This is a phase II, single-arm, open-label, clinical study to investigate the efficacy and tolerability of a combination of liposomal irinotecan (nal-IRI) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-nal-IRI) for treatment of patients with locally advanced pancreatic carcinoma (LAPC). Each subject will be screened for eligibility by evaluation including medical history, physical examination, performance status, blood tests, computed tomographic (CT) scans, and electrocardiogram. Within 28 days of screening, the consented subjects will have a central venous access device placed and then start treatment.
For every 2-week cycle of FOLFOX-nal-IRI, each subject will receive nal-IRI (irinotecan free base 50 mg/m2 intravenously over 90 minutes), oxaliplatin (60 mg/m2 intravenously over 2 hours), leucovorin (400 mg/m2 intravenously over 2 hours), and 5-fluorouracil 2,400 mg/m2 intravenously over 46 hours).
Tumor response/surgical assessment will be evaluated after every 4 cycles of treatment with CT scans using RECIST 1.1 criteria. If the tumor becomes surgically resectable and the subject is a surgical candidate as determined by a multidisciplinary team, the subject will undergo surgery (at which point he/she would enter survival follow-up). If the tumor remains unresectable and there is no tumor progression, each subject will be treated up to a total of 12 cycles of FOLFOX-nal-IRI.
Following treatment with 12 cycles of FOLFOX-nal-IRI, if tumor remains unresectable, the subjects may receive further treatment (chemotherapy using the same regimen or of the treating physician's choice, or chemoradiation therapy) or observation as determined by the physician. During the course of treatment, if the subjects develop unacceptable toxicity and/or disease progression, the treatment will be discontinued, and the subjects will be further managed at the discretion of the treating oncologists.
Inclusion Criteria:
- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.
- Age ≥ 18 years at the time of consent.
- ECOG Performance Status of 0-1 within 28 days prior to registration.
- Histological or cytological confirmation of pancreatic carcinoma.
- Measurable disease according to RECIST v1.1 within 28 days prior to registration.
- Previously untreated pancreatic carcinoma considered as locally advanced unresectable
according to NCCN guidelines.
- Demonstrate adequate organ function as defined in the table below; All screening labs
to be obtained within 14 days prior to initiation of study treatment.
- Hematological
- Absolute Neutrophil Count (ANC): >/=1500/uL
- Hemoglobin (Hgb): >/=8 g/dL with blood transfusion permitted
- Platelet (Plt): >/=100,000/uL
- Renal
- Serum creatinine:
- Calculated creatinine clearance using the Cockcroft-Gualt formula: >/=50
mL/min for subjects with creatinine levels >1.5 ULN
- Hepatic
- Total bilirubin:
- Aspartate aminotransferase (AST):
- Alanine aminotransferase (ALT):
- Albumin: >/=3.0 g/dL
- Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT):
- Female subjects of childbearing potential must have a negative serum pregnancy test
within 7 days of study registration and within 72 hours of Cycle 1 Day 1. NOTE: Female
subjects are considered of child bearing potential unless they are surgically sterile
(have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
or they are naturally postmenopausal for at least 12 consecutive months.
- Female subjects of childbearing potential and males must be willing to abstain from
behaviors that could lead to pregnancy (heterosexual activity, sperm donation, in
vitro fertilization, etc.) or to use 2 forms of effective methods of contraception
from the time of informed consent until 9 months (females) or 6 months (males) after
treatment discontinuation. The two contraception methods can be comprised of two
barrier methods, or a barrier method plus a hormonal method.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study. The
subject should be able to understand the purpose and risks of the study and provide a
signed and dated informed consent form.
Exclusion Criteria:
- Known hypersensitivity to irinotecan liposome, other liposomal products, oxaliplatin,
5-fluorouracil, leucovorin, or any ingredients in those preparations.
- Pre-existing peripheral neuropathy (Grade 3 or 4) during screening.
- Major surgery within 4 weeks of starting treatment.
- Active uncontrolled cardiac arrhythmia or congestive heart failure (class 3 or 4 as
defined by the New York Heart Association Functional Classification); or history of
myocardial infarction, unstable angina; or acute coronary syndrome within 6 months
prior to enrollment.
- Known history of human immunodeficiency virus (HIV), or hepatic cirrhosis caused by
active infection with hepatitis B virus (HBV, as defined by HBsAg positivity or
positive DNA). Testing is not required for study entry if there is no clinical
suspicion. Note: hepatic cirrhosis caused by other factors (ex. alcoholic cirrhosis)
may be considered on a case-by-case basis if, in the opinion of the treating
investigator, the disease is unlikely to compromise the subject's safety or put the
study outcomes at unnecessary risk.
- Any medical condition, life-threatening illness, or organ dysfunction, which in the
investigator's opinion, can compromise the subject's safety or put the study outcomes
at unnecessary risk.
- Uncontrolled active systemic infection.
- Concomitant medications that are prohibited in this study and they cannot be switched
to alternative medications.
- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
- Known additional malignancy that is active and/or progressive requiring treatment
within 2 years of screening for this study; exceptions include basal cell or squamous
cell skin cancer, in situ cervical or bladder cancer, low-grade prostate cancer, or
other cancer for which the subject has been disease-free for at least five years.
Additional exceptions could be considered if agreed by sponsor-investigator and site
investigator assuming the disease is considered extremely unlikely to confound
evaluation of disease status.
- Treatment with any investigational drug within 30 days prior to registration, or
within a time interval less than at least 5 half-lives of the investigational agent,
whichever is longer, prior to the first scheduled day of dosing of this study.
