Primary Objective of Phase I:
• Determine the safety and tolerability of CB-839 in combination with panitumumab and
Primary Objective of Phase II:
• Determine the efficacy of CB-839 in combination with panitumumab and irinotecan as measured
by the response rate (RR) in patients with previously EGFR treated RAS wildtype colorectal
Secondary Objectives of Phase II:
OUTLINE: This is a dose-escalation study of glutaminase inhibitor CB-839.
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. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 28 days and then every 3
months for up to 1 year.
- Determine the disease control rate (DCR), progression-free survival (PFS), and overall
- Perform the following correlative studies (in the Phase II component):
- Correlate radiological features of pre- and post-treatment 18F-FSPG PET/CT with
clinical outcome and biological correlates (plasma glutamate levels, exosomes)
- Quantify exosomal content in the plasma.
- 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.
- At least one measureable lesion as defined by RECIST 1.1 which can be followed by CT
- Adequate organ function including:
- Absolute neutrophil count (ANC) ≥ 1,500/μL
- Platelets ≥ 100,000/μL
- 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 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.
Women 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 (Appendix 4) 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).
, 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
- Known Grade 4 toxicity probably or definitely attributed to past irinotecan
- 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 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
- 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.