Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild Type KRAS and Refractory to Oxaliplatin-or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance to Panitumumab
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 74
- 主要终点
- PFS Hazard Ratio
研究概览
简要总结
This study is designed to evaluate the mechanism(s) of resistance to the anti-epidermal growth factor receptor (EGFR) antibody panitumumab given in combination with irinotecan in metastatic colorectal carcinoma (mCRC) patients with wild-type Kirsten rat sarcoma-2 virus oncogene (KRAS) tumor status at the time of initial diagnosis.
详细描述
In Part 1, all participants will undergo a baseline tumor biopsy and will receive panitumumab with irinotecan. Participants who respond or have stable disease will continue to receive treatment until radiographically-confirmed disease progression. These participants will then undergo a second tumor biopsy and blood sampling and then proceed to Part 2 of the study. Participants with radiographically confirmed disease progression at the time of the first tumor measurement will undergo blood sampling and proceed directly to Part 2.
In Part 2, participants will receive panitumumab with ganitumab. In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and ganitumab (Part 2) will be administered every 2 weeks until disease progression, intolerability, withdrawal of consent, death, or unless otherwise indicated by the study team.
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 or cytologically confirmed metastatic adenocarcinoma of the colon or rectum;
- •Subjects with wild-type KRAS tumor status confirmed by an Amgen approved central laboratory assessment or an experienced local laboratory assessment of archival tumor tissue (preferably from the primary tumor);
- •Radiographic evidence of disease progression while on or ≤ 6 months after completion of treatment with irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC;
- •Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of treatment with investigational product);
- •At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm by spiral CT scan per modified RECIST v1.
- •Lesion must not be chosen from a previously irradiated field, unless there has been documented disease progression in that field after irradiation and prior to enrollment. All sites of disease must be evaluated;
- •At least 1 tumor (preferably a metastasis or unresected primary tumour) that is amenable to core biopsy, as determined by the clinician who will perform the biopsy;
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
- •A life expectancy estimate of ≥ 3 months;
- •Willing to undergo two serial core biopsy procedures of tumors (metastasis or unresected primary);
- •other criteria may apply
排除标准
- •History of other primary cancer, unless:
- •Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician,
- •Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease,
- •Adequately treated cervical carcinoma in situ without evidence of disease,
- •Prostatic intraepithelial neoplasia without evidence of prostate cancer;
- •History of prior or concurrent central nervous system (CNS) metastases;
- •Prior treatment with anti-EGFR (eg, panitumumab, cetuximab or small molecule inhibitors (eg, erlotinib, gefitinib);
- •Prior treatment with monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) or small molecule inhibitors directed against IGF-1R;
- •Use of systemic chemotherapy or radiotherapy ≤ 21 days before enrollment. Subjects must have recovered from acute toxicities related to radiotherapy;
- •Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrolment;
- •Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules ≤ 30 days before enrolment;
- •Known allergy or hypersensitivity to any component of panitumumab, irinotecan, or AMG 479;
- •Known uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphisms predisposing to increased irinotecan toxicity;
- •History of irinotecan intolerance that may interfere with planned treatment;
- •History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan;
- •Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment;
- •Active inflammatory bowel disease or other active bowel disease causing chronic diarrhea (defined as ≥ grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) version 3.0);
- •Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection;
- •Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days before enrollment. Subjects must have recovered from surgery related toxicities. Core biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or paracentesis is not considered a major or minor surgical procedure; - Other investigational procedures or drugs (ie, participation in another clinical study) ≤ 30 days before enrolment;
- •other criteria may apply
研究组 & 干预措施
Panitumumab
Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
干预措施: Ganitumab (Biological)
Panitumumab
Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
干预措施: Panitumumab (Biological)
Panitumumab
Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
干预措施: Irinotecan (Drug)
结局指标
主要结局
PFS Hazard Ratio
时间窗: From baseline up to 152 weeks (from baseline to the time of the second biopsy prior to entering part 2) .
KRAS mutation status changed from wild-type at baseline to mutant at time of second biopsy in part 1, as measured by the PFS hazard ratio. Hazard ratio is presented as wild-type: mutant
Objective Response Rate in Part 2
时间窗: From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
次要结局
- Objective Response Rate for Part 1(from first dose of investigational product up to 152 weeks)
- Progression-Free Survival for Part 1(from first dose of investigational product up to 152 weeks)
- Progression-Free Survival for Part 2(119 weeks from the start of part 2, up to a maximum duration of 152 week)
- Overall Survival for Part 2(from the start of Part 2 up to 119 weeks)
- Time to Response for Part 1(from first dose of investigational product up to 152 weeks)
- Duration of Response for Part 1(from first dose of investigational product up to 152 weeks)
- Overall Survival for Part 1(from first dose of investigational product up to 152 weeks)
- Part 2 Time to Response and Duration of Response(From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks))