Metastatic Pancreatic Adenocarcinoma

The study is divided into two parts: Part 1: • To evaluate the safety and tolerability of nal-IRI + 5FU/LV + oxaliplatin • To characterize dose-limiting toxicities (DLTs) associated with nal-IRI +5FU/LV + oxaliplatin and determine the Part 2 dose of the triplet combination Part 2: • To assess the efficacy of nal-IRI-containing regimens in first-line metastatic pancreatic cancer patients compared to nab-Paclitaxel + gemcitabine using progression free survival (PFS)

MM-398

Irinotecan

Injection for IV use

5mg

Part 1
Assessments for safety will include all treated patients and will be based on adverse
events, laboratory data, and study treatment related dose-limiting toxicities. Patients
who discontinue prior to completion of Cycle 1 due to events that are not related to
study treatment toxicity will not be considered in the assessment for DLT, and will be
replaced for the purposes of DLT evaluation. Plasma samples will be analyzed for the
concentration of nal-IRI (irinotecan) and its metabolites (SN-38 and SN-38G) in order
to derive PK parameters of nal-IRI when given in combination with other anticancer
therapies. PK parameters of the combination therapies (5-FU and oxaliplatin) will also
be analyzed to evaluate any drug interactions with nal-IRI.
Part 2
The primary endpoint is progression free survival, which will be assessed in all 3
study arms. The secondary endpoints related to efficacy will include overall survival
and objective response (CR or PR, per RECIST, v 1.1). Achievement of a 20%/50%/90% or greater decrease in CA19-9 levels compared to baseline (at 8, 16, and 24 weeks post-treatment and overall) will also be assessed, along with a quality of life assessment (EORTC-QLQ-C30 and EQ-5D-5L). QTcF prolongation will be assessed in the Arm 2 (nal-IRI+5-FU/LV) in patients with PK and QTcF measurements.
Translational / Exploratory
Archived tumor tissue (if available) and blood samples will be collected and analyzed
for biomarkers (Parts 1 and 2). Samples will be used to explore potential markers of
sensitivity and resistance to irinotecan, including, but not limited to, the following:
DNA damage repair pathways (e.g. Topo1, BRCA1/2, and SLFN11), growth factor pathways (IGF1 and EGFR family receptors and ligands), and factors involved in CPT-11 conversion to SN-38 (e.g. macrophage content and CES activity).

In order for inclusion into the study, patients must have/be:
a) Pathologically confirmed adenocarcinoma of the pancreas that has not been previously
treated in the metastatic setting
 Part 1: unresectable, locally advanced or metastatic disease is allowed, diagnosed within 6 weeks prior to enrolllment
 Part 2: must have metastatic disease diagnosed within 6 weeks prior to randomization; locally advanced disease is not allowed
b) Measurable or non-measurable disease as defined by RECIST v1.1
c) ECOG performance status of 0 or 1
d) Adequate biological parameters as evidenced by the following blood counts:
 ANC > 1,500 cells/µl without the use of hematopoietic growth factors,
 Platelet count > 100,000 cells/µl, and
 Hemoglobin > 9 g/dL
e) Adequate hepatic function as evidenced by:
 Serum total bilirubin ≤ ULN (biliary drainage is allowed for biliary obstruction), and
 AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are present)
f) Adequate renal function as evidenced by serum creatinine ≤ 1.5 x ULN, and calculated
clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine levels above or below
the institutional normal value. Actual body weight should be used for calculating
creatinine clearance using the Cockcroft-Gault Equation (CreatClear = Sex * ((140 - Age)
/ (SerumCreat)) * (Weight / 72); for patients with body mass index (BMI) >30 kg/m2, lean body weight should be used instead.
g) Normal ECG or ECG without any clinically significant findings
h) Recovered from the effects of any prior surgery or radiotherapy
i) ≥ 18 years of age
j) Agreeable to submit unstained archived tumor tissue for analysis, if available
k) Able to understand and sign an informed consent (or have a legal representative who is
able to do so)

Patients must meet all the inclusion criteria listed above and none of the following exclusion
criteria:
a) Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy,
chemotherapy or investigational therapy (note: placement of biliary stent is allowed)
b) Prior treatment of pancreatic cancer with cytotoxic doses of chemotherapy (patients
receiving prior treatment with chemotherapy as a radiation sensitizer are eligible if ≥ 6
months has elapsed from completion of therapy)
c) Uncontrolled CNS metastases (patients who require steroids should be on a stable or
decreasing dose)
d) Clinically significant gastrointestinal disorder including hepatic disorders, bleeding,
inflammation, occlusion, diarrhea > grade 1, malabsorption syndrome, ulcerative colitis,
inflammatory bowel disease, or partial bowel obstruction
e) History of any second malignancy in the last 3 years; patients with prior history of in-situ
cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other
malignancies are eligible if they have been continuously disease free for at least 3 years.
f) Known hypersensitivity to any of the components of nal-IRI, other liposomal products, or
any components of 5-FU, leucovorin or oxaliplatin
g) Known hypersensitivity to any of the components of nab-paclitaxel or gemcitabine (Part
2 only)
h) Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease, including:
 Severe arterial thromboembolic events (myocardial infarction, unstable angina
pectoris, stroke) less than 6 months before inclusion
 NYHA Class III or IV congestive heart failure, ventricular arrhythmias or
uncontrolled blood pressure
 Known historical or active infection with HIV, hepatitis B, or hepatitis C
i) Active infection or an unexplained fever > 38.5°C during screening visits or on the first
scheduled day of dosing (at the discretion of the investigator, patients with tumor fever
may be enrolled), which in the investigator’s opinion might compromise the patient’s
participation in the trial or affect the study outcome
j) Use of strong CYP3A4 inhibitors or inducers, or presence of any other contraindications
for irinotecan1
k) Presence of any contraindications for 5-FU, leucovorin, or oxaliplatin
l) Use of strong CYP2C8 inhibitors or inducers, or presence of any other contraindications
for nab-paclitaxel or gemcitabine (Part 2 only)
m) Any other medical or social condition deemed by the Investigator to be likely to interfere
with a patient’s ability to sign informed consent, cooperate and participate in the study, or
interfere with the interpretation of the results
n) Pregnant or breast feeding; females of child-bearing potential must test negative for
pregnancy at the time of enrollment based on a urine or serum pregnancy test. Both male and female patients of reproductive potential must agree to use a highly effective method
of birth control, during the study and for 4 months following the last dose of study drug.