ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Colorectal Neoplasms, Colorectal Carcinoma, Colorectal Tumors

Intervention / Treatment
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* Drug: ISIS 183750
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Phase I: Patients must have histopathological confirmation of carcinoma by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study. Phase II: Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the Laboratory of Pathology of the NCI prior to entering this study. For this portion of the study patients must also have irinotecan-refractory colorectal cancer and have also received prior treatment for advanced/metastatic disease with an oxaliplatin-, bevacizumab-, or epidermal growth factor receptor (EGFR) inhibitor-containing (only for subjects with wild type Kras) regimen. Irinotecan-refractory will be defined as patients who have radiological evidence of disease progression whilst receiving irinotecan or within 3 months after completing it. Patients must have disease that is not amenable to potentially curative resection or ablative techniques and have received at least one prior standard chemotherapeutic regimen for metastatic disease. All patients enrolled will be required to have measurable disease. For the phase II portion of the study patients must have disease that is amenable to biopsy and be willing to undergo this. Age greater than18 years Life expectancy of greater than 3 months Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients must have acceptable organ and marrow function as defined below: leukocytes > 3,000/mcL absolute neutrophil count > 1,500/mcL platelets > 100,000/mcL total bilirubin Within normal institutional limits Serum albumin greater than or equal to 2.5 g/dL Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) measuring 3 x upper limit of normal (ULN) if no liver metastasis or up to 5 x ULN with liver metastasis. creatinine < 1.5X institution upper limit of normal OR creatinine clearance > 45 mL/min/1.73 m^2, as calculated below, for patients with creatinine levels above institutional normal Estimated creatinine clearance (mL/min) Females see calculations Males see calculations - May use a 24 hr. urine collection to determine creatinine clearance. Measured creatinine clearance (mL/min) Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be < grade 1 or returned to baseline. Patients must not have other invasive malignancies within the past 3 years (with the exception of non-melanoma skin cancers, carcinoma in situ of the cervix and noninvasive bladder cancer that has had successful curative treatment). The effects of ISIS 183750 on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months after dosing with study medication ceases. However, adequate contraception for male patients should be used for 16 weeks post- last dose due to sperm life cycle. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women of child-bearing potential must have a negative pregnancy test prior to entry. Patient must be able to understand and willing to sign a written informed consent document. Men and women of all races and ethnic groups are eligible for this trial. Ejection fraction > 55% on echocardiogram. EXCLUSION CRITERIA: Patients who have had chemotherapy (or so-called targeted systemic therapy), large field radiotherapy, or major surgery must wait 4 weeks after completing treatment prior to entering the study. Patients may not be receiving any antineoplastics or other drugs intended to treat cancer within 4 weeks prior to starting ISIS 183750. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with clinically significant ascites, pleural effusion, and/or peripheral edema, unless the ascites or pleural effusion occurred as a result of malignancy. Patients with known hypersensitivity to irinotecan. Patients with known homozygous mutations in the UTG1A1 UUDP-glucuronosyltransferase 1-1) allele, or with unknown UTG1A1 status but who could not tolerate irinotecan even after dose reduction. Patients with bleeding diathesis and subjects who are receiving anticoagulation treatment with International Normalized Ratio (INR) > 2.5 are excluded. Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure (BP) > 160, diastolic BP > 100), ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements. Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and the investigational agent. Known hepatitis B or hepatitis C infection. Pregnancy and breast feeding are exclusion factors. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 3 months after the end of the treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Level I<br>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. | Drug: ISIS 183750<br> <br> Drug: Irinotecan<br> <br> |
| Experimental: Phase I Dose Level II<br>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. | Drug: ISIS 183750<br> <br> Drug: Irinotecan<br> <br> |
| Experimental: Phase II Dose Level I<br>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. | Drug: ISIS 183750<br> <br> Drug: Irinotecan<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors | 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. | 2 years | 
| Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors | 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. | 2 years | 
| 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 | 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). | 2 weeks | 
| Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies | 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. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 21 months | 
| Objective Response | 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). | up to 2 cycles | 
| Number of Participants With Progression Free Survival | 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. | ≤ 6 months | 
| Overall Survival | Overall survival is defined as the time from the on study date until the date of death or date last known alive. | ≥ 12 months | 
| AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points) | 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). | up to 24 hours post end of infusion | 
| Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue | 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. | 2 weeks | 
| Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins | 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. | 2 weeks | 
| Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood | 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. | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein, Refractory, Oncogene, Maximum Tolerated Dose, Safety