| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
| To estimate the treatment effect as measured by progression free survival (PFS) in subjects receiving AMG 386 and FOLFIRI compared with FOLFIRI and placebo in the second line treatment of metastatic colorectal cancer (mCRC). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate other measures of efficacy or clinical response including objective
response rate (ORR), duration of response (DOR), overall survival (OS) in subjects
treated with AMG 386 + FOLFIRI relative to subjects treated with FOLFIRI + placebo
To evaluate progression free survival and measures of efficacy by KRAS status
To evaluate patient reported outcomes (PROs), relative dose intensity of AMG 386
and all FOLFIRI components, incidence of anti-AMG 386 antibody formation,
pharmacokinetics of AMG 386 (Cmax and AUC) and safety (incidence of AEs and
significant laboratory changes)
To evaluate the pharmacokinetics of FOLFIRI (Css and AUC for 5-FU; Cmax and
AUC for irinotecan and its active metabolite SN-38) in a sub-group of subjects
at selected sites outside of Europe |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub-study will only take place at sites outside of the EU
(A substudy conducted in subjects enrolled on this study at selected institutions. These subjects will undergo intensive PK sampling of AMG 386 at Week 5. Sparse PK samples for AMG 386 PK will be collected from all subjects as described in Section 7.2. In addition, a sub-group of subjects enrolled on this study at selected institutions outside of Europe will undergo intensive (if feasible) and/or sparse PK sampling of irinotecan (and its active metabolite, SN-38) and 5-FU at Week 5 and at subsequent visits as described in Section 7.2.) |
|
| E.3 | Principal inclusion criteria |
Disease related
Histologically confirmed adenocarcinoma of the colon or rectum in patients who are
presenting with metastatic disease
One and only one prior chemotherapy regimen for metastatic disease consisting of
the combination of a fluoropyrimidine-based chemotherapy and oxaliplatin-based
chemotherapy. Prior adjuvant chemotherapy used prior to the onset of metastatic
disease is permitted. Subjects must never have received prior irinotecan
At least 1 uni-dimensionally measurable lesion per modified RECIST criteria
(Appendix G). (All sites of disease must be evaluated ≤ 28 days prior to enrollment)
Radiographically documented disease progression per modified RECIST criteria
either while receiving or ≤ 6 months after the last dose of prior chemotherapy
regimen for metastatic disease
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Formalin-fixed paraffin-embedded tumor block or unstained tumor slides from
the primary tumor or metastasis is required for KRAS status
Demographic
Man or woman ≥ 18 years of age
Laboratory
Adequate organ and hematological function as evidenced by the following laboratory
studies within 14 days of randomization:
Hematological function, as follows:
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L
Hemoglobin ≥ 9 g/dL
Renal function, as follows:
Creatinine clearance ≥ 50 mL/min per 24-hour urine collection or calculated
according to the Cockcroft-Gault formula
(140-age) x actual body weight (kg)
CrCl (mL/min) (x 0.85 for females)
72 x serum creatinine (mg/dL)
Or
CrCl (140-age) x actual body weight (kg)
(x 0.85 for females)
(mL/min) 0.8136 x serum creatinine (umol/L)
Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick,
unless quantitative protein is < 1000 mg in a 24-hour urine sample
Hepatic function, as follows:
Aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) (if liver
metastases are present, ≤ 5 x ULN)
Alanine aminotransferase (ALT) ≤ 3 x ULN (if liver metastases are present,
≤ 5 x ULN)
Alkaline phosphatase ≤ 3 x ULN (if bone or liver metastases are present, ≤ 5 x ULN)
Bilirubin ≤ 1.5 x ULN
Hemostatic function, as follows:
International Normalized Ratio (INR) ≤ 1.5
Partial thromboplastin time (PTT) or activated partial thromboplastin (aPTT)
≤ 1.5 x ULN per institutional laboratory range
General
Competent to comprehend, sign, and date an institutional review board (IRB) /
Independent Ethics Committee (IEC) -approved informed consent form
Life expectancy ≥ 3 months
Subject plans to begin protocol directed therapy within 7 days of randomization |
|
| E.4 | Principal exclusion criteria |
Disease Related
Current or prior history of central nervous system metastasis
History of arterial or deep venous thromboembolism within 12 months prior to
randomization
History of clinically significant bleeding within 6 months prior to randomization
Medications
Prior irinotecan therapy
Systemic chemotherapy, hormonal therapy, or immunotherapy ≤ 21 days prior to
randomization
Experimental or approved proteins/antibodies (eg, bevacizumab) ≤ 30 days prior to randomization
Unresolved toxicities from prior systemic therapy that, in the opinion of the
investigator, does not qualify the patient for randomization
Radiotherapy ≤ 14 days prior to randomization. Patients must have recovered from
all radiotherapy-related toxicities
o If all sites of measurable disease have been irradiated, documented
progression must have occurred in at least 1 site of measurable disease
subsequent to the radiation therapy.
