E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Second-line treatment of KRAS mutant-type metastatic colorectal cancer. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to estimate the treatment effect on progression-free survival (PFS) of AMG 655 plus FOLFIRI or AMG 479 plus FOLFIRI relative to FOLFIRI alone when administered as a second-line treatment for subjects with metastatic colorectal cancer (mCRC) whose tumors express mutant-type Kirsten rat sarcoma virus oncogene homolog (KRAS). |
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E.2.2 | Secondary objectives of the trial |
• To estimate treatment effect on overall survival (OS), Objective Response Rate (ORR = complete response [CR] + partial response [PR]), rates of disease control (= complete [CR] + partial [PR] + stable disease [SD]), duration of response (DOR), and time to response (TTR) • To evaluate the incidence of adverse events and significant laboratory abnormalities, and the incidence of anti-AMG 655 or anti-AMG 479 antibody formation • To evaluate treatment effect on patient-reported outcomes (PRO) using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire - core questionnaire (EORTC QLQ-C30) and the FACT/NCCN-Colorectal Symptom Index (FCSI) • To evaluate pharmacokinetics (PK) of AMG 655, AMG 479 and FOLFIRI components (irinotecan and 5-FU), and estimate the impact of administration of AMG 655 and AMG 479 on the PK of FOLFIRI components (irinotecan and 5-FU) For further secondary objectives see protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease Related • Histologically confirmed adenocarcinoma of the colon or rectum in patients with metastatic disease • Mutant-type KRAS tumor status confirmed by central laboratory assessment of formalin-fixed paraffin-embedded tumor tissue from the primary tumor or metastasis or by another experienced laboratory using a validated test method per local regulatory guidelines – Subjects with local KRAS test results are required to submit a pathology sample to the central laboratory, Amgen reserves the right to request the central laboratory retest the tumor sample for KRAS mutation status for sharing the data with regulatory agencies (if requested)
• One and only one prior anti-cancer therapy regimen for metastatic disease consisting of the combination of a fluoropyrimidine and oxaliplatin-based chemotherapy with or without anti-VEGF therapy. Prior adjuvant or neoadjuvant chemotherapy used prior to the onset of metastatic disease is permitted. • Documented disease progression while receiving or ≤ 6 months after the last dose of prior first-line fluoropyrimidine and oxaliplatin-based chemotherapy with or without bevacizumab for metastatic disease • Measurable or non-measurable disease according to modified RECIST criteria. Lesions must not be chosen from a previously irradiated field, unless there has been documented disease progression in that field after irradiation and prior to randomization. All sites of disease must be evaluated ≤ 28 days prior to randomization. • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Demographic • Men or women 18 years of age or older at the time the informed consent is obtained Laboratory To be performed ≤ 7 days prior to randomization, unless otherwise specified: • Hematologic function within the following limits: − Absolute neutrophil count (ANC) ≥ 1.5 x 109/L − Platelet count ≥ 100 x 109/L (without platelet transfusion ≤ 14 days prior to randomization) − Hemoglobin ≥ 9.0 g/dL • Renal function within the following limits: − Creatinine clearance (GFR) ≥ 40 mL/min calculated by the Cockcroft-Gault method as follows: o Male creatinine clearance = (140 – age in years) x (weight in Kg) / (serum creatinine in mg/dL x 72) o Female creatinine clearance = (140 – age) x (weight in Kg) x 0.85 / (serum creatinine in mg/dL x 72) • Hepatic function within the following limits − Total bilirubin ≤ 1.5 mg/dL; − Alkaline phosphatase ≤ 2.5 x ULN (if liver metastases, ≤ 5 x ULN) − Aspartate aminotransferase (AST) ≤ 2.5 x ULN (if liver metastases, ≤ 5 x ULN) − Alanine aminotransferase (ALT) ≤ 2.5 x ULN (if liver metastases, ≤ 5 x ULN) • Coagulation function within the following limits: - Partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤ 1.3 x ULN and international normalized ratio (INR) < 1.3
• Glycosylated hemoglobin (HgbA1c) ≤ 8%
• Negative pregnancy test ≤ 3 days prior to randomization (for woman of childbearing potential only) General • Competent to comprehend, sign, and date an institutional review board (IRB)/ Independent Ethics Committee (IEC) -approved informed consent form • Subject plans to begin protocol-specified therapy within 7 days of randomization |
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E.4 | Principal exclusion criteria |
