ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer

This is an interventional treatment trial for Colorectal Neoplasms focused on measuring Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein, Refractory, Oncogene, Maximum Tolerated Dose, Safety Read More

• 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.