Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

Inclusion Criteria:

* Signed and dated written informed consent
* Histologically or cytologically-confirmed diagnosis of metastatic KRAS wildtype colorectal cancer (CRC)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* In dose escalation, patients must have had at least one prior line of chemotherapy for advanced disease or progressed within 6 months of adjuvant therapy (prior chemotherapy and/or anti-EGFR therapy is permitted)
* In dose expansion, patients must have received prior anti-EGFR therapy and achieved at least stable disease on at least one scan as their best response
* In dose expansion, patients must be willing to undergo a pre-treatment biopsy, and four research PET imaging techniques (11C-Glutamine and 18F-FSPG), two pre-treatment and two after one cycle of treatment
* In dose expansion, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 which can be followed by CT or magnetic resonance imaging (MRI)
* Absolute neutrophil count (ANC) \>= 1,500/uL
* Platelets \>= 100,000/uL
* Serum albumin \>= 3.0 g/dL
* Serum creatinine =\< 2 mg/dL, or calculated creatinine clearance \> 50 mL/min (per the Cockcroft-Gault formula)
* Total bilirubin =\< 1.5 times upper limit of normal (ULN)
* Aspartate transaminase (AST) and alanine aminotransferase (ALT) =\< 5.0 x ULN
* Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of protocol-indicated treatment; and additionally agree to use at least 2 methods of acceptable contraception or abstain from heterosexual intercourse from the time of signing consent, and until 2 months after patient's last dose of protocol-indicated treatment; WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women
* Men able to father children who are sexually active with WOCBP must agree to use at least 2 methods of acceptable contraception from the time of signing consent and until 2 months after patient's last dose of protocol-indicated treatment; men able to father children are defined as those who are not surgically sterile (i.e. patient has not had a vasectomy)

Exclusion Criteria:

* Within 28 days before first dose of protocol-indicated treatment:

  * Anti-cancer treatment including chemotherapy, radiation, hormonal therapy, targeted therapy, immunotherapy, or biological therapy
  * Major surgery requiring general anesthesia; (Note: within this time frame, placement of a central line or portacath is acceptable and does not exclude)
  * Receipt of an investigational agent
* Within 14 days before first dose of protocol-indicated treatment:

  \* Active uncontrolled infection; patients with infection under active treatment and controlled with antibiotics initiated at least 14 days prior to initiation of protocol-indicated treatment are not excluded (e.g. urinary tract infection controlled with antibiotics)
* Dose escalation only: known grade 4 toxicity probably or definitely attributed to past irinotecan treatment
* Active inflammatory bowel disease, other bowel disease causing chronic diarrhea (defined as \> 4 loose stools per day), or bowel obstruction
* History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest CT scan
* Unable to receive oral medication
* Central nervous system (CNS) metastasis, unless asymptomatic or previously treated and stable; and no evidence of CNS progression for at least 30 days prior to initiating protocol-indicated treatment; anticonvulsant and/or corticosteroid therapy will be allowed if patient is on a stable or decreasing dose of such treatment for at least 30 days prior to initiating protocol-indicated treatment
* Patients with known Gilbert's disease
* Patient is pregnant or breastfeeding
* Current or previous malignant disease (other than colorectal cancer) within the last 5 years; with the exception of the following if considered curatively treated: non-melanoma skin cancer(s), carcinoma in situ of the cervix, and ductal carcinoma in situ; subjects with another active malignancy requiring concurrent anti-cancer intervention are excluded; (Note the following does not exclude: effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured AND no additional anti-cancer therapy is ongoing and required during the study period)
* Known positive test for human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis A, hepatitis B, hepatitis C, or cytomegalovirus (CMV)
* Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patient's study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements.