ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer
- Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the DNA of growing cancer cells. It is most often used with other chemotherapy drugs. Researchers want to test it with an experimental drug, ISIS 183750. They want to see if the drugs are a safe and effective treatment for advanced solid tumors or colorectal cancer that has not responded to other treatments.
- To test the safety and effectiveness of ISIS 183750 with irinotecan for advanced solid tumors or colorectal cancer.
- Individuals at least 18 years of age who have solid tumors or colorectal cancer that has not responded to other treatments.
- Participants will be screened with a physical exam and medical history. Blood and urine samples will also be collected. Tumor tissue samples may be collected as well before and after treatment. Imaging studies will also be performed.
- Participants will take ISIS 183750 once a week for 28-day cycles of treatment. On the first cycle, they will also have ISIS 183750 on days 3 and 5.
- Participants will take irinotecan every second week, beginning on day 15 of the first cycle.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Treatment will continue as long as the cancer does not grow and the side effects are not severe.
Drug: ISIS 183750
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer|
- Maximum tolerated dose [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
- Change of eIF4e and protein (HC) in pre- and post- tumor biopies [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Evaluate the effect of eIF4E on relevant regulated proteins and immune cells [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Evaluate Response Rate, PFS, and OS [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Pharmacokinetic parameters [ Time Frame: 2 years ] [ Designated as safety issue: No ]
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Phase I
ISIS 183750 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22.
Drug: ISIS 183750
Experimental: Phase II
ISIS 183750 will be administered as an intravenousinfusion every week without break, i.e. Days 1, 8, 15and 22 of a 28-day cycle. Patients will be re-stagedevery 8 weeks.
Drug: ISIS 183750
The eukaryotic translation initiation factor - eIF4E - is a potent oncogene that is found to be dysregulated in approximately 30% of human cancers. Upregulation of eIF4E is an early event in colorectal cancer (CRC) and correlates with CRC progression. ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the human eukaryotic translation initiation factor 4E (eIF4E) protein.
To establish Maximum Tolerated Dose (MTD) and establish safety for the combination of ISIS 183750 and irinotecan in advanced solid tumors.
- To evaluate Response Rate, PFS, OS for the combination of ISIS 183750 and irinotecan in advanced irinotecan-refractory colorectal cancer.
- To perform correlative studies to evaluate the effect of eIF4E inhibition on relevant regulated proteins and immune cells.
- To characterize the plasma pharmacokinetic (PK) parameters for ISIS 183750 in the absence and presence of irinotecan
- To characterize the plasma PK parameters for irinotecan in the presence of ISIS 183750
-Adult patients with irinotecan-resistant colorectal cancer.
- This is a single-arm phase I/II study whereby all patients will receive the combination of ISIS 183750 and irinotecan. All cycles are 28 days.
- Cycle 1 only: ISIS 183750 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22.
- Cycle 2 and beyond: ISIS 183750 will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.
- Irinotecan will be administered at a dose of 160mg/m2 as an intravenous infusion every second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be to establish MTD for the combination of ISIS 183750 and irinotecan in advanced solid tumors. The phase II portion of the study will be confined to irinotecan-refractory colorectoal cancer. Irinotecan-refractory will be defined as patients who have radiological evidence of disease progression whilst receiving irinotecan or within 3 months after completing it.
- Correlative studies will comprise: Mandatory pre- and post- dose biopsies for eIF4e mRNA and protein (IHC) analysis will be performed in the phase II portion of the study; Immune subsets; PET responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of irinotecan and ISIS183750 in 10-12 patients.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01675128
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Tim F Greten, M.D.||National Cancer Institute (NCI)|