Inclusion Criteria

- INCLUSION CRITERIA:

- Phase I: Patients must have histopathological confirmation of carcinoma by the
Laboratory of Pathology of the 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 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

- 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 ALT or AST measuring 3 x ULN if no liver metastasis
or up to5 x ULN with liver metastasis.

- creatinine < 1.5X institution upper limit of normal

- OR

- creatinine clearance > 45 mL/min/1.73 m2, 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 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 INR > 2.5 are excluded.

- Uncontrolled intercurrent illness including, but not limited to, hypertension
(systolic 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.

- 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.