Lenalidomide and Cetuximab in Treating Patients With Metastatic Colorectal Cancer

Inclusion

* Wild type metastatic colorectal cancer that failed (progressed, refused or not tolerated) on at least two treatment regimens including a fluoropyrimidine, oxaliplatin and irinotecan with or without bevacizumab
* At least 28 days must have lapsed since completion of prior chemotherapy
* Subjects must understand and voluntarily sign an informed consent document
* Subjects must be able to adhere to the study visit schedule and other protocol requirements
* Histological or cytological diagnosis of colorectal carcinoma
* Radiographic or clinical evidence of a measurable disease (by RECIST criteria)
* Subjects must have received prior treatment with at least 2 prior regimens of therapy
* ECOG performance status of =\< 1
* Anticipated survival \>= 3 months
* Must agree to also take low dose aspirin (or other anticoagulation if unable to take ASA) while receiving study drug and for 30 days after study drug is discontinued
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing
* Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy

Exclusion

* Pregnant or lactating females
* CrCl \< 50 mL/min by Cock-Croft and Gault
* Any serious medical condition or psychiatric illness that places the subject at an unacceptable risk for study participation or would prevent the subject from signing the informed consent
* Use of any cytotoxic chemotherapy within 28 days of study Day 1
* Use of therapeutic radiation =\< 14 days prior to study Day 1
* Use of thalidomide, or structurally related compounds or biologic response modifier therapy within 14 days of study Day 1
* Prior desquamating rash while taking thalidomide, or structurally related compound therapy
* Prior \>= Grade 2 allergic reaction to thalidomide or structurally related compounds
* Any prior use of Lenalidomide
* Subjects may have received prior thalidomide
* Known or suspected brain metastases
* Concurrent use or anticipated use of any other anti-cancer agents (except for stable dose steroid use for control of metastases symptoms) during participation in this study
* Absolute Neutrophil Count =\< 1500/mm\^3 (or 1.5 X10\^9/L)
* Platelet Count =\< 100,000/mm\^3 (or 100 X 10\^9/L)
* Hemoglobin \< 8.0 g/dL
* Total Bilirubin \> 2.0mg/dL
* Alanine Aminotransferase (ALT/SGPT) \>= 3 x upper limit of normal (ULN)
* Aspartate Aminotransferase (AST/SGOT) \>= 3 x upper limit of normal (ULN)
* Peripheral neuropathy \>= Grade 2
* Active infection
* Subjects with an infection that is amenable to curative treatment may be eligible for screening once the infection has been treated, cured and not recurred for at least 14 days
* Uncontrolled hyper- or hypo- calcemia, glycosemia or thyroidism
* Arterial or venous thrombotic event in the preceding six months
* Known history of HIV infection
* Active viral hepatitis who is on active treatment
* No other malignancies, other than previously treated non-melanoma skin cancer or carcinoma insitu of the cervix or breast