The primary objective of this study is to compare overall survival (OS) in patients with metastatic colorectal carcinoma (CRC) when treated with FOLFIRI in combination with placebo versus FOLFIRI in combination with ramucirumab DP.Secondary…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy: Efficacy assessments include imaging studies/tumor assessments,
according to RECIST v. 1.1, performed every 6 weeks (±3 days); PRO assessments;
serum carcinoembryonic antigen; and survival.
Safety: Safety will be evaluated based on recorded adverse events (AEs),
physical examinations, vital sign measurements, and clinical laboratory
assessments. Adverse events will be coded using the Medical Dictionary for
Regulatory Activities (MedDRA*). Adverse events and clinical laboratory values
will be graded using the National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 4.02 (NCI CTCAE v. 4.02).
Secondary outcome
Immunogenicity: Serum samples will be analyzed for antibodies to ramucirumab
at baseline, on study, and following the last ramucirumab infusion.
Pharmacokinetics: Pharmacokinetic parameters may be analyzed, including, but
not limited to, calculation of mean serum peak and trough concentrations (Cmax
and Cmin, respectively).
Translational Research: Blood samples will be analyzed for potential
pharmacodynamic markers, including, but not limited to, placental growth
factor, vascular endothelial growth factor A (VEGF-A), VEGF-C, VEGF-D, soluble
vascular endothelial growth factor receptor 1 (VEGFR-1), and soluble VEGFR-2.
In addition, whole blood samples will be used for DNA/genotype analysis and
will include an examination of, but will not be limited to, VEGFR-2, CXC
chemokine receptor 2, intercellular adhesion molecule 1, and VEGF-A.
Historical tumor tissue samples will be collected from all patients for an
evaluation of tumor-specific mutations and other biomarkers of interest.
Progression-free survival is defined as the time from the date of randomization
until the date of objectively determined progressive disease (according to
RECIST v. 1.1) or death due to any cause, whichever is first.
The ORR in each treatment group will be compared using the
Cochran-Mantel-Haenszel test adjusting for the stratification variables. Exact
confidence bounds (confidence interval: 95%) will be determined. The objective
response rate (for patients with measurable disease per RECIST v. 1.1) is
defined as the proportion of patients with a best overall response of partial
response or complete response.
The EORTC QLQ-C30 and EQ-5D will be analyzed using descriptive statistics.
Safety analyses will be performed on all randomized patients who received any
quantity of study treatment. Safety evaluation will be performed based on the
actual study treatment a patient has received. Adverse events that are
considered unrelated to treatment by the investigator and that occur more than
30 days after the decision is made to discontinue study treatment will not be
reported or analyzed. Safety analyses will include summaries of the incidence
of AEs by maximum CTCAE grade (Version 4.02) that occur during the study
treatment period or within 30 days (± 3 days) after the decision is made to
discontinue study treatment. Additionally, the following safety-related
outcomes will be summarized:
* study treatment discontinuations due to AEs
* deaths during the study treatment period or within 30 days after the decision
is made to discontinue study treatment
* serious adverse events during the study treatment period or within 30 days
after the decision is made to discontinue study treatment
* hospitalizations and transfusions during the study treatment period or within
30 days after the decision is made to discontinue study treatment
Pharmacokinetics/Pharmacodynamics/Immunogenicity: Serum and/or plasma
concentrations of ramucirumab and pharmacodynamic biomarkers, polymorphisms of
genes involved in angiogenesis, and incidence of anti-ramucirumab antibodies
will be tabulated.
Translational Research: Translational research will be performed to analyze
relevant biomarkers and to correlate them to clinical outcome.
Background summary
Inhibition of angiogenesis is considered a promising approach to the treatment
of cancer. Vascular endothelial growth factor (VEGF) family members are
important regulators of angiogenesis and VEGF-A (also known as VEGF) has been
shown to be an important therapeutic target in advanced colorectal carcinoma
(CRC). VEGF is overexpressed in CRC tissue and may be the single most
important tumor angiogenic factor.
Disabling the function of the vascular endothelial growth factor receptor-2
(VEGFR-2) signaling pathway via a number of approaches, including anti-VEGF
antibodies, anti-VEGFR-2 antibodies, and small molecule tyrosine kinase
inhibitors, has been shown to inhibit new blood vessel formation and tumor
growth in a variety of animal models. Therapeutic agents that interfere with
the function of VEGF and its receptors may represent efficacious approaches to
antiangiogenic and antitumor therapy.
Ramucirumab (IMC-1121B, LY3009806) is a recombinant human monoclonal antibody
(mAb) that specifically binds to the extracellular domain of VEGFR-2 with high
affinity. Phase 1 studies and initial Phase 2 studies investigating
ramucirumab drug product (DP) have provided information regarding safety and
tolerability at clinically relevant doses, with preliminary evidence of
clinical efficacy in a variety of human cancers.
