Clinical trial NCT01675128
Conditions: Colorectal Neoplasms Colorectal Carcinoma Colorectal Tumors
Keywords: Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein Refractory Oncogene Maximum Tolerated Dose Safety
Sponsor: National Cancer Institute (NCI)
Start date: 2012-08-01; Completion date: 2015-12-01
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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.

Secondary:

* To evaluate Response Rate, Progression Free Survival (PFS), Overall Survival (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

Eligibility:

-Adult patients with irinotecan-resistant colorectal cancer (or advanced solid tumor in phase I part).

Design:

* 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/m\^2 as an intravenous infusion every second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be to establish maximum tolerated dose (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 colorectal 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 messenger ribonucleic acid (mRNA) and protein (IHC) analysis will be performed in the phase II portion of the study; Immune subsets; positron emission tomography (PET) responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of irinotecan and ISIS183750 in 10-12 patients.

Arms: arm 1: 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. arm 2: 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. arm 3: 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.
Interventions: intervention 1: ISIS 183750 intervention 2: Irinotecan
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents: