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

Phase 2

Completed

Conditions: Locally Advanced Pancreatic Carcinoma(LAPC)

Interventions: Drug: FOLFOX regimen
Drug: Liposomal Irinotecan

Registration Number: NCT03861702

Lead Sponsor: Nelson Yee

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
FOLFOX + Irinotecan	Liposomal Irinotecan	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.
FOLFOX + Irinotecan	FOLFOX regimen	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.

Primary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR)	Up to 22 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Disease Control Rate (DCR) = CR +PR+SD

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) at 24 Weeks	24 weeks	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Overall Response (OR) = CR + PR.
Stable Disease Rate (SDR) at 8 Weeks	8 Weeks	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Stable disease rate (SDR) is 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.
Stable Disease Rate (SDR) at 16 Weeks	16 Weeks	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. 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.
Stable Disease Rate (SDR) at 24 Weeks	24 Weeks	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. 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.
Proportion of Subjects Able to Undergo Surgical Resection	12 months	Rate of resectability as determined by the proportion of subjects who undergo surgical resection of tumors.
Response of Serum CA19-9 Levels	Up to 7 months	A CA 19-9 test measures the amount of a protein called CA19-9 (cancer antigen 19-9) in a sample of blood. Healthy people can have small amounts of CA 19-9 in their blood. High levels of CA 19-9 are often a sign of pancreatic cancer. Increasing CA 19-9 levels mean the tumor is growing, whether decreasing CA 19-9 levels may mean the tumor is shrinking. The Mean of the percentage change from baseline in serum CA19-9 levels associated with best confirmed response (PR, SD, PD) per RECIST 1.1 are reported in the outcome measure data table.
Progression-Free Survival (PFS)	Up to 22 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. 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.
Overall Survival (OS)	Up to 31 months	Overall survival (OS) is defined as time from the first dose of study drug to date of death from any cause.
Number of Participants With Adverse Events	Up to 7 months	Adverse events will be assessed to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Quality of Life (QoL) Assessment: Global Health Status (EORTC QLQ-C30)	Treatment Cycle 1 (14 days), Treatment Cycle 5 (70 days), Treatment Cycle 9 (126 days), Follow-Up (7 Months)	This secondary outcome measure evaluates overall quality of life using the Global Health Status scale from the EORTC QLQ-C30. Scores range from 0 to 100, with higher scores indicating better global health and quality of life. Mean (SD) scores are reported by assessment period, including only those participants who reached the defined time points (e.g., Cycle 9).
Objective Response Rate (ORR) at 8 Weeks	8 weeks	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Overall Response (OR) = CR + PR.
Objective Response Rate (ORR) at 16 Weeks	16 weeks	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Overall Response (OR) = CR + PR.

Trial Locations

Locations (4): Northwestern University Feinberg School of Medicine
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Chicago, Illinois, United States
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
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Indianapolis, Indiana, United States
Rutgers Cancer Institute of new Jersey
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New Brunswick, New Jersey, United States
Penn State Cancer Institute
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Hershey, Pennsylvania, United States