Disease Related • History or known presence of central nervous system (CNS) metastases • History of other malignancy, except: − Malignancy treated with curative intent and with no known active disease present for ≥ 3 years prior to randomization 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 Cancer Therapy • Prior irinotecan-based chemotherapy for advanced/metastatic disease • Prior death receptor agonists (such as rhApo2/TRAIL [AMG 951]), apomab, mapatumumab, lexatumumab, CS-1008), or other systemic IGF-1R antagonists (such as CP-751, 951, MK0646, IMC-A12) in any setting. • Systemic chemotherapy, hormonal therapy, immunotherapy or experimental or approved anticancer proteins/antibodies therapy ≤ 21 days prior to randomization • Radiotherapy ≤ 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities. • Unresolved toxicities from prior anti-cancer therapy that, in the opinion of the investigator, exclude subject from participation Other Medications • Course of systemic anti-infective that was completed ≤ 14 days before randomization(exception can be made at the judgment of the investigator for oral treatment of anuncomplicated urinary tract infection [UTI]) • Currently being treated with full dose anti-coagulation therapy (ie, coumadin with a goal INR between 2 to 3, or full dose low molecular weight heparin)
General • Myocardial infarction, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, percutaneous transluminal coronary angioplasty/stent, hypertension not stably controlled pharmacologically, ongoing arrhythmias requiring medication or unstable angina ≤ 24 weeks prior to randomization • Pulmonary embolism, deep vein thrombosis, or other venous/arterial thromboembolic events ≤ 12 months before randomization • Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as ≥ CTCAE grade 2, [CTCAE version 3.0]) • Major surgical procedure ≤ 28 days before randomization or not yet recovered from prior major surgery • Anticipation of need for major elective surgical procedures during the course of the study • Minor surgical procedure ≤ 7 days before randomization or not yet recovered from prior minor surgery (Uncomplicated placement of vascular access device, fine needle aspiration, thoracocentesis or paracentesis ≥ 3 days prior to enrollment is acceptable) • Any co-morbid disease or condition that in the judgment of the investigator could increase the risk of toxicity (such as clinically significant ascites) • Subjects known to be human immunodeficiency virus positive or known to have chronic or active hepatitis B or C infection • Subject is currently enrolled in, or ≤ 30 days has passed since subject completed another investigational device or drug study(s), or subject is receiving other investigational agent(s) • Woman of child-bearing potential is pregnant or is breast feeding • Women of childbearing potential and men who do not consent to use adequate contraception during the course of the study and 24 weeks (for men) or 12 weeks (for women) after the last dose of protocol-specified therapy. Adequate contraceptive precautions include double barrier contraceptive methods (eg, diaphragm and condom) or abstinence. • Subjects allergic to any components that are part of the treatment regimen (such as known allergy or hypersensitivity to irinotecan, 5-FU [known dihydropyrimidine dehydrogenase deficiency] or leucovorin) • History of any medical or psychiatric condition or addictive disorder, or laboratory abnormality that, in the opinion of the investigator, may increase the risks associated with study participation or study drug administration or may interfere with the conduct of the study or interpretation of study results • Subject has previously been randomized into this study • Subject unwilling or unable to comply with study requirements (eg, will not be available for follow-up assessment) • Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedure
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival (PFS) PFS time is defined as the time from the date of randomization to the first observation of disease progression (as classified by modified RECIST based on the investigator assessment of radiographic scans, or clinical progression whichever occurs first,) or death due to any cause. If a subject’s disease has not progressed and the subject is alive by the analysis data cut-off date, PFS will be censored at the last date they are known to be progression-free (ie, the last evaluable disease assessment date). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study will occur when all subjects have died or completed the long-term follow-up period (maximum of 36 months from the date that the last subject has been randomized), whichever is earlier. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |