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Liposomal Irinotecan, Fluorouracil and Leucovorin in Treating Patients With Refractory Advanced High Grade Neuroendocrine Cancer of Gastrointestinal, Unknown, or Pancreatic Origin

Primary Purpose

Locally Advanced Digestive System Neuroendocrine Carcinoma, Locally Advanced Pancreatic Neuroendocrine Carcinoma, Metastatic Digestive System Neuroendocrine Carcinoma

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fluorouracil
Leucovorin
Liposomal Irinotecan
Quality-of-Life Assessment
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Digestive System Neuroendocrine Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participant must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma of the gastrointestinal (GI) tract, pancreas, or of other known or unknown primary site where 5FU based therapy would be considered reasonable by the treated MD, lung primary is excluded. Patients may have either progressed on therapy or within 6 months of completing therapy, or be intolerant of therapy to be considered eligible.
  • Participant must have tissue available for central pathology review and, must have pathologically/histologically confirmed high grade neuro endocrine defined as Ki-67 proliferative index of 20-100% or, must have evidence of at least 10 mitotic figures per 10 high powered fields.
  • Comprehensive Genomic Profiling will be performed on archival tissue available prior to enrollment. If no archival tissue is available, then patient must have fresh biopsy prior to treatment administration if clinically indicated.
  • Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2.
  • Leukocytes >= 3,000/mm^3 .
  • Absolute neutrophil count >= 1,500/mm^3.
  • Hemoglobin >= 9 g/dL.
  • Platelets >= 100,000/mm^3.
  • Total bilirubin =< institutional upper limit of normal (ULN) or =< 1.5 x institutional ULN (if the patient has liver metastases.
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN or (=< 5 x institutional ULN if the patient has liver metastases).
  • Serum creatinine =< 1.5 x institutional ULN or measured or calculated creatinine clearance by Cockcroft Gault Equation >= 50ml/min for subjects with creatinine levels > 1.5 x ULN.
  • Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present.
  • Participant must have a life expectancy of >= 12 weeks as determined clinically by the treating physician.
  • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
    • Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study.
  • Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

Exclusion Criteria:

  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  • Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency.
  • Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  • Known hypersensitivity to any of the components of Nal-IRI, other liposomal products, fluoropyrimidines or leucovorin.
  • Investigational therapy administered within 4 weeks, 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 in this study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant or nursing female participants.
  • Unwilling or unable to follow protocol requirements.
  • Any condition which in the Investigator?s opinion deems the participant an unsuitable candidate to receive study drug.

Sites / Locations

  • Roswell Park Cancer Institute
  • Stony Brook Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (liposomal irinotecan, leucovorin, fluorouracil)

Arm Description

Patients receive liposomal irinotecan IV over 90 minutes, leucovorin IV over 30 minutes, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 28 days for in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Will be summarized using frequencies and relative frequencies; with the ORR estimated using an 80% confidence interval obtained using Jeffrey?s prior method.

Secondary Outcome Measures

Overall survival
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Progression-free survival assessed by RECIST 1.1
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Time-to treatment failure
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Proportion of patients achieving an objective response based on prior response to platinum etoposide
Clinical benefit response
Defined as either achievement of pronounced and sustained (>=4 weeks contiguous) improvement in pain intensity, analgesic consumption, or performance status, or a combination of these, without any worsening in any of the other factors, or stability in pain intensity, analgesic consumption, and performance status with pronounced and sustained (>= 4 weeks contiguous) weight gain. Will be treated as binary data and summarized using frequencies and relative frequencies. The clinical benefit response rate will be estimated using a 90% confidence interval obtained by Jeffrey?s prior method.
Quality of life (QOL) as assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30)
Will be treated as quantitative data and summarized by time-point using the mean and standard deviation. The QOL scores at each follow-up time may be compared with base-line levels using the paired t-test or sign test.
Incidence of adverse events
Toxicities and adverse events will be summarized by attribution and grade using frequencies and relative frequencies. High grade (3+) toxicity and adverse event rates may be estimated using 90% confidence intervals obtained by Jeffrey?s prior method. Data Safety Monitoring Board (DSMB) monitoring will also occur periodically to ensure safety of study subjects.

