Marker Evaluation for Avastin Research in colorectal cancer

• Register: EUCTR
• Last refreshed on: 17 May 2016
• Main ID: EUCTR2011-004755-39-PT
• Date of registration: 24/05/2012
• Prospective Registration: Yes
• Primary sponsor: Genentech, Inc.
• Public title: Marker Evaluation for Avastin Research in colorectal cancer
• Scientific title: A randomized phase II study of Bevacizumab/mFOLFOX6 vs. Bevacizumab/FOLFIRI with biomarker stratification in patients with previously untreated metastatic colorectal cancer - MAVERICC
• Date of first enrolment: 03/08/2012
• Target sample size: 360
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004755-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Bevacizumab with mFOLFOX6 as standard of care versus bevacizumab with FOLFIRI as standard of care. Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Estonia, European Union, Ireland, Portugal, Switzerland, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: Genentech Inc. c/o F. Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: Genentech Inc. c/o F. Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
a. Disease-specific inclusion criteria
1. Histologically or cytologically confirmed CRC with at least one
measurable metastatic lesion by RECIST, v1.1. (Baseline tumor assessments must be done within 28 days of randomization)
2. Archival tumor tissue sample (i.e., representative tumor tissue specimens in paraffin block [preferred] or at least 15 unstained slides) must be requested and available prior to study entry. If no archival tumor tissue sample is available, a fresh biopsy tissue sample must be obtained but should be discussed first with the medical monitor. A copy of the local pathology report must be submitted along with the specimens
b. General inclusion criteria
3. Signed informed consent prior to initiation of any study-specific procedure or treatment
4. Age >= 18 years
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see Appendix D)
6. Able to comply with the protocol, including tissue and blood sampling
7. Adequate hematological function:
Absolute neutrophil count >= 1500 per mm3 AND
Platelet count >= 100,000 per mm3 AND
Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)
8. Adequate liver function:
Total bilirubin < 1.5 x upper limit of normal (ULN) AND
Aspartate aminotransferase and alanine aminotransferase < 2.5 x ULN in
patients without liver metastases or < 5 x ULN in patients with liver
metastases
9. Adequate renal function:
Calculated creatinine clearance according to the formula of Cockroft and
Gault >= 50 mL/min AND
Urine for proteinuria should be < 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
10. International normalized ratio <= 1.5 and activated prothrombin time <= 1.5 x ULN within 7 days prior to randomization
11. Patients with treated brain metastases are eligible for study participation. Patients may not receive ongoing treatment with steroids at screening. Anticonvulsants (at stable dose) are allowed. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician. Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization
12. Female patients should not be pregnant or breast-feeding. Female patients with childbearing potential should agree to use effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of at least 6 months following the last administration of study drugs. Female patients with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study
13. Male patients must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 216
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 144

