A Phase III Study of BBI-608 plus nab-Paclitaxel with Gemcitabine in Adult Patients with Metastatic Pancreatic Adenocarcinoma.

Patients must fulfill all of the following criteria to be eligible for
admission to the study:, 4.1.1. 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., 4.1.2. Must have histologically or
cytologically confirmed advanced PDAC that is metastatic. The definitive
diagnosis of metastatic PDAC will be made by integrating the histopathological
data within the context of the clinical and radiographic data. Patients with
islet cell neoplasms are excluded., 4.1.3. Must not have previously received
chemotherapy or any investigational agent for the treatment of PDAC.
* A fluoropyrimidine or gemcitabine administered as a radiation sensitizer in
the adjuvant setting is allowed for as long as last dose was administered > 6
months prior to randomization and no lingering toxicities are present., 4.1.4.
Nab-paclitaxel with gemcitabine therapy is appropriate for the patient and
recommended by the Investigator., 4.1.5. Patient has one or more metastatic
tumors evaluable by CT scan with contrast (or MRI, if patient is allergic to CT
contrast media) per RECIST 1.1. Imaging investigations including CT/MRI of
chest/abdomen/pelvis or other scans as necessary to document all sites of
disease must be performed within 14 days prior to randomization. Qualifying
scans performed as part of standard of care prior to patient signature of the
study informed consent will be acceptable as baseline scanning as long as
scanning is performed < 14 days prior to randomization., 4.1.6. Must have ECOG
Performance Status of 0 or 1, assessed within 14 days prior to randomization.
Two observers qualified to perform assessment of the performance status will be
required to perform this assessment. If discrepant, the one with the most
deteriorated performance status will be considered true.
* Patients must not require any help with activities of daily living (ADLs),
including eating, dressing, washing or using the toilet.
* Patients must not need to stay in bed or chair for 50% or more of waking
hours.
* Patients with factors that limit accurate assessment of performance status
will not be eligible for the study. This includes but is not limited to
patients with pre-existing conditions preventing them from full mobility
(including but not limited to spinal or orthopedic conditions, amputees, morbid
obesity defined by BMI > 40)., 4.1.7. Must have life-expectancy of > 12 weeks.,
4.1.8. Must be * 18 years of age.
* Due to increased risk of sepsis in patients >80 years old, candidate patients
in this age group should be thoroughly evaluated prior to study randomization
to ensure they are fit to receive chemotherapy. In addition to all of the
inclusion/exclusion criteria listed, clinical judgment should be used regarding
patients* susceptibility to infection (including but not limited to presence of
ascites or diabetes mellitus increasing risk of infection). Furthermore, the
expected stability of their performance status while receiving repeat weekly
chemotherapy cycles should be given special attention. Patients in this age
group should not be randomized on the study should there be any hesitation on
any of these considerations., 4.1.9. For male or female patients of child
producing potential: Must agree to use contraception or take measures to avoid
pregnancy during the study and for 180 days after the final dose of
nab-paclitaxel and gemcitabine or for 30 days for female patients and for 90
days for male patients, after the final BBI-608 dose if nab-paclitaxel and
gemcitabine were not administered., Adequate contraception is defined as
follows:
1. Complete true abstinence: when this is in line with the preferred and usual
lifestyle of the subject.
2. Consistent and correct use of one of the following methods of birth control:
a. male partner who is sterile prior to the female subjects entry into the
study and is the sole sexual partner for that female subject; or
b. implants of levonorgesterol; or
c. injectable progestagen; or
d. any intrauterine device (IUD) with a documented failure rate of less than 1%
per year; or
e. any intrauterine hormone-releasing system (IUS) with a documented failure
rate of less than
1% per year; or
f. oral contraceptive pill (either combined or progesterone only); or
g. one barrier method, for example diaphragm with spermicide or condom with
spermicide in combination with either implants of levonorgesterol or injectable
progestagen, any intrauterine device (IUD) or intrauterine hormone-releasing
system (IUS) with a documented failure rate of less than 1% per year, or oral
contraceptive pill (either combined or progesterone only)., 4.1.10. 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 human chorionic
gonadotropin (HCG)., WOCBP include any female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy,
bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal
(defined as amenorrhoea > 12 consecutive months; or women on hormone
replacement therapy (HRT) with documented serum follicle stimulating hormone
(FSH) level > 35 mIU/mL). Even women who are using oral, implanted or
injectable contraceptive hormones or mechanical products such as an
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to
prevent pregnancy or practicing abstinence or where partner is sterile (e.g.
vasectomy), should be considered to be of child bearing potential., 4.1.11.
