chimeric structure.
Panitumumab is a human IgG2 mAb that targets EGFR. But unlike cetuximab, it mediates its effects through mechanisms other than ADCC, which has a different binding site on EGFR extracellular domain from that of cetuximab, is also approved for colorectal cancer and head/neck cancer. However, the side effects, especially skin reactions, is more pronounced in patients receiving panitumumab, which also limiting its clinical use.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Histologically-confirmed, unidimensionally-measurable and/or evaluable carcinoma which has failed standard therapy or for whom no standard therapy is available.
- •ECOG performance status score of ≤ 2 at study entry.
- •Able to provide written informed consent.
- •White blood cell (WBC) count ≥3 x 109/L;an absolute neutrophil count ≥ 1.5 x 109/L;a hemoglobin level > 90 g/L; and a platelet count ≥ 100 x 109/L.
- •Adequate hepatic function as defined by: alkaline phosphatase level ≤ 5.0 x the ULN, bilirubin level ≤ 1.5 x the ULN, aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2.5 x the ULN or ≤ 5 x the ULN for patients with liver metastases
- •Adequate renal function as defined by a serum creatinine level within normal limits.
- •Use of effective contraception if procreative potential exists.
- •Life expectancy of approximately 3 months or longer in the opinion of the investigator.
排除标准
- •Chemotherapy, radiation, and/or hormonal therapy (except palliative radiation therapy for disease-related pain and chronic hormonal therapy for prostate carcinoma) within 4 weeks of study entry.
- •Concurrent unstable or uncontrolled medical disease (e.g., active uncontrolled systemic infection, poorly controlled hypertension or history of poor compliance with an anti-hypertensive regimen, unstable angina, congestive heart failure, uncontrolled diabetes) or other chronic disease, which, in the opinion of the investigator, could compromise the patient or the study.
- •Newly-diagnosed or symptomatic brain metastases (patients with a history of brain metastases must have received definitive surgery or radiotherapy, be clinically stable, and not taking steroids; anticonvulsants are allowed).
- •Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the cervix. Patients with a previous malignancy but without evidence of disease for more than 3 years will be allowed to enter the trial.
- •Any condition that prevents the patient from providing informed consent.
- •Pregnancy (confirmed by serum beta human chorionic gonadotropin [beta-HCG]) or breast-feeding.
- •Any investigational agent(s) or device(s) within 4 weeks of study entry.
- •Prior treatment with cetuximab, or any other anti-EGFR monoclonal antibody therapy for less than 3 months. Prior treatment with other monoclonal antibodies targeting receptors other than the EGFR is permitted if the drug has been discontinued more than (include) 4 weeks prior to study entry.
- •Tumor cells with either K-ras, N-ras or B-raf mutations.
- •Known history of human immunodeficiency virus infection.
- •Employees of the investigator or study center with direct involvement in this study or other studies under the direction of the investigator or study center, as well as family members of the employees.
研究组 & 干预措施
HLX07, in patients with solid cancers.
Each cycle of treatment consists of 4 weeks. Patients who enroll into this study will receive weekly infusion of assigned dose of HLX07. No intra-patient dose escalation is allowed.The proposed dose escalation sequence is 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg.
Acetaminophen 500 mg PO 30 minutes before the infusion of HLX07, followed by dexamethasone 10 mg intravenous infusion for 10 minutes, and followed by diphenhydramine 30 mg intravenous infusion for 10 minutes. If the patient experience grade 2 or 3 nausea and vomiting during the first infusion of HLX07, the addition of 5-HT3 inhibitor may be included in the premedication before subsequent infusions.
干预措施: HLX07 (Drug)
HLX07, in patients with solid cancers.
Each cycle of treatment consists of 4 weeks. Patients who enroll into this study will receive weekly infusion of assigned dose of HLX07. No intra-patient dose escalation is allowed.The proposed dose escalation sequence is 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg.
Acetaminophen 500 mg PO 30 minutes before the infusion of HLX07, followed by dexamethasone 10 mg intravenous infusion for 10 minutes, and followed by diphenhydramine 30 mg intravenous infusion for 10 minutes. If the patient experience grade 2 or 3 nausea and vomiting during the first infusion of HLX07, the addition of 5-HT3 inhibitor may be included in the premedication before subsequent infusions.
干预措施: Acetaminophen (Drug)
HLX07, in patients with solid cancers.
Each cycle of treatment consists of 4 weeks. Patients who enroll into this study will receive weekly infusion of assigned dose of HLX07. No intra-patient dose escalation is allowed.The proposed dose escalation sequence is 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg.
Acetaminophen 500 mg PO 30 minutes before the infusion of HLX07, followed by dexamethasone 10 mg intravenous infusion for 10 minutes, and followed by diphenhydramine 30 mg intravenous infusion for 10 minutes. If the patient experience grade 2 or 3 nausea and vomiting during the first infusion of HLX07, the addition of 5-HT3 inhibitor may be included in the premedication before subsequent infusions.
干预措施: dexamethasone (Drug)
HLX07, in patients with solid cancers.
Each cycle of treatment consists of 4 weeks. Patients who enroll into this study will receive weekly infusion of assigned dose of HLX07. No intra-patient dose escalation is allowed.The proposed dose escalation sequence is 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg.
Acetaminophen 500 mg PO 30 minutes before the infusion of HLX07, followed by dexamethasone 10 mg intravenous infusion for 10 minutes, and followed by diphenhydramine 30 mg intravenous infusion for 10 minutes. If the patient experience grade 2 or 3 nausea and vomiting during the first infusion of HLX07, the addition of 5-HT3 inhibitor may be included in the premedication before subsequent infusions.
干预措施: diphenhydramine (Drug)
HLX07, in patients with solid cancers.
Each cycle of treatment consists of 4 weeks. Patients who enroll into this study will receive weekly infusion of assigned dose of HLX07. No intra-patient dose escalation is allowed.The proposed dose escalation sequence is 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg.
Acetaminophen 500 mg PO 30 minutes before the infusion of HLX07, followed by dexamethasone 10 mg intravenous infusion for 10 minutes, and followed by diphenhydramine 30 mg intravenous infusion for 10 minutes. If the patient experience grade 2 or 3 nausea and vomiting during the first infusion of HLX07, the addition of 5-HT3 inhibitor may be included in the premedication before subsequent infusions.
干预措施: 5-HT3 inhibitor (Drug)
结局指标
主要结局
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
时间窗: 1 year
次要结局
- Number of participants with treatment-related pathological Complete Response assessed using RECIST 1.1 criteria.(1 year)