Liposomal Irinotecan in Combination With Oxaliplatin, Leucovorin, and 5-fluorouracil for Patients With Locally Advanced Pancreatic Carcinoma:

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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A Phase II Study to Evaluate the Efficacy of Liposomal Irinotecan in Combination With Oxaliplatin, Leucovorin, and 5-fluorouracil for Patients With Locally Advanced Pancreatic Carcinoma: Big Ten Cancer Research Consortium BTCRC-GI15-067

Conditions
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Locally Advanced Pancreatic Carcinoma(LAPC)

Intervention / Treatment
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* Drug: FOLFOX regimen
* Drug: Liposomal Irinotecan


Participation Criteria
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Eligibility Criteria
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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: </=1.5 x upper limit of normal (ULN) OR Calculated creatinine clearance using the Cockcroft-Gualt formula: >/=50 mL/min for subjects with creatinine levels >1.5 ULN Hepatic Total bilirubin: </=1.5 x ULN (biliary drainage is allowed for biliary obstruction). Patients with Gilbert's syndrome with a total bilirubin </=3.0 x ULN and direct bilirubin within normal limits are permitted Aspartate aminotransferase (AST): </=2.5 x ULN Alanine aminotransferase (ALT): </=2.5 x ULN Albumin: >/=3.0 g/dL Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT): </=1.5 x ULN unless subject is receiving anticoagulant therapy, as long as PT, INR or PTT is within therapeutic range of intended use of anticoagulants 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a phase II, single-arm, open-label, clinical study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOX + Irinotecan<br>Oxaliplatin 60 mg/m2 Intravenously (IV) over 2 hours Liposomal Irinotecan (free base) 50 mg/m2 IV over 90 minutes after completion of oxaliplatin Leucovorin 400 mg/m2 IV over 30 minutes after completion of liposomal irinotecan 5-Fluorouracil 2,400 mg/m2 IV over 46 hours via infusion pump at home All drugs administered on day 1 of each 14 day cycle. | Drug: FOLFOX regimen<br>* FOLFOX (Oxaliplatin, Leucovorin, 5-Fluorouracil)<br>Drug: Liposomal Irinotecan<br>* Liposomal Irinotecan<br>* Other names: nal-Irinotecan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | Disease Control Rate (DCR) as determined by the proportion of subjects with complete response, partial response, or stable disease, as defined by RECIST 1.1 at 24 weeks for nal-IRI in combination with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-nal-IRI), in subjects with locally advanced pancreatic carcinoma (for the subjects whose tumors remain unresectable following 12 cycles of FOLFOX-nal-IRI). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) at 8 Weeks | Objective response rate (ORR) as determined by the proportion of subjects with either complete response or partial response, as defined by RECIST 1.1, at 8 weeks following initiation of FOLFOX-nal-IRI. | 8 weeks | 
| Objective Response Rate (ORR) at 16 Weeks | Objective response rate (ORR) as determined by the proportion of subjects with either complete response or partial response, as defined by RECIST 1.1, at 16 weeks following initiation of FOLFOX-nal-IRI. | 16 weeks | 
| Objective Response Rate (ORR) at 24 Weeks | Objective response rate (ORR) as determined by the proportion of subjects with either complete response or partial response, as defined by RECIST 1.1, at 24 weeks following initiation of FOLFOX-nal-IRI. | 24 weeks | 
| Stable Disease Rate (SDR) at 8 Weeks | Stable disease rate (SDR) as determined by the proportion of subjects with no progression of disease as defined by RECIST 1.1, at 8 weeks following initiation of FOLFOX-nal-IRI. | 8 Weeks | 
| Stable Disease Rate (SDR) at 16 Weeks | Stable disease rate (SDR) as determined by the proportion of subjects with no progression of disease as defined by RECIST 1.1, at 16 weeks following initiation of FOLFOX-nal-IRI. | 16 Weeks | 
| Stable Disease Rate (SDR) at 24 Weeks | Stable disease rate (SDR) as determined by the proportion of subjects with no progression of disease as defined by RECIST 1.1, at 24 weeks following initiation of FOLFOX-nal-IRI. | 24 Weeks | 
| Proportion of Subjects able to undergo surgical resection | Rate of resectability as determined by the proportion of subjects who undergo surgical resection of tumors. | 6 months | 
| Response of serum CA19-9 levels | The serum levels of CA19-9 prior to initiation of chemotherapy and after every 2 cycles (every 4 weeks) following initiation of FOLFOX-nal-IRI. | Every 4 weeks, up to 6 months | 
| Progression-Free Survival (PFS) | Progression-free survival (PFS) as determined by the time interval from the date of first dose of study drug to first documented disease progression or death from any cause, whichever occurs first, if evaluable. | 18 months | 
| Overall Survival (OS) | Overall survival (OS) as defined as the time interval from the date of the first dose of study drug to date of death from any cause. | 18 months | 
| Adverse Events | Describe safety and tolerability of (FOLFOX-nal-IRI) by reporting Grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5. | 6 months | 
| Quality of Life Assessment | Quality of life as measured at baseline and after every 4 cycles (every 8 weeks) using the European Organization for Research and Treatment of Cancer Quality-of-Life Core Questionnaire (EORTC-QLQ-C30). | 6 months |