Brief Summary
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.
Brief Title
Study of REOLYSIN® in Combination With FOLFIRI and Bevacizumab in FOLFIRI Naive Patients With KRAS Mutant Metastatic Colorectal Cancer
Detailed Description
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
KRAS Mutant Metastatic Colorectal Cancer
Eligibility Criteria
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 an oxaliplatin-based chemotherapy regimen in the metastatic setting or relapsed within 6 months of completion of adjuvant therapy containing oxaliplatin.
* 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 been resolved.
* Be at least 18 years of age.
* 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 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 \>20 Gy of radiation to the pelvis.
* Have received chemotherapy, immunotherapy, hormonal therapy or had major surgery within 28 days; or received radiotherapy within 14 days; or minor surgery within 7 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.
* 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 an oxaliplatin-based chemotherapy regimen in the metastatic setting or relapsed within 6 months of completion of adjuvant therapy containing oxaliplatin.
* 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 been resolved.
* Be at least 18 years of age.
* 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 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 \>20 Gy of radiation to the pelvis.
* Have received chemotherapy, immunotherapy, hormonal therapy or had major surgery within 28 days; or received radiotherapy within 14 days; or minor surgery within 7 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.
Inclusion Criteria
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 an oxaliplatin-based chemotherapy regimen in the metastatic setting or relapsed within 6 months of completion of adjuvant therapy containing oxaliplatin.
* 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 been resolved.
* Be at least 18 years of age.
* 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 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
* 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 an oxaliplatin-based chemotherapy regimen in the metastatic setting or relapsed within 6 months of completion of adjuvant therapy containing oxaliplatin.
* 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 been resolved.
* Be at least 18 years of age.
* 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 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
Gender
All
Gender Based
false
Keywords
Colorectal
Cancer
REOLYSIN®
Chemotherapy
FOLFIRI
Reovirus
Oncolytic virus
Fluorouracil
Irinotecan
Leucovorin
Bevacizumab
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01274624
Org Class
Industry
Org Full Name
Oncolytics Biotech
Org Study Id
REO 022
Overall Status
Completed
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Multicenter Phase 1 Study of Intravenous Administration of REOLYSIN® (Reovirus Type 3 Dearing) in Combination With Irinotecan/Fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in FOLFIRI Naive Patients With KRAS Mutant Metastatic Colorectal Cancer
Primary Outcomes
Outcome Measure
Dose limiting toxicity to define maximum tolerated dose and recommended Phase 2 dose
Outcome Time Frame
During the first cycle of treatment (4 week cycle)
Outcome Measure
Pharmacokinetic parameters for irinotecan and 5-FU when combined with REOLYSIN®
Outcome Time Frame
During the first cycle of treatment (4 week cycle)
Secondary Outcomes
Outcome Time Frame
Assessed every 8 weeks until disease progression or death
Outcome Measure
CEA and Objective Response, Clinical Benefit Rate (PR, CR, SD), progression-free survival, and overall survival (PFS and OS)
Outcome Time Frame
During study and within 30 days of the last dose of REOLYSIN
Outcome Measure
Safety and tolerability of REOLYSIN® when administered in combination with FOLFIRI and bevacizumab
Outcome Time Frame
During and within 30 days of the last dose of REOLYSIN®
Outcome Measure
Correlative studies including determination of specific genetic mutations and aberrant signalling pathways from tumor tissue to identify novel biomarkers of response and efficacy
Outcome Time Frame
During study and within 30 days of the last dose of REOLYSIN®
Outcome Measure
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
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sanjay Goel
Investigator Email
sgoel@montefiore.org
Investigator Phone
718-405-8404
Categories Mesh Debug
Cancer --- NEOPLASMS
MeSH Terms
NEOPLASMS
REOLYSIN
IRINOTECAN
LEUCOVORIN
FLUOROURACIL
BEVACIZUMAB
CAMPTOTHECIN
ALKALOIDS
HETEROCYCLIC COMPOUNDS
FORMYLTETRAHYDROFOLATES
TETRAHYDROFOLATES
FOLIC ACID
PTERINS
PTERIDINES
HETEROCYCLIC COMPOUNDS, 2-RING
HETEROCYCLIC COMPOUNDS, FUSED-RING
COENZYMES
ENZYMES AND COENZYMES
URACIL
PYRIMIDINONES
PYRIMIDINES
HETEROCYCLIC COMPOUNDS, 1-RING
ANTIBODIES, MONOCLONAL, HUMANIZED
ANTIBODIES, MONOCLONAL
ANTIBODIES
IMMUNOGLOBULINS
IMMUNOPROTEINS
BLOOD PROTEINS
PROTEINS
AMINO ACIDS, PEPTIDES, AND PROTEINS
SERUM GLOBULINS
GLOBULINS