| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC COLORECTAL CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
Colorectal cancer that has spread to other parts of the body for those patients that have not received chemotherapy before
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 efficacy of MEGF0444A used in combination with FOLFOX + bevacizumab therapy in patients with previously untreated mCRC, as measured by progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of MEGF0444A in combination with FOLFOX + bevacizumab therapy in patients with previously untreated mCRC
• To estimate the efficacy of MEGF0444A in combination with FOLFOX + bevacizumab therapy in patients with previously untreated metastatic CRC, as measured by overall survival (OS), objective response
rate (ORR), and duration of objective response and OS
• To characterize the PK of MEGF0444A and FOLFOX when combined with bevacizumab |
|
| 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 |
DNA REPOSITORY SUBSTUDY IN ASSOCIATION
WITH MEGF0444A STUDY MEF4982g
Protocol number: MEF4982g (DNA Substudy)
Protocol version: Final
Protocol date: 20 June 2011
The primary objective of this study is to perform exploratory analyses to generate hypotheses identifying genes associated with treatment response, toxicity, or disease risk. If such genetic hypotheses are identified, they may be tested in future clinical studies within this therapeutic area. |
|
| E.3 | Principal inclusion criteria |
a. Disease-Specific Inclusion Criteria
• Histologically or cytologically confirmed CRC not amenable to potentially curative resection with at least one measurable metastatic lesion, as defined by RECIST v1.1 (see Appendix C)
Representative tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides with an associated pathology report must be confirmed to be available (located at the site or sent to the site from a referring institution) at any time prior to study entry
b. General Inclusion Criteria
• Signed informed consent form
• Age ≥ 18 years
• ECOG performance status of 0 or 1 (see Appendix E)
• Able to comply with the protocol
• Adequate hematologic and end organ function, defined by the following
laboratory results obtained within 14 days prior to the first study treatment:
Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to randomization)
Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to randomization)
Hemoglobin ≥ 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this criterion.
AST and ALT ≤ 3 × ULN, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:
Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN
Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN
Serum bilirubin ≤ 1.5× ULN
Patients with known Gilbert disease who have serum bilirubin level ≤ 3× ULN may be enrolled
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN within 7 days prior to randomization
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of the Cockroft−Gault glomerular filtration rate estimation:
(140 − age) × (weight in kg) × (0.85 if female) / 72 × (serum creatinine in mg/dL)
Urine dipstick for proteinuria < 2+.
Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours.
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for 6 months after the last dose of bevacizumab or MEGF0444A/placebo
• Negative serum pregnancy test within 7 days prior to starting study treatment in premenopausal women and women < 2 years after the onset of menopause
• Willingness and capability to be accessible for study follow-up |
|
| E.4 | Principal exclusion criteria |
a. Disease-Specific Exclusions
• Any prior systemic therapy (including chemotherapy, antibody therapy, tyrosine
kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy or
investigational therapy) before Day 1 of Cycle 1 for treatment of mCRC
Patients who received prior adjuvant systemic therapy or radiotherapy for
CRC are not excluded if the time interval from last administration of adjuvant therapy until disease progression is > 12 months.
Patients who receive hormone-replacement therapy or oral contraceptives are not excluded
Patients who received herbal therapy intended as anti-cancer therapy ≥ 2 weeks prior to Day 1 are not excluded
b. General Medical Exclusions
•Malignancies other than CRC within 5 years prior to randomization, except for those with a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent
•Radiotherapy to any site for any reason within 28 days prior to Day 1 of Cycle 1
Palliative radiotherapy to bone lesions > 7 days prior to Day 1 of Cycle 1 is allowed
•Clinically detectable (by physical exam) third-space fluid collections (e.g., ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry
•Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to Day 1 of Cycle 1
•Lactating women
•Known hypersensitivity to Chinese hamster ovary cell products, recombinant human antibodies or any of the chemotherapy agents to be used in this study
•Any disorder that compromises the ability of the patient to provide written informed consent and/or to comply with study procedures
•Clinically suspected or confirmed CNS metastases or carcinomatous meningitis
•Active infection requiring IV antibiotics
•Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs, inhaled corticosteroids, or the equivalent of ≤ 10 mg/day prednisone
•Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, or cirrhosis
•Sensory peripheral neuropathy ≥ Grade 2
c. Bevacizumab-Specific Exclusions
•Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of bevacizumab or an investigational drug or that may affect the interpretation of the results or render the patient at high risk for treatment complications
•Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
Anti-hypertensive therapy to achieve these parameters is allowable.
•Prior history of hypertensive crisis or hypertensive encephalopathy
•NYHA Class II or greater CHF (see Appendix F)
•History of myocardial infarction or unstable angina within 6 months prior to Day 1
•History of stroke or transient ischemic attack (TIA) within 6 months prior to Day 1
•Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
•Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
•Current or recent (within 10 days of first dose of study treatment) use of aspirin (> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel and cilostazol
•Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an international normalized ratio (INR) < 1.5 ULN and activated partial thromboplastin time (aPTT) is within normal limits within 1 week of Day 1
Prophylactic use of low molecular-weight heparin (i.e., enoxaprin [40 mg QD]) is allowed
•Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study
•Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
•History of abdominal or tracheo-oesophageal fistula or GI perforation within 6 months prior to Day 1
•Clinical signs or symptoms of GI obstruction or that requires routine parenteral hydration, parenteral nutrition or tube feeding
•Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
•Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
d. 5-FU-Specific Exclusion
• Please refer to protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is progression-free survival (PFS) defined as the time from randomization to the first occurrence of documented disease progression or death from any cause on study, whichever occurs earlier, determined by the investigator. Death on study is defined as death from any cause within 30 days of the last study treatment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Data for patients without disease progression or death on study will be censored at the time of the last tumor assessment (or, if no tumor assessments were performed after the baseline visit, at the time of randomization plus 1 day). |
|
| E.5.2 | Secondary end point(s) |
| Objective Response, Duration of Objective Response and Overall Survival. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective Response - Objective response is defined as a complete or partial response by RECIST v1.1 determined on two consecutive occasions ≥ 4 weeks apart.
Duration of Objective Response. For patients with an objective response, duration of objective response is defined as the time from the initial response to disease progression or death from any cause on study.
Overall Survival - For patients who have not died, overall survival will be censored at the date of last contact. Analysis methods are the same as those described for PFS |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | No |
| 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 |
| Australia |
| Belgium |
| Poland |
| Spain |
| United States |
|
| 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
|
| Last visit of the last subject undergoing the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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