A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Number of Subjects With Tumor Uptake of 111^In-CS-1008 in Target Lesions Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions
研究概览
简要总结
This was a Phase 1, open-label, single-center study of CS-1008, an immunoglobulin G subclass 1 (IgG1) humanized monoclonal antibody, in subjects with advanced colorectal carcinoma who had received ≥ 1 prior chemotherapy regimen for metastatic disease. Primary study objectives were to determine the influence of the CS-1008 dose on the biodistribution, pharmacokinetics (PK) and tumor uptake of radiolabeled CS-1008 following a single infusion and following continuous sequential doses of CS-1008. Secondary objectives were to evaluate changes in tumor metabolism, antitumor response, and changes in serum apoptosis biomarkers and tumor response markers following treatment with CS-1008.
详细描述
Eligible subjects were to be enrolled into one of 5 dose-escalation cohorts to receive CS-1008 administered weekly as an intravenous (IV) infusion over 30 ± 10 minutes. Each cohort initially comprised 2 subjects but was expanded in up to 5 subjects if additional biodistribution and/or PK data were required.
The initial infusion of CS-1008 on Day 1 was trace labeled with Indium-111 (111^In-CS-1008; 5-7 mCi) and was investigated at escalating doses up to the standard loading dose, as follows: Cohort 1 (0.2 mg/kg), Cohort 2 (1 mg/kg), Cohort 3 (2 mg/kg), Cohort 4 (4 mg/kg), and Cohort 5 (6 mg/kg). The initial 111^In-CS-1008 dose was followed by gamma camera imaging with blood sampling over a 10-day period to evaluate biodistribution, tumor uptake, PK, and serum biomarkers. Day 8 dosing comprised non-labeled CS-1008 at doses of 6 mg/kg in Cohorts 1-3, 4 mg/kg in Cohort 4, and 2 mg/kg in Cohort 5. Subsequent weekly infusions of standard dose CS-1008 (2 mg/kg) were administered on Days 15, 22, 29, 36, and 43. The Day 36 infusion of CS-1008 was also trace labeled with 111^In (5-7 mCi), with subsequent gamma camera imaging and blood sampling.
Subjects were assessed for disease status using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, serum tumor biomarkers (carcinoembryonic antigen [CEA]), and human-anti-CS-1008-antibody development (HAHA). Subjects were assessed for changes in tumor metabolism following CS-1008 administration using computed tomography (CT) or fluorodeoxyglucose positron emission tomography (18^F-FDG PET) scans.
Cycle 1 encompassed the first 7 weeks of therapy. Within 1 week (Days 44-50) after the last infusion of CS-1008, subjects completed an End of Study/End of Cycle 1 assessment. Subjects with stable disease or better (according to RECIST version 1.1) at the Day 44-50 reassessment were permitted to receive additional 4-week cycles of CS-1008 (2 mg/kg) until disease progression, unacceptable toxicity, or subject/physician decision.
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
- •Histologically proven metastatic colorectal cancer with 1 target lesion ≥ 2 cm and evaluable by gamma camera imaging. If this lesion was previously irradiated, progression must have been documented following radiotherapy.
- •Received at least 1 prior course of chemotherapy for metastatic disease.
- •Expected survival of at least 3 months.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Age ≥ 18 years old.
- •Able and willing to give valid written informed consent.
- •Within the last 1 week prior to first study drug administration, laboratory parameters for vital functions were to be in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which were to be within the ranges specified:
- •Neutrophil count: ≥ 1.5 x 10^9/L
- •Platelet count: ≥ 90 x 10^9/L
- •International normalized ratio: ≤ 1.5
- •Serum bilirubin: ≤ 1.5 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2 x ULN (≤ 5 x ULN if liver metastases)
- •Calculated creatinine clearance (Cockcroft-Gault formula): ≥ 55 mL/min
排除标准
- •Active central nervous system metastases. Definitively treated metastases were allowed if stable for 6 weeks off therapy.
- •Known immunodeficiency or human immunodeficiency virus positivity.
- •Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would have interfered with the ability of the subject to fulfill the study requirements.
- •Other malignancy, apart from non-melanoma skin cancer, within 3 years prior to first study drug administration, that in the opinion of the Investigator had >10% risk of relapse within 12 months.
- •Chemotherapy, radiotherapy, or investigational agent within 4 weeks prior to first study drug administration.
- •Regular corticosteroid, nonsteroidal anti-inflammatory drug (NSAID) (other than paracetamol or low-dose aspirin) or other immunosuppressive treatment within 3 weeks prior to first drug administration. Intermittent dosing of corticosteroid or NSAID was permitted if less than 4 doses within a 3-day period.
- •Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
- •Lack of availability for clinical follow-up assessments.
- •Pregnancy or breastfeeding.
- •Women of childbearing potential: refusal or inability to use effective means of contraception.
研究组 & 干预措施
Cohort 1
Subjects received an initial loading dose of 111^In-CS-1008 (0.2 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
干预措施: CS-1008 (Drug)
Cohort 2
Subjects received an initial loading dose of 111^In-CS-1008 (1 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
干预措施: CS-1008 (Drug)
Cohort 3
Subjects received an initial loading dose of 111^In-CS-1008 (2 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
干预措施: CS-1008 (Drug)
Cohort 4
Subjects received an initial loading dose of 111^In-CS-1008 (4 mg/kg) on Day 1, CS-1008 (4 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
干预措施: CS-1008 (Drug)
Cohort 5
Subjects received an initial loading dose of 111^In-CS-1008 (6 mg/kg) on Day 1, CS-1008 (2 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
干预措施: CS-1008 (Drug)
结局指标
主要结局
Number of Subjects With Tumor Uptake of 111^In-CS-1008 in Target Lesions Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions
时间窗: Up to 43 days
Tumor localization was assessed using gamma camera imaging performed after the initial infusion of 111\^In-CS-1008 on Day 1 and then on Days 2, 4/5, 7/8, and 11/12 (collectively, "After Day 1 Infusion" in the table) and after the second infusion of 111\^In-CS-1008 on Day 36 and then on Days 37, 39/40, and 42/43 (collectively, "After Day 36 Infusion" in the table). Dosimetry calculations were performed to determine the tumor localization properties of 111\^In-CS-1008. Calculation of whole body dose and doses to individual organs by 111\^In-CS-1008 were performed based on conjugate view images obtained from quantitative whole body images obtained at multiple time points. MIRD formalism was used in the calculation of doses.
Mean Tumor Uptake of 111^In-CS-1008 Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions
时间窗: Up to 43 days
Tumor localization was assessed using gamma camera imaging performed on Days 7/8 and 42/43. Dosimetry calculations were performed to determine the tumor localization properties of 111\^In-CS-1008. Calculation of whole body dose and doses to individual organs by 111\^In-CS-1008 were performed based on conjugate view images obtained from quantitative whole body images obtained at multiple time points. MIRD formalism was used in the calculation of doses.
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
时间窗: Up to 36 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
时间窗: Up to 36 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
时间窗: Up to 36 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
时间窗: Up to 36 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
时间窗: Up to 36 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
时间窗: Up to 50 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
时间窗: Up to 50 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
时间窗: Up to 50 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
时间窗: Up to 50 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
时间窗: Up to 50 days
The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).
次要结局
- Number of Subjects With Best Overall Tumor Response(Up to 7 months)
- Number of Subjects With Best Overall Metabolic Response(Up to 50 days)