EGF-Depleting Therapy CIMAvax-EGF in Combination With Standard Therapy for RAS- and BRAF Wild-Type Metastatic Colorectal Cancer

Inclusion Criteria:

* Histologically or cytologically confirmed metastatic adenocarcinoma of colon or rectum that cannot be removed by surgery without prior systemic therapy for advanced disease (prior adjuvant chemotherapy completed \>12 months from diagnosis of metastatic or advanced disease is allowed) for cohorts A and C and with one prior line of therapy but no more than 2 prior lines of therapy for advanced disease (prior adjuvant chemotherapy completed \<12 months from diagnosis of metastatic or advanced disease is considered one line of therapy).

  * Cohort A: May have received 1 cycle of chemotherapy± appropriate biologic agent pending results of RAS and BRAF. If results determine patient is eligible, the patient will be enrolled and will receive the addition of CIMAvax + Bevacizumab or CIMAvax+ anti-EGFR therapy in their second cycle.
  * Cohort B: Patients with RAS- and BRAF wild-type metastatic CRC who have received at least one but no more than 2 prior therapies for advanced disease
  * Cohort C: Patients with RAS- and BRAF wild-type metastatic CRC who have not received prior therapy for advanced disease and are candidates for metastatic disease resistant resection (one cycle of standard chemotherapy with or without appropriate biologic agent is allowed)
* KRAS/NRAS/BRAF wild-type.
* Have an ECOG Performance Status of 0-2
* Patients must have adequate organ and marrow function as defined below:

  * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  * Platelets ≥ 75 x 10\^9/L
  * Hemoglobin ≥ 8 g/dL
  * Creatinine clearance\> 60 mL/min (Cockcroft-Gault Equation)
  * ALT and AST ≤ 3 x ULN (ALT and AST ≤ 5 x ULN is acceptable if liver metastases are present
  * Total bilirubin ≤ 1.5x ULN. For patients with well documented Gilbert's syndrome, total bilirubin ≤ 3x ULN with direct bilirubin within normal range
* Have measurable disease per RECIST 1.1 criteria present.
* Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. 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.
* Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.
* Participant agrees to provide paired-tumor biopsy tissue while on study (cohort A and B) or allow tissue to be taken during surgery (cohort C)

Exclusion Criteria:

* Toxicity ≥Grade 2 from prior chemotherapy with exception to Grade 2 peripheral neuropathy..
* Other cancer requiring active treatment.
* Prior exposure to anti-EGFR monoclonal antibody (i.e. cetuximab or panitumumab) for colorectal cancer treatment is exclusionary to Cohort A and C only
* Participants with Her2 positive mutational status
* Had major surgery within 4 weeks prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered major surgery) resulting from a prior surgery.
* Has known immunosuppressive disease (e.g. HIV, AIDS or other immune depressing disease). Testing is not mandatory.
* Participants with known active brain metastases should 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.
* Active, clinically serious infections or other serious uncontrolled medical conditions or psychiatric illness/social situations that would limit compliance with study requirements.
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:

  * Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease
  * History of documented congestive heart failure (New York Heart Association functional classification III or IV) within 6 months prior to baseline
  * Uncontrolled hypertension (SBP\>160/DBP\>100 despite medical intervention).
  * History of myocarditis of any etiology
  * History of ventricular arrhythmias
* Active major or clinically significant bleeding based on the International Society on Thrombosis and Hemostasis definition.
* Pregnant or nursing female participants.