Bevacizumab, a recombinant humanized mAb that selectively inhibits VEGF-A, has
demonstrated efficacy in the treatment of metastatic CRC. This approved agent
provides proof of concept for the use of ramucirumab DP in metastatic CRC,
owing to a similar mechanism of action. Yet, since ramucirumab DP blocks the
binding of several VEGF ligands (VEGF-A, VEGF-C, and possibly VEGF-D) to VEGFR
2, its use may be efficacious among patients who have previously had disease
progression on a first-line regimen containing bevacizumab.
Recent evidence suggests that patients whose tumors have an activating mutation
in KRAS have a poor response to mAbs targeting the epidermal growth factor
receptor. Therefore, treatment options for such patients are limited.
Importantly, recent data suggest that the clinical benefit of bevacizumab in
metastatic CRC is independent of KRAS mutation status, suggesting that both
patients with an activating mutation in KRAS as well as those who are KRAS
wild-type may derive benefit from ramucirumab DP.
Study objective
The primary objective of this study is to compare overall survival (OS) in
patients with metastatic colorectal carcinoma (CRC) when treated with FOLFIRI
in combination with placebo versus FOLFIRI in combination with ramucirumab DP.
Secondary objectives are to compare FOLFIRI plus placebo treatment with FOLFIRI
plus ramucirumab DP treatment for:
* progression-free survival (PFS)
* objective response rate (ORR)
* patient-reported outcome (PRO) measures (using European Organisation for
Research and Treatment of Cancer [EORTC] QLQ-C30 and EuroQol EQ 5D)
* safety profile
* assessment of the association between biomarkers and clinical outcome
In addition, secondary objectives include:
* assessment of anti-ramucirumab antibodies (immunogenicity)
* assessment of serum levels of ramucirumab
Study design
This is a randomized, double-blind, placebo-controlled Phase 3 trial in which
patients with metastatic CRC who have had disease progression during or
following first-line combination therapy with bevacizumab, oxaliplatin, and a
fluoropyrimidine will be randomized to receive either FOLFIRI plus placebo or
FOLFIRI plus ramucirumab DP. Approximately 1050 patients (525 patients per
treatment arm) will be randomized to observe 756 OS events.
Patients will be randomized in a 1:1 ratio to 1 of 2 treatment arms as
follows: FOLFIRI plus placebo every 14 days or FOLFIRI plus ramucirumab DP
every 14 days. Randomization will be stratified by geographic region (North
America versus Europe versus all other regions), KRAS status (mutant versus
wild-type), and time to disease progression after beginning first-line
treatment (< 6 months versus > 6 months).
Treatment will continue until disease progression, the development of
unacceptable toxicity, noncompliance or withdrawal of consent by the patient,
or investigator decision. Radiological evaluation of disease response will be
conducted approximately every 6 weeks (±3 days) from first dose of study
treatment until disease progression. Following discontinuation of study
treatment, all patients will be followed for survival at regularly scheduled
intervals (approximately every 3 months) until death or until the required
number of OS events has been observed.
Intervention
-Blood and urine samples will be collected for specified standard laboratory
tests
-Four blood samples will be collected so that the sponsor can measure the
proteins (antibodies) generated by the body*s immune system in response to
treatment with ramucirumab.
-A blood sample for plasma will be collected 4 times during the study.
-The sponsor would also like to collect an additional eight blood samples to
measure the amount of study drug that is in the body and how the body breaks it
down (This is an optional part of the study, which the patient may decline)
-Collection of a colorectal cancer tissue sample is a mandatory part of this
study
-chest CT and a CT or MRI of the abdomen and pelvis will be performed
- an ECG will performed
Study burden and risks
Very Common Side Effects (At least 10% of patients)
* Nausea.
* Diarrhea.
* Loss of appetite
* Fatigue.
* Headache.
* High blood pressure. Life-threatening high blood pressure has been reported.
* Abnormal bleeding
Furthermore patients might experience discomforts during the study procedures:
blood sampling, providing urine, Echocardiogram, Magnetic Resonance
Imaging(MRI), CT scan, contrasts for CT scans. Please refer to Appendix 2 of
the Patient Information Sheet for more information regarding the possible
discomforts of these procedures
Lilly Corporate Center
Indianapolis, Indiana 46285
US
Lilly Corporate Center
Indianapolis, Indiana 46285
US
Listed location countries
Age
Inclusion criteria
Patients will be at least 18 years of age with metastatic CRC progressive during or following first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients may have either measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v. 1.1), and must have Eastern Cooperative Oncology Group status of 0 or 1as well as adequate hematologic, coagulation, and organ function.
Exclusion criteria
Patients must have received no more than 2 prior systemic chemotherapy regimens in any setting and must not have experienced a Grade 3 or higher bleeding event within 3 months prior to randomization, or an arterial thrombotic event within 12 months of randomization. Patients must also not have an uncontrolled intercurrent illness, leptomeningeal disease or brain metastases, or active infection requiring parenteral therapy. Lastly, patients must not have received bevacizumab within 28 days of randomization.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-021037-32-NL |
| ClinicalTrials.gov | NCT01183780 |
| CCMO | NL34026.096.10 |