A Phase 1/2, Multiple-Dose, Dose-Escalation Study to Assess the Safety, Efficacy, and Pharmacokinetics of Intravenous CNTO 328, an Anti-Interleukin 6 (IL-6) Monoclonal Antibody, in Subjects With Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 84
- 主要终点
- Percentage of Participants With Clinical Benefit Response (CBR)
研究概览
简要总结
The purpose of this study is to determine the recommended dose of siltuximab monotherapy, in participants with solid malignant (cancerous) tumors (a mass in a specific area) and to estimate the clinical benefit of siltuximab monotherapy in participants with ovarian cancer and with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant tumors.
详细描述
This is a 2-part, Phase 1/2, open-label (all people know the identity of the intervention), multiple-dose and dose-escalation study of intravenous (directly into a vein) siltuximab in participants with malignant solid tumors. The study tests the safety and effectiveness of the experimental drug, siltuximab, in participants with advanced cancer (abnormal tissue that grows and spreads in the body). This study also tests how siltuximab is cleared from the body and how the body reacts to it. For this reason blood tests will be performed and some characteristics of the tumor will be analyzed. Siltuximab will be given by intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over 1 hour. In Phase 1 (Cohort 1-4) doses will be administered in a range of 2.8-15 milligram per kilogram (mg/kg). Cohort 5 of Phase 1 will receive the recommended dose and schedule as determined from Cohort 1-4. Participants in Phase 1 (Cohort 1-4) will receive 4 administrations of siltuximab over a 10-13 week period, while participants in Cohort 5 and Phase 2 will receive 12 administrations over a 33 week period. Follow-up visits up to 12 weeks after last dose will be scheduled. Participants may then be contacted for up to 1 year after the last dose for follow-up survival and disease status information. Efficacy will primarily be evaluated as per response evaluation criteria in solid tumors (RECIST) criteria. Participants' safety will be monitored at every visit.
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
- •Histologic (pertaining to body tissues) or cytologic (pertaining to cells) documentation of malignancy (cancer or other progressively enlarging and spreading tumor) as follows: malignant solid tumors (Cohort 1-4 only); Cohorts 5 and Phase 2: epithelial (tissue covering outer layers of most body organs and parts) ovarian cancers (abnormal tissue growth) that have progressed on or after standard therapy, or for which there is no effective therapy or platinum resistant and taxane resistant, defined as progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy, or participants with known KRAS mutant tumors or pancreatic cancer, or non-small cell lung cancer (NSCLC), colorectal cancer (CRC) or head and neck (H&N) cancer that are refractory or resistant to anti-epidermal growth factor receptor (EGFR) therapy and all participants must have received at least 1 line of standard chemotherapy
- •Eastern cooperative oncology group (ECOG) performance status score less than or equal to 2
- •Participants must have recovered from reversible toxicity (any harmful effect of a drug or poison) of previous treatment to less than or equal to grade 1 or an acceptable baseline
- •Women of child bearing potential must have a negative pregnancy test at screening
- •Cohort 5 and Phase 2 cohorts must have evaluable or measurable disease (defined by response evaluation criteria in solid tumors [RECIST], as applicable)
排除标准
- •Received any prior systemic therapy or had major surgery for the cancer under study within 4 weeks (in the case of nitrosoureas and mitomycin C within 6 weeks) prior to first siltuximab administration
- •Prior anti-interleukin 6 (IL-6) targeted therapy
- •Serious concurrent illness or history of uncontrolled heart disease such as: unstable angina (chest pain due to decreased oxygen being supplied to the heart), congestive heart failure (failure of the heart resulting in fluid build-up in the lungs, other body tissues, or both), myocardial infarction (heart attack) within preceding 12 months, clinically significant rhythm or conduction abnormality
- •Participants with known allergies (over sensitivity to a substance) or clinically significant reactions to murine, chimeric, or human proteins
- •Any uncontrolled medical condition, including the presence of laboratory abnormalities, that places the participant at unacceptable risk by participating in the study or confounds the ability to interpret data from the study
研究组 & 干预措施
Siltuximab 2.8 mg/kg (Cohort 1)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
Siltuximab 5.5 mg/kg (Cohort 2)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
Siltuximab 11 mg/kg (Cohort 3)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
Siltuximab 15 mg/kg (Cohort 4)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
Siltuximab 15 mg/kg (Expansion Cohort 5)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
Siltuximab 15 mg/kg (Ovarian Cancer Cohort 6)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
Siltuximab 15 mg/kg (KRAS Mutant Tumors Cohort 7)
干预措施: CNTO 328; Anti-interleukin-6 monoclonal antibody (Drug)
结局指标
主要结局
Percentage of Participants With Clinical Benefit Response (CBR)
时间窗: Baseline until disease progression or withdrawal of consent, assessed every 9 weeks up to Week 4 after last dose administration
The CBR is a confirmed complete response (CR), partial response (PR), or stable disease (SD) lasting at least for 6 weeks as per response evaluation criteria in solid tumors (RECIST) criteria. CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least 30 percent decrease in sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since treatment started.
次要结局
- Percentage of Participants With Overall Response(Baseline until disease progression or withdrawal of consent, assessed every 9 weeks up to Week 4 after last dose administration)
- Number of Participants With Tumor Marker Response(Baseline until disease progression or withdrawal of consent, assessed every 9 weeks up to Week 4 after last dose administration)
- Percentage of Participants With Hemoglobin (Hb) Response(Baseline up to Week 4 after last dose administration)
- Progression Free Survival (PFS)(Baseline until disease progression or death, assessed every 9 weeks up to Week 4 after last dose administration)
- Overall Survival (OS)(From first dose administration until death, assessed every 3 months up to 12 months after last dose administration)
- European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score(Baseline up to 4 weeks after last dose administration)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-OV28) Score at Week 4 After Last Dose Administration(Baseline and Week 4 after last dose administration)
- Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf])(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC[0-t])(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Minimum Observed Serum Concentration at Steady-State (Cmin,ss)(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Maximum Observed Serum Concentration (Cmax)(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Terminal Elimination Half Life (t1/2)(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Total Systemic Clearance (CL)(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Volume of Distribution at Steady State (Vss)(Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7))
- Percent Change From Baseline in C-Reactive Protein (CRP) Level(Baseline; Day (D) 1,8,15 (post-dose) for cohort 1 to 7; Day 22 (post-dose), 28 (pre-dose) for cohort 1 to 4; Day 42,56 (pre-dose) for cohort 1, 2; Day 49,70 (pre-dose) for cohort 3, 4; Day 21,42,63,84,105,126,147,168,189,210 (pre-dose) for cohort 5 to 7)
- Percent Change From Baseline in Inflammatory Cytokines Level(Baseline; Day 8 and 15 (post-dose) for cohort (C) 1 to 7; Day 22 (post-dose) and 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7)
- Percent Change From Baseline in the Angiogenesis Related Factors Level(Baseline; Day 8 and 15 (post-dose) for cohort 1 to 7; Day 22 (post-dose) and 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7)
- Percent Change From Baseline in Interleukin 6 Receptor (IL-6R) Subunits Level(Baseline; Day 8 and 15 (post-dose) for cohort 1 to 7; Day 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7)
- Number of Participants Assessed Positive for Antibodies to Siltuximab(Day 1 (pre-dose) up to Week 12 after last dose administration)
- Percent Change From Baseline in Hepcidin Level(Baseline; Day 8 and 15 (post-dose) for cohort 1 to 7; Day 22 (post-dose) and 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7)