Exclusion criteria:
a. Disease-specific exclusions
1. Any prior systemic treatment for metastatic CRC
2. Adjuvant chemotherapy for CRC completed < 12 months
3. Sensory peripheral neuropathy >= grade 2
4. Evidence of Gilbert’s Syndrome or of homozygosity for the UGT1A1*28 allele.
Patients with Gilbert’s Syndrome may have a greater risk of irinotecan
toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert’s Syndrome would include a prior finding of an isolated elevation of indirect bilirubin. UGT1A1 genotyping is not required on this study
5. Known positivity for human immunodeficiency virus (HIV)
b. General medical exclusions
6. Malignancies other than metastatic CRC within 5 years prior to
randomization, except for adequately treated carcinoma in situ of the
cervix, basal or squamous cell skin cancer, localized prostate cancer
treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
7. Radiotherapy to any site for any reason within 28 days prior to
randomization, except for palliative radiotherapy to bone lesions within
14 days prior to randomization
8. 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
9. Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
c. Bevacizumab-specific exclusions
10. Evidence of any other disease, neurological or metabolic dysfunction,
physical examination finding, or laboratory finding giving reasonable
suspicion of a disease or condition that contraindicates the use of
bevacizumab or puts the patient at high risk for treatment-related
complications
11. Surgery (including open biopsy), significant traumatic injury within
28 days prior to randomization, or anticipation of the need for major
surgery during study treatment
12. Minor surgery, including insertion of an indwelling catheter, within
24 hours prior to the first bevacizumab infusion
13. Current or recent (within 10 days prior to first dose of bevacizumab) use of aspirin (> 325 mg/day) Current or recent (within 10 days prior to first dose of bevacizumab) use of full-dose (i.e., therapeutic dose) of oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes. Prophylactic use of anticoagulants is allowed, e.g., warfarin (1 mg QD) for catheter prophylaxis, and prophylactic low molecular-weight heparin (i.e., enoxaparin [40 mg QD])
14. History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding
15. Inadequately controlled hypertension (blood pressure: systolic > 150 mmHg and/or diastolic > 100 mmHg)
16. Clinically significant (i.e., active) cardiovascular disease (e.g.,
cerebrovascular accident or myocardial infarction within 6 months prior
to randomization), unstable angina, congestive heart failure (New York
Heart Association Class >= II,) or serious cardiac arrhythmia that is
uncontrolled by medication or may interfere with administration of study
treatment
17. Serious non-healing wound, active peptic ulcer, or untreated bone fracture
18. History of abdominal fistula, gastrointestinal (GI) perforation, or
intra-abdominal abscess within 6 months of randomization
19. Known hypersensitivity to bevacizumab or any of its excipients or any other study drug


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Metastatic colorectal cancer
MedDRA version: 14.1 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Avastin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: BEVACIZUMAB
CAS Number: 216974-75-3
Current Sponsor code: RO4876646
Other descriptive name: rhuMAb VEGF, anti-VEGF
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Primary Outcome(s)

Main Objective: To assess whether:
• Expression of chemotherapy resistance marker ERCC-1 is associated with progression-free survival (PFS) in first-line metastatic colorectal cancer (CRC) patients treated with bevacizumab in combination with mFOLFOX6 or FOLFIRI
• Plasma level of vascular endothelial growth factor A (VEGF-A) as a potential biomarker for bevacizumab, and in combination with ERCC-1 expression as a chemotherapy regimen biomarker, is associated with different PFS

Timepoint(s) of evaluation of this end point: The primary analysis of PFS will occur when the required number of events for PFS is reached, i.e. 249 events. This is anticipated to happen approximately 12 months after the last patient is randomized.

Secondary Objective: To assess whether:
• High vs. low plasma VEGF-A is associated with overall survival (OS), objective response (OR), hepatic colorectal metastases resection (including R0 resection), or risk of specific toxicities
• High vs. low ERCC1 expression is associated with OS, OR, hepatic colorectal metastases resection (including R0 resection), or risk of specific toxicities
• Other potential biomarkers are associated with clinical outcomes
• mFOLFOX6 vs. FOLFIRI in combination with bevacizumab is associated with PFS within biomarker subgroups (e.g., ERCC1 [high vs. low] and pVEGF-A [high vs. low])
• Hepatic colorectal metastases resection rates (including R0 rates) differ between the two treatment arms.

Primary end point(s): PFS, defined as the time from randomization to documented disease progression or death on study, whichever occurs first, as determined by the investigator using RECIST, v1.1

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy Outcome Measures:
• OS, defined as the time from randomization to death from any cause
• OR, as assessed by the investigator using RECIST, v1.1 (imaging every 6 weeks)
• Hepatic colorectal metastases resection (see details in protocol)

Secondary Safety Outcome Measures:
• Incidence and nature of adverse events (AEs)
• Incidence and nature of serious AEs (SAEs)
• Incidence and nature of AEs of special interest for bevacizumab (grades according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE, v4.0]): see list in protocol

Timepoint(s) of evaluation of this end point: The analysis will occur when the required number of events for PFS is reached, i.e. 249 events. This is anticipated to happen approximately 12 months after the last patient is randomized.

Secondary ID(s)

2011-004755-39-IE

ML25710

Source(s) of Monetary Support

Genentech Inc. c/o F. Hoffmann-La Roche Ltd