Full Information

First Posted
November 5, 2018
Last Updated
March 23, 2023
Sponsor
Roswell Park Cancer Institute
Collaborators
Ipsen
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1. Study Identification

Unique Protocol Identification Number
NCT03736720
Brief Title
Liposomal Irinotecan, Fluorouracil and Leucovorin in Treating Patients With Refractory Advanced High Grade Neuroendocrine Cancer of Gastrointestinal, Unknown, or Pancreatic Origin
Official Title
Phase 2 Single-Arm Study of Nanoliposomal Irinotecan With Fluorouracil and Leucovorin in Refractory Advanced High Grade Neuroendocrine Cancer of GI, Unknown or Pancreatic Origin
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 17, 2019 (Actual)
Primary Completion Date
October 18, 2022 (Actual)
Study Completion Date
June 17, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute
Collaborators
Ipsen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well liposomal irinotecan, leucovorin, and fluorouracil work in treating patients with high grade neuroendocrine cancer of gastrointestinal, unknown, or pancreatic origin that does not respond to treatment and has spread to other places in the body. Lliposomal irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving liposomal irinotecan, leucovorin and fluorouracil may work better in treating patients with neuroendocrine cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the objective response rate liposomal irinotecan (nanoliposomal irinotecan [Nal-IRI]) + fluorouracil (5FU) and leucovorin in patients with refractory advanced high grade neuroendocrine cancer of gastrointestinal (GI), unknown or pancreatic origin. SECONDARY OBJECTIVES: I. To determine overall survival, progression-free survival, time to treatment failure, safety, clinical response and, quality of life (QOL) changes resulting from the combination treatment of nanoliposomal irinotecan (Nal-IRI) + fluorouracil (5FU) and leucovorin. EXPLORATORY OBJECTIVES: I. Genetic profiling for mutations will be conducted on all pre-study tumor samples and compared to changes in immune response. OUTLINE: Patients receive liposomal irinotecan intravenously (IV) over 90 minutes, leucovorin IV over 30 minutes, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 28 days for in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days, then every 2 months thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Digestive System Neuroendocrine Carcinoma, Locally Advanced Pancreatic Neuroendocrine Carcinoma, Metastatic Digestive System Neuroendocrine Carcinoma, Metastatic Pancreatic Neuroendocrine Carcinoma, Refractory Digestive System Neuroendocrine Carcinoma, Refractory Pancreatic Neuroendocrine Carcinoma, Unresectable Digestive System Neuroendocrine Carcinoma, Unresectable Pancreatic Neuroendocrine Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (liposomal irinotecan, leucovorin, fluorouracil)
Arm Type
Experimental
Arm Description
Patients receive liposomal irinotecan IV over 90 minutes, leucovorin IV over 30 minutes, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 28 days for in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Fluorouracil
Other Intervention Name(s)
5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
Folinic acid
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Liposomal Irinotecan
Other Intervention Name(s)
Irinotecan Liposome, MM-398, nal-IRI, Nanoliposomal Irinotecan, Nanoparticle Liposome Formulation of Irinotecan, Onivyde, PEP02
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Quality-of-Life Assessment
Other Intervention Name(s)
Quality of Life Assessment
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Description
Will be summarized using frequencies and relative frequencies; with the ORR estimated using an 80% confidence interval obtained using Jeffrey?s prior method.
Time Frame
Within 6 months of treatment initiation
Secondary Outcome Measure Information:
Title
Overall survival
Description
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Time Frame
From first dosing of study treatment combination to time of death or imitation of a new therapy, assessed up to 3 years
Title
Progression-free survival assessed by RECIST 1.1
Description
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Time Frame
From first dosing of study treatment combination to disease progression, assessed up to 3 years
Title
Time-to treatment failure
Description
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Time Frame
From enrollment to discontinuation of treatment, assessed up to 3 years
Title
Proportion of patients achieving an objective response based on prior response to platinum etoposide
Time Frame
Up to 3 years
Title
Clinical benefit response
Description
