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All Drugs and Chemicals

Irinotecan

Topoisomerase I Inhibitors

Enzyme Inhibitors

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.

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.

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.

ISIS 183750

Tim F Greten, M.D.

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.

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.

ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer

A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer

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.

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).

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.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Objective response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to \<10mm. Partial response (PR) is at least a 30% reduction in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of athe diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more lesions is also considered progression).

Progression free survival is defined as the time beginning on the on study date and continuing until date of progression or date removed from study for an adverse event.

Overall survival is defined as the time from the on study date until the date of death or date last known alive.

AUC(ALL) (Area under the plasma concentration vs. time curve for all time points) was assessed for CPT-11 (irinotecan), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G to derive the total AUC(ALL).

Intracellular and stromal presence of ISIS in tumor tissue was assessed by immunohistochemistry (IHC) and Crystal Violet staining to determine effectiveness of drug. Tissue that retains stain indicates intracellular and stromal presence of ISIS and determines if the drug is working. Relative staining intensity (intensity criteria unavailable) was evaluated by a pathologist.

Protein levels in the biopsy sample was assessed by immunohistochemistry using anti-oligonucleotide antibody to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a reduced effect (criteria unavailable) of elF4E inhibition on relevant regulated proteins determines if the drug is working.

Peripheral blood analysis of elF4E mRNA expression was performed using real time quantitative polymerase chain reaction (q-PCR) to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a decrease (criteria unavailable) in elF4E determines if the drug is working. Cell proliferation or reduction was evaluated by a pathologist.

National Cancer Institute (NCI)

Principal Investigator

Irinotecan 160 mg/m\^2 every other week; ISIS 183750 started 800mg/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.

Phase I Dose Level I

Irinotecan 180 mg/m\^2 every other week; ISIS 183750 1000mg/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.

Phase I Dose Level II

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.

Phase II Dose Level I

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr.Tim Greten

ISIS 183750 started 800mg/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.

All Phase I Participants

Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors

Irinotecan 160 (and 180) mg/m\^2 every other week.

Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors

Mandatory pre- and post-dose biopsies for elF4e messenger ribonucleic acid (mRNA) analysis was performed in the phase II portion of the study.

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

Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies

Number of Participants With Adverse Events

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive (PD)

Phase I Dose Level 2

Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable for response. Per protocol, no responses were to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus there are no objective responses for Phase I Dose Level I.

Objective Response

Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable. Per protocol, progression free survival was not to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus there is no progression free survival data for Phase I Dose Level I.

Number of Participants With Progression Free Survival

Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable. Per protocol, overall survival was not to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus overall survival data for Phase I Dose Level I.

Overall Survival

CPT-11 (irinotecan)

SN38

SN38-G

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.

Phase I Dose Level II Irinotecan 180 mg/m\^2 every other week; ISIS 183750 1000mg/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.

Phase I Dose Level I & Phase I Dose Level II

Phase I Dose Level I and Phase I Dose Level II were grouped together for this outcome measure. Complete pharmacokinetic data for only ten of the fourteen participants enrolled on the phase I portion of the study were available for analysis. Data is unavailable to report each individual time point.

AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)

Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.

Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue

Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins

Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood

Irinotecan 180 mg/m\^2 every other week; ISIS 183750 1000mg 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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer	NCT01675128	Colorectal Neop... Colorectal Carc... Colorectal Tumo...	ISIS 183750 Irinotecan	18 Years -	National Institutes of Health Clinical Center (CC)
ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer	NCT01675128	Colorectal Neop... Colorectal Carc... Colorectal Tumo...	ISIS 183750 Irinotecan	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for human eukaryotic translation initiation factor 4e (eif4e) protein