Description:
This is a Phase 1 dose-escalation study with three dose levels to determine the maximum tolerated dose of REOLYSIN® combined with FOLFIRI and bevacizumab.
This is a Phase 1 dose-escalation study with three dose levels to determine the maximum tolerated dose of REOLYSIN® combined with FOLFIRI and bevacizumab.
Completed
Phase 1
NCT ID: NCT01274624
ORG ID: REO 022
KRAS Mutant Metastatic Colorectal Cancer
Drug | Synonyms | Arms |
---|---|---|
Irinotecan | ||
Leucovorin | ||
Fluorouracil (5-FU) | ||
Bevacizumab |
This is a Phase 1 dose-escalation study with three dose levels to determine the maximum
tolerated dose of REOLYSIN combined with FOLFIRI and bevacizumab.
Reovirus Serotype 3 - Dearing Strain (REOLYSIN) is a naturally occurring, ubiquitous,
non-enveloped human reovirus. Reovirus has been shown to replicate selectively in
Ras-transformed cells causing cell lysis. Activating mutations in ras or mutation in
oncogenes signaling through the ras pathway may occur in as many as 80% of human tumors. The
specificity of the reovirus for Ras-transformed cells, coupled with its relatively
nonpathogenic nature in humans, makes it an attractive anti-cancer therapy candidate.
Eligible patients for this study include those with histologically confirmed cancer of the
colon or rectum with Kras mutation and measurable disease.
Cetuximab and panitumumab have shown to be ineffective in patients whose tumors have a KRAS
mutation. Therefore, currently, for patients with a KRAS mutation, the only option after
failure of front-line therapy is irinotecan or FOLFIRI. Over the past year, two randomized
phase III trials have demonstrated that OS and PFS for these patients increase when
bevacizumab is combined with the standard FOLFIRI therapy.
The trial is a Phase I dose escalation study with four dose levels, comprising cohorts of
three to six patients, to determine a maximum tolerated dose and dose-limiting toxicities
with the combination of REOLYSIN, bevacizumab, and FOLFIRI. FOLFIRI and bevacizumab will be
administered on the first day of a two week (14-day) cycle, while REOLYSIN will be
administered on days one through five of a four week (28-day) cycle.
The study is expected to enroll 20 to 32 patients.
Name | Type | Description | Interventions |
---|
Inclusion Criteria: Each patient MUST:
- Have histologically confirmed cancer of the colon or rectum with radiologically
documented and measurable metastases (high CEA alone is insufficient for study
entry).
- Have received 3 or fewer regimens in the metastatic setting.
- Not have received prior FOLFIRI or irinotecan in the metastatic setting.
- Have his/her tumor assessed for KRAS status and found to be mutation positive.
- Have NO continuing acute toxic effects (except alopecia) of any prior radiotherapy,
chemotherapy, or surgical procedures, i.e., all such effects must have resolved.
- Have an ECOG Performance Score of 2.
- Have a life expectancy of at least 3 months.
- Have baseline laboratory results as follows:
- Absolute neutrophil count (ANC) 1.5 x 10^9 [SI unit 10^9/L]
- Platelets 100 x10^9 [SI units 10^9/L] (without platelet transfusion)
- Hemoglobin 9.0 g/dL [SI units gm/L] (with or without RBC transfusion)
- Serum creatinine 1.5 x upper limit of normal (ULN)
- Bilirubin ULN
- AST/ALT 2.5 x ULN ( 5 x ULN if with liver metastases)
- Negative pregnancy test for females with childbearing potential.
- Proteinuria < grade 2.
- Have signed an informed consent indicating that the patient is aware of the
neoplastic nature of their disease and have been informed of the procedures of the
protocol, the experimental nature of the therapy, alternatives, potential benefits,
side effects, risks, and discomforts.
- Be willing and able to comply with scheduled visits, the treatment plan, and
laboratory tests.
- Be medically eligible to receive bevacizumab
Exclusion Criteria: No patient may:
- Receive concurrent therapy with any other investigational anticancer agent while on
study.
- Have previously received irinotecan or FOLFIRI in the metastatic setting (patient is
eligible if he/she had received irinotecan or FOLFIRI as adjuvant therapy more than 6
months before entry into the study)
- Have brain metastases.
- Be on immunosuppressive therapy or have known HIV infection or active hepatitis B or
C.
- Have received chemotherapy, radiotherapy, immunotherapy or hormonal therapy or had
surgery (except biopsies) within 28 days prior to receiving the study drug.
- Be a pregnant or breast-feeding woman. Female patients of childbearing potential
must agree to use effective contraception, be surgically sterile, or be
postmenopausal. Male patients must agree to use effective contraception or be
surgically sterile. Barrier methods are a recommended form of contraception.
- Have clinically significant cardiac disease (New York Heart Association, Class III or
IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial
infarction within 1 year prior to study entry, or Grade 2 or higher compromised left
ventricular ejection fraction.
- Have dementia or altered mental status that would prohibit informed consent.
- Have any other acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results and, in
the judgment of the Principal Investigator, would make the patient inappropriate for
this study.
- Have uncontrolled hypertension, proteinuria, or recent major surgery (all clinical
parameters related to bevacizumab use). Any other clinical parameter considered
important should be discussed with the medical monitor.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
Dose limiting toxicity to define maximum tolerated dose and recommended Phase 2 dose
Pharmacokinetic parameters for irinotecan and 5-FU when combined with REOLYSIN
CEA and Objective Response, Clinical Benefit Rate (PR, CR, SD), progression-free survival, and overall survival (PFS and OS)
Safety and tolerability of REOLYSIN when administered in combination with FOLFIRI and bevacizumab
Correlative studies including determination of specific genetic mutations and aberrant signalling pathways from tumor tissue to identify novel biomarkers of response and efficacy
In vitro studies in human-derived colorectal cancer cells including the isogenic cell lines, to study the mechanism and scientific basis of synergy between irinotecan and reovirus
Colorectal
Cancer
REOLYSIN
Chemotherapy
FOLFIRI
Reovirus
Oncolytic virus
Fluorouracil
Irinotecan
Leucovorin
Bevacizumab