This phase I/II trial studies the best dose and side effects of glutaminase inhibitor CB-839 and how well it works with panitumumab and irinotecan hydrochloride (phase I only) in treating patients with RAS wildtype colorectal cancer that has spread to other places in the body and does not respond to treatment. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving glutaminase inhibitor CB-839 with panitumumab and irinotecan hydrochloride may work better in treating patients with colorectal cancer.

Objectives:

Primary Objective of Phase I:

• Determine the safety and tolerability of CB-839 in combination with panitumumab and irinotecan.

Exploratory Objective of Phase I (Optional Imaging Sub-study):

• Correlate radiological features of pre- and post-treatment 11C-Glutamine PET/CT and 18F-FSPG PET/CT with clinical outcome.

Primary Objective of Phase II:

• Determine the efficacy of CB-839 in combination with panitumumab as measured by the response rate (RR).

Secondary Objectives of Phase II:

• Determine the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
• Perform the following correlative studies (in the phase 2 component):
• Correlate radiological features of pre- and post-treatment 18F-FSPG PET/CT with clinical outcome and biological correlates (tissue gene signature, exosomes).
• Collect blood samples during each radiotracer injection to assess pharmacokinetics.
• Collect pre-treatment biopsy tissue and prospectively correlate clinical outcome with a glutamine metabolism gene signature.
• Quantify exosomal content in the plasma.

Exploratory Objective of Phase II:

• Development of patient-derived organoids from pre-treatment tissue biopsy

OUTLINE: Phase I is a dose-escalation study of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab and irinotecan hydrochloride. Phase II will study efficacy of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab.

Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28, panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 28 days and then every 3 months for up to 1 year.

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.