| Eligibility |
Inclusion Criteria:
1. Signed written informed consent must be obtained and documented according to
International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP), the
local regulatory requirements, and permission to use private health information in
accordance with the Health Insurance Portability and Accountability Act (HIPAA) prior
to study-specific screening procedures.
2. Patients must have histologic or cytologic evidence of adenocarcinoma of the pancreas,
such as a core tissue biopsy or a surgical resection specimen.
3. Patients must have metastatic disease. Baseline imaging of chest, abdomen and pelvis
(CT or MRI) within 21 days prior to initiation of protocol therapy is required.
1. Patients must have measurable disease as defined by RECIST 1.1.
2. Patients with locally advanced unresectable pancreatic ductal adenocarcinoma are
excluded.
4. Patients enrolling onto Arm A (Gemcitabine and nab-Paclitaxel) or Arm B (mFOLFIRINOX)
are allowed to have up to two prior lines of systemic therapy, with adjuvant therapy
counted as one line of therapy as long as disease recurrence occurred > 6 months of
last dose of therapy. Prior systemic therapy in the metastatic setting is allowed for
as long as the therapy contained BBI608 in combination with either Gemcitabine and
nab-Paclitaxel or mFOLFIRINOX. Toxicities related to prior therapy must have
completely resolved (except for alopecia and anemia), or be deemed irreversible.
1. Patients who received Gemcitabine-based therapy in an adjuvant setting will be
allowed to be enrolled on Arm A of the trial (Gemcitabine with nab-Paclitaxel) as
long as their last Gemcitabine administration was at least 6 months prior to the
first dose of BBI608.
2. Patients enrolling onto Arm A (Gemcitabine with nab-Paclitaxel) are allowed to
have prior mFOLFIRINOX in combination with BBI608 in the metastatic setting.
3. Patients enrolling onto Arm B (mFOLFIRINOX) are allowed to have prior Gemcitabine
with nab-Paclitaxel in combination with BBI608 in the metastatic setting.
4. Prior treatment with radiotherapy is allowed.
5. Patients enrolling onto Arm C (FOLFIRI) or Arm D (MM-398 with 5-FU and leucovorin)
must have failed one prior line of gemcitabine-based therapy with or without BBI608 in
the metastatic setting. No additional lines of therapy in the metastatic setting are
allowed. Prior adjuvant therapy with gemcitabine is allowed as long as disease
recurrence occurred > 6 months of last dose of therapy. Toxicities related to prior
therapy must have completely resolved (except for alopecia and anemia), or be deemed
irreversible. Prior treatment with radiotherapy is allowed.
6. = 18 years of age.
7. Patients must have an ECOG Performance Status = 1.
8. Male or female patients of child-producing potential agree to use contraception or
avoidance of pregnancy measures during the study and for 30 days after the last BBI608
dose.
9. Females of childbearing potential have a negative serum pregnancy test (preceding 72
hours of first day of BBI608 treatment).
10. Patients with biliary or gastro-duodenal obstruction must have drainage or surgical
bypass prior to starting chemotherapy.
11. Significant or symptomatic amount of ascites should be drained prior to first dose of
BBI608.
12. Patients on Warfarin/Dabigatran/Rivaroxaban anticoagulation may be enrolled for as
long as they undergo weekly INR checks for the first 2 months of therapy.
a. Patients who switch to low molecular weight heparin may be enrolled and weekly INR
labs are not mandated for these patients.
13. Aspartate transaminase (AST) level = 2.5 x upper limit of normal (ULN) and alanine
transaminase (ALT) = 2.5 × upper limit of normal (ULN). For patients with liver
metastases, AST = 5 ULN, and AST = 5 ULN may be enrolled if agreed upon by the
investigator and medical monitor for the sponsor.
14. Patients must have a total bilirubin level = 1.5 x ULN (= 2 x ULN if it is non-rising
for a period of 10 days prior to initiation of therapy).
15. Creatinine level < 1.0 x ULN or creatinine clearance = 60 mL/min/1.73 m^2 for patients
with creatinine levels above or below the institutional normal (as determined by
Cockcroft-Gault equation). For patients with a Body Mass Index (BMI) > 30 kg/m^2, lean
body weight should be used to calculate the GFR.