Known active or ongoing infection (except uncomplicated urinary tract
infection [UTI]) within 14 days prior to randomization
Known allergy or hypersensitivity to irinotecan, 5-FU (known dihydropyrimidine
dehydrogenase deficiency) or leucovorin
Currently or previously treated with AMG 386, or other molecules that inhibit the
angiopoietins or Tie2 receptor including but not limited to, XL-820, XL-184, or
CVX-060/PF-4856884
CYP3A4 enzyme inducing anti-convulsant medication (eg phenytoin,
phenobarbital or carbamazepine), rifampin and rifabutin, and St. John’s Wort
≤ 14 days before randomization
Ketoconazole ≤ 7 days before randomization (Itraconazole should be used with
caution)
Current or within 30 days of randomization treatment with immune modulators such
as cyclosporine and tacrolimus
Any investigational agent or therapy ≤ 30 days before randomization
General Medical
Clinically significant cardiovascular disease within 12 months prior to
randomization, including myocardial infarction, unstable angina, grade 2 or greater
peripheral vascular disease, cerebrovascular accident, transient ischemic attack,
congestive heart failure, or arrhythmias not controlled by outpatient medication,
percutaneous transluminal coronary angioplasty/stent
Non-healing wound, ulcer (including gastrointestinal) or fracture
Exclude subjects with a history of prior malignancy, except:
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 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
Major surgery within 28 days before randomization or still recovering from prior
surgery
Minor surgical procedures, placement of central venous access device (excludes
PICC or peripherally inserted central catheter lines), or fine needle aspiration
within 3 days prior to randomization
History of allergic reactions to bacterially produced proteins
Subject known positive test(s) for human immunodeficiency virus (HIV) infection,
hepatitis C virus, acute or chronic active hepatitis B infection
Any condition which in the investigator’s opinion makes the subject unsuitable for
study participation
Any co-morbid disease or condition that could increase the risk of toxicity (eg, known
dihydropyrimidine deficiency, significant ascites or pleural effusion)
Any uncontrolled concurrent illness or history of any medical condition that may
interfere with the interpretation of the study results
Active inflammatory bowel disease or other bowel disease causing chronic diarrhea
(defined as ≥ CTC grade 2 [CTCAE version 3.0])
Concurrent or prior (within 7 days prior to randomization) anticoagulation therapy,
excluding aspirin and anti-platelet agents. The concurrent use of low molecular
weight heparin, heparanoids, or low dose warfarin (ie, ≤ 1 mg daily) for prophylaxis
against thrombosis is acceptable while on study.
Other
Subject not consenting to the use of highly effective contraceptive, eg, double barrier
method (ie, condom plus diaphragm) precautions during the course of the study and
for 6 months after administration of the last study medication
Subject has previously been randomized onto this study
Subject 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 procedures |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS): time from date of randomization to date of disease progression per the modified RECIST criteria or death. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | Yes |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | 27 |
| 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 is when all subjects have completed the treatment period or safety follow-up or long-term follow-up (maximum 30 months from the date the last subject was randomized), whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 48 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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