Patient has adequate biological parameters as demonstrated by the following
blood counts at baseline (obtained < 14 days prior to randomization; laboratory
testing performed as part of standard of care prior to patient signature of
informed consent for the study will be acceptable as baseline laboratory work
as long as testing is performed < 14 days prior to randomization):
* Absolute neutrophil count (ANC) > 1.5 x 109/L
* Platelet count > 100,000/mm3 (100 x 109/L). Must not have required
transfusion of platelets within 1 week of baseline platelet count assessment
* Hemoglobin (HgB) > 9 g/dL. Must not have required transfusion of red blood
cells within 1
week of baseline Hgb assessment, 4.1.12. Patient has the following blood
chemistry levels at baseline (obtained < 14 days prior to randomization;
laboratory testing performed as part of standard of care prior to patient
signature of informed consent for the study will be acceptable as baseline
laboratory work as long as testing is performed < 14 days prior to
randomization):
* AST (SGOT) and ALT (SGPT) * 2.5 × institutional upper limit of normal (ULN)
[* 5 × ULN in presence of liver metastases]
* Total bilirubin * 1.5 x institutional ULN. If total bilirubin is > ULN and <
1.5 x ULN, it must be non-rising
for at least 7 days
* Serum creatinine within normal limits or calculated clearance > 60
mL/min/1.73 m2 for patients with serum creatinine levels above or below the
institutional normal value. If using creatinine clearance, actual body weight
should be used for calculating creatinine clearance (eg. Using the
Cockroft-Gault formula). For patients with a Body Mass Index (BMI) > 30 kg/m2,
lean body weight should be used instead., 4.1.13. Patient not on
anticoagulation has acceptable coagulation studies (obtained < 14 days prior to
randomization; laboratory testing performed as part of standard of care prior
to patient signature of informed consent for the study will be acceptable as
baseline laboratory work as long as testing is performed < 14 days prior to
randomization) as demonstrated by prothrombin time (PT) and partial
thromboplastin time (PTT) below or within normal limits (+15%).
* Patients on anticoagulation must have coagulation values within the
therapeutic range
appropriate for the anti-coagulation indication, 4.1.14. Patient has no
clinically significant abnormalities on urinalysis results (obtained < 14 days
prior to randomization; laboratory testing performed as part of standard of
care prior to patient signature of informed consent for the study will be
acceptable as baseline laboratory work as long as testing is performed < 14
days prior to randomization). , 4.1.15. 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., 4.1.16. Baseline laboratory evaluations must be done
within 14 days prior to randomization and some must be repeated < 72 hours
prior to randomization, as listed in Section 6.0. , 4.1.17. Patients requiring
biliary stent placement must have biliary stent placed > 7 days prior to
screening. , 4.1.18. Pain symptoms should be stable (of tolerable Grade 2 or
less)., 4.1.19. Only patients with available archival tumor tissue 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 correlative marker assays proscribed in Section 13.6 (Correlative
Studies) of this protocol may be conducted. Submission of the tissue does not
have to occur prior to randomization. Where local center regulations prohibit
submission of blocks of tumor tissue, two 2 mm cores of tumor from the block
and 5-20 unstained slides of whole sections of representative tumor tissue are
preferred. Where it is not possible to obtain two 2 mm cores of tumor from the
block, 5-20 unstained slides of representative tumor tissue are also
acceptable. Where no previously resected or biopsied tumor tissue exists or is
available, on the approval of the Sponsor/designated CRO, the patient may still
be considered eligible for the study., 4.1.20. Patient must consent to
provision of a sample of blood in order that the specific correlative marker
assays proscribed in Section 13.6 (Correlative Studies) may be conducted.,
4.1.21. Patients must be accessible for treatment and follow up. Patients
registered on this trial must receive protocol treatment and be followed at the
participating center. This implies there must be reasonable geographical limits
placed on patients being considered for this trial. Investigators must ensure
that the patients randomized on this trial will be available for complete
documentation of the treatment, response assessment, adverse events, and
follow-up., 4.1.22. 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.,
4.1.23. 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. Patients
participating in surveys or observational studies are eligible to participate
in this study.

