E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with cancer of the colon or rectum where the tumor has already spread to other organs(s), |
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E.1.1.1 | Medical condition in easily understood language |
Patients with cancer of the colon or rectum where the tumor has already spread to other organs(s), |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055097 |
E.1.2 | Term | Rectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055114 |
E.1.2 | Term | Colon cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 of Study BP29262 is to estimate the efficacy of RO5520985 in combination with oxaliplatin, folinic acid, and 5 fluorouracil (mFOLFOX-6) vs. bevacizumab in combination with mFOLFOX-6, as measured by progression-free survival (PFS). |
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E.2.2 | Secondary objectives of the trial |
•Evaluate the safety and tolerability of RO5520985 in combination with mFOLFOX-6
•Estimate the efficacy of RO5520985 in combination with mFOLFOX-6, as measured by overall survival, objective response rate, and duration of objective response
•Characterize the pharmacokinetics of RO5520985 when combined with mFOLFOX-6
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Histologically or cytologically confirmed mCRC not amenable to potentially curative resection with at least one measurable metastatic lesion, as defined by RECIST v1.1
a)Results of local RAS mutational analysis must be available for stratified randomization
b)Representative tumor specimens in FFPE blocks (preferred) or slides must be available for central extended RAS mutational analysis testing
2.Signed written informed consent, obtained prior to any screening procedure
3.Age> 18 years
4.ECOG (WHO) performance status of 0 or 1
5.Adequate hematologic, liver, renal, coagulation and cardiovascular function
6.Recovery from all reversible adverse events of previous medical therapies to baseline or NCI CTCAE Grade 1, except for alopecia (any grade)
7.Negative serum pregnancy test within 7 days prior to starting study treatment in premenopausal women and women < 2 years after the onset of menopause
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E.4 | Principal exclusion criteria |
1.Any prior systemic therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, immunotherapy, hormonal therapy) before Day 1 of Cycle 1 for treatment of mCRC
Patients who received prior systemic adjuvant therapy or radiotherapy for CRC are not excluded if the time interval from last administration of adjuvant therapy until disease progression is > 12 months
2.Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to Day 1 of Cycle 1, except palliative radiotherapy to bone lesions within 7 days prior to Day 1 of Cycle 1
3.Symptomatic CNS metastases or carcinomatous meningitis:
4.Significant cardiovascular or cerebrovascular disease within 6 months prior to Day 1 of Cycle 1
5.Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
6.Current use of anticoagulants (e.g., warfarin or any other coumadin-derivate coagulants) at therapeutic doses within 7 days prior to study drug administration. Prophylactic use of unfractioned heparin or low molecular weight heparin (LMWH) is permitted (e.g., enoxaparin 40 mg QD)
7.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 or nonrecovery from side effects of any such procedure
8.History of abdominal or tracheo-oesophageal fistula or GI perforation or intra abdominal abscess within 6 months prior to Day 1
9.Clinical signs or symptoms of GI obstruction or a requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
10.Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
11.History of bronchopulmonary hemorrhage NCI CTCAE > Grade 2 within 4 weeks prior to Day 1 of Cycle 1
12.Severe, nonhealing or dehiscing wound, active ulcer, or untreated bone fracture
13.Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the patient for 5 FU toxicity
14. History of intra-abdominal inflammatory process within 6 months prior to Day 1 of Cycle 1, including but not limited to peptic ulcer disease, diverticulitis,or colitis.
15. Colonic prosthesis (stent) implant in place.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for Study BP29262 is progression-free survival (PFS), defined as the time from randomization to the date of first documented occurrence of progression based on RECIST v1.1 criteria as determined by the Investigator or death from any cause on study, whichever occurs first. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
endpoint Tumor assessments will be performed every 8 (+/-1) weeks acc. RECIST 1.1. |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy End Points •Objective response rate (ORR). Objective response rate is defined as the rate of patients with an objective tumor response, i.e. partial response (PR) or complete response (CR) as determined by the Investigator using RECIST v1.1 criteria on two consecutive occasions at least 4 weeks apart
•Duration of response, defined as the first occurrence of a documented objective response until the time of progression or death from any cause on study
•Overall Survival, defined as the time from randomization until death from any cause
Secondary Safety End Points
•Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03
•Changes in hematology, biochemistry, coagulation, specifically those associated with vascular and renal function
•Physical examinations (including ECOG), vital signs and ECG
•Incidence and titers of human anti-human antibodies (HAHAs)
•Adverse events leading to RO5520985, bevacizumab, or chemotherapy discontinuation
•Incidence of the following selected adverse events according to NCI CTCAE, v4.03:
Arterial hypertension (Grade 3)
Proteinuria (Grade 3)
Arterial thromboembolic events (any grade)
Venous thromboembolic events (Grade 3)
Vascular disorder - other: Thrombotic microangiopathy (any grade)
Gastrointestinal perforation (any grade)
Fistula involving an internal organ (any grade)
Fistulae (Grade 4)
Wound dehiscence/complication (Grade 3)
Bleeding/hemorrhage (Grade 3)
Pulmonary bleeding (Grade 2)
CNS bleeding (Grade 2)
Congestive heart failure (Grade 3)
Reversible posterior leukoencephalopathy syndrome (any grade)
Secondary PK End Points :
•The PK profile of RO5520985 will be characterized with the plasma concentration time data following IV administration of RO5520985, and will include the following parameters: Cmax, Cmin, Tmax, t1/2, AUC, AUC, CL, Vss, accumulation ratio (RA)
•The PK profiles of oxaliplatin (free and total) and 5-FU will be characterized with the plasma concentration-time data following IV administration of FOLFOX, and will include the following parameters: Cmax, Cmin, Tmax, t1/2, AUC (when applicable)
•Additional PK parameters may be evaluated as appropriate
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please see Schedule of assessment for the different timepoints of safety, PK and efficacy measurements. |
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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 | 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 | 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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Austria |
Belgium |
Canada |
France |
Italy |
Spain |
United Kingdom |
United States |
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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 study will formally end once the survival follow-up is complete or the last patient has completed the EoS Visit or is withdrawn from the study prior to that time (whichever occurs last), but may be prematurely terminated by the Sponsor. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |