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

Objectives:

Primary Objective of Phase I:

• Determine the maximum tolerated dose (MTD) of CB839 in combination with panitumumab and
irinotecan

Primary Objective of Phase II:

• Determine the efficacy of CB-839 in combination with panitumumab and irinotecan as measured
by the objective response rate (RR) in patients with previously EGFR treated RAS wildtype
colorectal adenocarcinoma.

Secondary Objectives of Phase II:

- Determine the disease control rate, progression-free survival, and overall survival
(phase II).

- Correlate radiological features of pre- and post-treatment carbon C 11 glutamine
(11C-glutamine) positron emission tomography (PET)/computed tomography (CT) and fluorine
F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) PET/CT with clinical outcome and
biological correlates (tissue gene signature, plasma glutamate levels, exosomes). (Phase
II).

- Collect pre-treatment biopsy tissue and prospectively correlate clinical outcome with a
glutamate-biased gene set. (Phase II)

- Quantify exosomal content in the plasma (Phase II).

EXPLORATORY OBJECTIVES:

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

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 (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 up 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

- 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.