A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer
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 assess the change of eIF4e mRNA and protein (IHC) in pre- and post-dose tumor biopsies.
- 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.
- Phase II participants must have disease that is amenable to biopsy and be willing to
undergo tumor biopsy.
- 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 180mg/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
cancer. Irinotecan-refractory will be defined as patients who have radiological
evidence of disease progression whilst receiving irinotecan or within 3 months after
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose
Tim F Greten, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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