A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors
Study Overview
Brief Summary
Background:
- Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the deoxyribonucleic acid (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.
Objectives:
- To test the safety and effectiveness of ISIS 183750 with irinotecan for advanced solid tumors or colorectal cancer.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or colorectal cancer that has not responded to other treatments.
Design:
- 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.
Detailed Description
Background:
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.
Objectives:
Primary:
To establish Maximum Tolerated Dose (MTD) and establish safety for the combination of ISIS 183750 and irinotecan in advanced solid tumors.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Phase I Dose Level I
Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.
Intervention: ISIS 183750 (Drug)
Phase I Dose Level I
Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.
Intervention: Irinotecan (Drug)
Phase I Dose Level II
Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.
Intervention: ISIS 183750 (Drug)
Phase I Dose Level II
Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.
Intervention: Irinotecan (Drug)
Phase II Dose Level I
Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week 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.
Intervention: ISIS 183750 (Drug)
Phase II Dose Level I
Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week 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.
Intervention: Irinotecan (Drug)
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors
Time Frame: 2 years
MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of \</=6) patients have DLT as a result of the drug.
Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors
Time Frame: 2 years
MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of \</=6) patients have DLT as a result of the drug.
Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies
Time Frame: 2 weeks
A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).
Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies
Time Frame: 2 weeks
A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.
Secondary Outcomes
- Number of Participants With Progression Free Survival(≤ 6 months)
- Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue(2 weeks)
- Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood(2 weeks)
- Number of Participants With Adverse Events(21 months)
- Objective Response(up to 2 cycles)
- Overall Survival(≥ 12 months)
- Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins(2 weeks)
- AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)(up to 24 hours post end of infusion)
Investigators
Tim Greten, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)