16. Hemoglobin (Hgb) = 9 g/dl
17. Absolute neutrophil count = 1.5 x 10^9/L
18. Platelets = 100 x 10^9/L
19. Acceptable coagulation studies as demonstrated by prothrombin time (PT) and partial
thromboplastin time (PTT) within normal limits (+/-15%).
20. Patient has no clinically significant abnormalities on urinalysis results.
21. Life expectancy estimated at = 3 months.
Exclusion Criteria:
1. Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents
within 14 days of the first dose of BBI608, except for BBI608 for which a washout
period is not required.
1. Patients may begin BBI608 on a date determined by the investigator and medical
monitor for the sponsor after a minimum of 14 days since last receiving
anti-cancer treatment which did not include BBI608, provided that all
treatment-related adverse events have resolved or have been deemed irreversible
(except for alopecia).
2. Patients who previously received BBI608 for treatment of PDAC on the BBI608-118
(BBI608-201PANC) study may continue with BBI608 in monotherapy between
discontinuation of the first chemotherapy backbone and start of the second
chemotherapy backbone. Patients may begin chemotherapy backbone on a date
determined by the investigator and medical monitor for the sponsor after a
minimum of 14 days and a maximum of 30 days since last receiving anti-cancer
treatment which included BBI608, provided that all treatment-related adverse
events have resolved or have been deemed irreversible (except for alopecia).
2. Patients with neuroendocrine neoplasms will be excluded.
3. Major surgery, other than diagnostic surgery (e.g., surgery done to obtain a biopsy
for diagnosis without removal of an organ), within 4 weeks prior to first dose.
4. Any brain metastases including leptomeningeal metastases, are excluded, even if
treated and stable.
5. History of posterior reversible encephalopathy syndrome.
6. Neurosensory neuropathy = grade 2 at baseline.
7. Pregnant or breastfeeding.
8. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal
Investigator, prevent absorption of an orally available agent (e.g., Crohn's disease,
ulcerative colitis, extensive gastric resection and small intestinal resection).
9. Unable or unwilling to swallow BBI608 capsules daily.
10. Uncontrolled chronic diarrhea = grade 2 at baseline.
11. Uncontrolled intercurrent illness including, but not limited to uncontrolled active
infection (including bacterial, viral or fungal requiring systemic therapy),
clinically significant non-healing or healing wounds, symptomatic congestive heart
failure, unstable angina pectoris, uncontrolled 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.
12. Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung.
13. History of other active malignancies.
14. Enrollment on any additional investigational agent study. Enrollment on concurrent
observational study is allowed following consultation with the Sponsor.
15. Patients planning to take a vacation for 7 or more consecutive days during the course
of the study.
16. For patients enrolling onto Arm A (Gemcitabine with nab-Paclitaxel)
a. Known hypersensitivity to Gemcitabine or taxanes. i. Patients with history of
Gemcitabine toxicity in the adjuvant setting requiring more than 1 dose level
reduction are excluded.
b. Significant cardiac disease, including the following: unstable angina, New York
Heart Association class III-IV congestive heart failure, myocardial infarction within
six months prior to study enrollment.
c. History of hemolytic-uremic syndrome. d. History of posterior reversible
encephalopathy syndrome. e. Known infection with Human Immunodeficiency Virus (HIV),
and/or active infection with hepatitis B, or hepatitis C.
f. History of active Peripheral Artery Disease (treated peripheral artery disease that
is stable for at least 6 months is allowed).
17. For patients enrolling onto Arm B (mFOLFIRINOX) or Arm C (FOLFIRI)
1. Known hypersensitivity to 5-fluorouracil/leucovorin
2. Known dihydropyrimidine dehydrogenase (DPD) deficiency
3. Known hypersensitivity to oxaliplatin or other platinum containing compounds
4. Known hypersensitivity to irinotecan
5. Uncontrolled seizure disorder, active neurological disease, or known CNS disease.
6. Known Gilbert's syndrome
7. Significant cardiac disease, including the following: unstable angina, New York
Heart Association class II-IV congestive heart failure, myocardial infarction
within six months prior to study enrollment.
18. For patients enrolling onto Arm D (MM-398 with 5-FU and leucovorin)
1. Prior irinotecan treatment
2. Arterial thromboembolic events (myocardial infarction, unstable angina pectoris,
stroke) < 6 months prior to enrollment
3. Known hypersensitivity to any of the components of MM-398, other liposomal
products, fluoropyrimidines or leucovorin
4. Known dihydropyrimidine dehydrogenase (DPD) deficiency
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