Patients who fulfill any of the following criteria are not eligible for
admission to the study:, 4.2.1. Patients with no evidence of metastatic disease
as well as patients with a local recurrence following surgical resection of
primary lesion., 4.2.2. Patient has experienced a decline in ECOG performance
status between Baseline visit and within 72 hours prior to randomization.,
4.2.3. Patient has a > 20% decrease in serum albumin level between Baseline
visit and within 72 hours prior to randomization., 4.2.4 Patient has a > 10%
decrease in weight between Baseline visit and within 72 hours prior to
randomization, 4.2.5. Any prior anti-cancer chemotherapy, biologic or
investigational therapy for PDAC.
a. Patients receiving immunotherapy for non-cancer related treatment within * 4
weeks of first planned dose of study treatment will be excluded.
b. A fluoropyrimidine or gemcitabine administered as a radiation sensitizer in
the adjuvant setting is allowed for as long as last dose was administered > 6
months prior to randomization., 4.2.6. Major surgery within 4 weeks prior to
randomization., 4.2.7. Any known brain or leptomeningeal metastases are
excluded, even if treated., 4.2.8. Patients with clinically significant ascites
or pleural effusions., 4.2.9. 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 nab-paclitaxel and
gemcitabine and for 180 days after the last dose of nab-paclitaxel and
gemcitabine., 4.2.10. Gastrointestinal disorder(s) which, in the opinion of the
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)., 4.2.11. Unable or unwilling to swallow BBI-608
capsules daily., 4.2.12. Uncontrolled inter-current 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. History of cardiac disease: congestive heart failure (CHF) > NYHA Class II;
active coronary artery disease, myocardial infarction or coronary stenting
within 6 months prior to randomization; unevaluated new onset angina within 3
months or unstable angina (angina symptoms at rest) or cardiac arrhythmias
requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
b. Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg
or diastolic pressure > 90 mmHg despite optimal medical management) as well as
prior history of hypertensive crisis or hypertensive encephalopathy.
c. Significant vascular disease (e.g., aortic aneurysm, aortic dissection,
symptomatic peripheral vascular disease including claudication, Leo Buerger*s
disease). Treated peripheral vascular disease that is stable for at least 6
months is allowed.
d. Evidence of bleeding diathesis or clinically significant coagulopathy.
e. Major surgical procedure (including open biopsy, significant traumatic
injury, etc.) within 28 days, or anticipation of the need for major surgical
procedure during the course of the study as well as minor surgical procedure
(excluding placement of a vascular access device or bone marrow biopsy) within
7 days prior to randomization.
f. Patients with clinically significant abnormalities on urinalysis at < 14
days prior to randomization.
g. History of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within 6 months prior to randomization.
h. Ongoing serious, non-healing wound, ulcer, or bone fracture.
i. Known infection with Human Immunodeficiency Virus (HIV), and/or active
infection with hepatitis B, or hepatitis C.
j. History of interstitial lung disease, history of slowly progressive dyspnea
and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis,
pulmonary hypersensitivity pneumonitis or multiple allergies.
k. History of hemolytic-uremic syndrome.
l. History of connective tissue disorders (eg, lupus, scleroderma, arteritis
nodosa).
m. Serious medical risk factors involving any of the major organ systems, or
serious psychiatric disorders that could compromise the patient*s safety or the
study data integrity., 4.2 13. Known hypersensitivity to gemcitabine, taxanes
or any of their excipients, or the patient exhibits any of the events outlined
in the Contraindications or Special Warnings and Precautions sections of the
product or comparator SmPC or Prescribing Information. Possible
hypersensitivity to BBI-608 or one of the excipients which include the azo dyes
sunset yellow and allura red., 4.2.14. Neurosensory neuropathy > grade 2 at
baseline., 4.2.15. Uncontrolled chronic diarrhea > grade 2 at baseline.,
4.2.16. Patients being treated with Warfarin., 4.2.17. Patients with active,
uncontrolled bacterial, viral or fungal infection(s) requiring systemic
therapy, 4.2.18. 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 by surgery alone or
surgery plus radiotherapy with no evidence of disease continuously for > 5
years., 4.2.19. Any active disease condition which would render the protocol
treatment dangerous or impair the ability of the patient to receive protocol
therapy., 4.2.20. Any condition (e.g. psychological, geographical, etc.) that
does not permit compliance with the protocol, including patients with history
of poor compliance or history of drug/alcohol abuse, or excessive alcohol
beverage consumption that would interfere with the ability to comply with the
study protocol. Patients planning to take a vacation for 14 or more consecutive
days during the course of the study are ineligible.