| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Tratamiento de segunda línea del cáncer colorrectal metastásico con KRAS mutado
Second-line treatment of KRAS mutant-type metastatic colorectal cancer. |
|
| 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 |
|
| 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). |
|
| 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. |
|
| 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
? 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) ? 1.5, unless subject is on
anti-coagulation therapy. Subjects on therapeutic anti-coagulation are eligible if:
o there is no bleeding and they are on a stable dose of anticoagulation therapy
(eg, warfarin with an INR of 2 to 3) for at least 14 days before randomization,
and o the patient has no active bleeding or pathological condition that carries high
risk of bleeding (eg, tumor involving major vessels or known varices)
? Subjects with diabetes (Type 1 or 2) must be adequately controlled with glycosylated hemoglobin (HgbA1c) ? 8% and fasting blood glucose level ?160 mg/dL; diabetic subjects who have recently had their glycemic control regimens adjusted and have documented fasting blood glucose concentrations ? 160 mg/dL may be considered, regardless of HgbA1c value, if per investigator discretion they are considered to have adequate glycemic function
? 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 |
|
| 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 an
uncomplicated urinary tract infection [UTI])
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 |
|
| 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). |
|
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| 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 | 6 |
| 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 |
|
| 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
|
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. |
|
| 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 |
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