A Phase III Study of BBI-608 in combination with 5-Fluorouracil, Leucovorin, Irinotecan (FOLFIRI) in Adult Patients with Previously Treated Metastatic Colorectal Cancer (CRC)

1.1 Written, signed consent for trial participation must be obtained from the
patient appropriately in accordance with applicable ICH guidelines and local
and regulatory requirements prior to the performance of any study specific
procedure., 1.2 Must have histologically confirmed advanced CRC that is
metastatic., 1.3 Must have failed treatment with one regimen containing only a
fluoropyrimidine and oxaliplatin with or without bevacizumab for metastatic
disease. All patients must have received a minimum of 6 weeks of the first-line
regimen that included bevacizumab, oxaliplatin and a fluoropyrimidine with or
without bevacizumab in the same cycle. Treatment failure is defined as
radiologic progression during or < 6 months after the last dose of first-line
therapy., 1.4 FOLFIRI therapy is appropriate for the patient and is recommended
by the Investigator., 1.5 Imaging investigations including CT/MRI of
chest/abdomen/pelvis or other scans as necessary to document all sites of
disease performed within 21 days prior to randomization. Patients with either
measurable disease or non-measurable evaluable disease are eligible., 1.6 Must
have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
1., 1.7 Must be * 18 years of age., 1.8 For male or female patient of child
bearing potential: Must agree to use contraception or take measures to avoid
pregnancy during the study and for 180 days for female and for male patients,
of the final FOLFIRI dose. Patients who receive single agent BBI-608 without
FOLFIRI must agree to use contraception or take measures to avoid pregnancy
during the study and for 30 days for female patients and 90 days for male
patients, of the final BBI-608 dose. , 1.9 Women of child bearing potential
(WOCBP) must have a negative serum or urine pregnancy test within 5 days prior
to randomization. The minimum sensitivity of the pregnancy test must be 25 IU/L
or equivalent units of HCG., 1.10 Must have alanine transaminase (ALT) * 3 ×
institutional upper limit of normal (ULN) [* 5 × ULN in presence of liver
metastases] within 14 days prior to randomization., 1.11 Must have hemoglobin
(Hgb) * 9.0 g/dL within 14 days prior to randomization. Must not have required
transfusion of red blood cells within 1 week of baseline Hgb assessment., 1.12
Must have total bilirubin * 1.5 × institutional ULN [* 2.0 x ULN in presence of
liver metastases] within 14 days prior to randomization., 1.13 Must have
creatinine * 1.5 × institutional ULN or Creatinine Clearance > 50 ml/min as
calculated by the Cockcroft-Gault equation (Chronic Kidney Disease Epidemiology
Collaboration [CKD-EPI] equation may also be used) within 14 days prior to
randomization., 1.14 Must have absolute neutrophil count * 1.5 x 109/L within
14 days prior to randomization., 1.15 Must have platelet count * 100 x 109/L
within 14 days prior to randomization. Must not have required transfusion of
platelets within 1 week of baseline platelet assessment., 1.16 Patient must
have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m2 and body
weight of > 40 kg with serum albumin > 3 g/dL., 1.17 Other baseline laboratory
evaluations, listed in Section 5, must be done within 14 days prior to
randomization., 1.18 Patient must consent to provision of, and Investigator(s)
must confirm access to and agree to submit a representative formalin fixed
paraffin block of tumor tissue in order that the specific biomarker assays
proscribed may be conducted (Section 12.2.1. and Section 13.2)., 1.19 Patient
must consent to provision of a sample of blood in order that the specific
correlative marker assays may be conducted (Section 12.2.1)., 1.20 Patients
must be accessible for treatment and follow-up., 1.21 Protocol treatment is to
begin within 2 calendar days of patient randomization for patients randomized
to Arm 1. Patients randomized to Arm 2 must begin protocol treatment within 7
calendar days of randomization., 1.22 The patient is not receiving therapy in a
concurrent clinical study and the patient agrees not to participate in other
interventional clinical studies during their participation in this trial while
on study treatment. , (Please refer to protocol for further information)

2.1 Anti-cancer chemotherapy or biologic therapy if administered prior to the
first planned dose of study medication (BBI-608 or FOLFIRI) within period of
time equivalent to the usual cycle length of the regimen. An exception is made
for oral fluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10 days
since last dose must be observed prior to the first planned dose of study
medication., 2.2 More than one prior chemotherapy regimen administered in the
metastatic setting., 2.3 Major surgery within 4 weeks prior to randomization.,
2.4 Patients with any known brain or leptomeningeal metastases are excluded,
even if treated., 2.5 Women who are pregnant or breastfeeding. Women should not
breastfeed while taking study treatment and for 4 weeks after the last dose of
BBI-608 or while undergoing treatment with FOLFIRI and for 180 days after the
last dose of FOLFIRI., 2.6 Gastrointestinal disorder(s) which, in the opinion
of the Qualified/Principal Investigator, would significantly impede the
absorption of an oral agent (e.g. active Crohn*s disease, ulcerative colitis,
extensive gastric and small intestine resection)., 2.7 Unable or unwilling to
swallow BBI-608 capsules daily., 2.8 Prior treatment with BBI-608 or possible
hypersensitivity to BBI-608 or one of the excipients which include azo dyes
sunset yellow and allura red., 2.9 Uncontrolled intercurrent illness including,
but not limited to, ongoing or active infection, clinically significant
non-healing or healing wounds, symptomatic congestive heart failure, unstable
angina pectoris, clinically significant cardiac arrhythmia, significant
pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled
infection or psychiatric illness/social situations that would limit compliance
with study requirements.
a. Known infection with HIV, and/or active infection with hep B or hep C
b. patients with clinically significant ascites or pleural effusions, 2.10
Known hypersensitivity to 5-fluorouracil/leucovorin, 2.11 Known
dihydropyrimidine dehydrogenase (DPD) deficiency, 2.12 Known hypersensitivity
to irinotecan, 2.13 Abnormal glucuronidation of bilirubin, known Gilbert*s
syndrome, 2.14 Patients with QTc interval > 470 milliseconds, 2.15 For
patients to be treated with a regimen containing bevacizumab: please refer to
protocol, 2.16 Patients with a history of other malignancies except: adequately
treated non-melanoma skin cancer, curatively treated in-situ cancer of the
cervix, or other solid tumors curatively treated with no evidence of disease
for > 3 years., 2.17 Any active disease condition which would render the
protocol treatment dangerous or impair the ability of the patient to receive
protocol therapy., 2.18 Any condition (e.g. psychological, geographical, etc.)
that does not permit compliance with the protocol., Please refer to protocol
for further information.