Defined as either achievement of pronounced and sustained (>=4 weeks contiguous) improvement in pain intensity, analgesic consumption, or performance status, or a combination of these, without any worsening in any of the other factors, or stability in pain intensity, analgesic consumption, and performance status with pronounced and sustained (>= 4 weeks contiguous) weight gain. Will be treated as binary data and summarized using frequencies and relative frequencies. The clinical benefit response rate will be estimated using a 90% confidence interval obtained by Jeffrey?s prior method.
Time Frame
Up to 3 years
Title
Quality of life (QOL) as assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30)
Description
Will be treated as quantitative data and summarized by time-point using the mean and standard deviation. The QOL scores at each follow-up time may be compared with base-line levels using the paired t-test or sign test.
Time Frame
Up to 3 years
Title
Incidence of adverse events
Description
Toxicities and adverse events will be summarized by attribution and grade using frequencies and relative frequencies. High grade (3+) toxicity and adverse event rates may be estimated using 90% confidence intervals obtained by Jeffrey?s prior method. Data Safety Monitoring Board (DSMB) monitoring will also occur periodically to ensure safety of study subjects.
Time Frame
Up to 3 years
Other Pre-specified Outcome Measures:
Title
molecular profiling for mutations, immune-oncology Will be conducted on all pre-study tumor samples and will be compared to patient treatment outcome.
Description
Genetic profiling
Time Frame
Up to 3 years
Title
molecular profiling for select protein expression biomarker ERCC1
Description
Genetic profiling for mutations
Time Frame
Up to 3 years
Title
molecular profiling for select protein expression biomarker MGMT
Description
Genetic profiling for mutations
Time Frame
Up to 3 years
Title
Molecular profiling for select protein expression biomarker PD-L1
Description
Genetic profiling for mutations
Time Frame
Up to 3 years
Title
Molecular profiling for select protein expression biomarker TOP2A
Description
Genetic profiling for mutations
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participant must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma of the gastrointestinal (GI) tract, pancreas, or of other known or unknown primary site where 5FU based therapy would be considered reasonable by the treated MD, lung primary is excluded. Patients may have either progressed on therapy or within 6 months of completing therapy, or be intolerant of therapy to be considered eligible. Participant must have tissue available for central pathology review and, must have pathologically/histologically confirmed high grade neuro endocrine defined as Ki-67 proliferative index of 20-100% or, must have evidence of at least 10 mitotic figures per 10 high powered fields. Comprehensive Genomic Profiling will be performed on archival tissue available prior to enrollment. If no archival tissue is available, then patient must have fresh biopsy prior to treatment administration if clinically indicated. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2. Leukocytes >= 3,000/mm^3 . Absolute neutrophil count >= 1,500/mm^3. Hemoglobin >= 9 g/dL. Platelets >= 100,000/mm^3. Total bilirubin =< institutional upper limit of normal (ULN) or =< 1.5 x institutional ULN (if the patient has liver metastases. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN or (=< 5 x institutional ULN if the patient has liver metastases). Serum creatinine =< 1.5 x institutional ULN or measured or calculated creatinine clearance by Cockcroft Gault Equation >= 50ml/min for subjects with creatinine levels > 1.5 x ULN. Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present. Participant must have a life expectancy of >= 12 weeks as determined clinically by the treating physician. Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study. Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure. Exclusion Criteria: Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known hypersensitivity to any of the components of Nal-IRI, other liposomal products, fluoropyrimidines or leucovorin. Investigational therapy administered within 4 weeks, 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 in this study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant or nursing female participants. Unwilling or unable to follow protocol requirements. Any condition which in the Investigator?s opinion deems the participant an unsuitable candidate to receive study drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Renuka Iyer
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Stony Brook Cancer Center
City
Stony Brook
State/Province
New York
ZIP/Postal Code
11794
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33835977
Citation
Abstracts Presented at the 13th Annual Multidisciplinary Neuroendocrine Tumor Medical Virtual Symposium of the North American Neuroendocrine Tumor Society, October 2-3, 2020. Pancreas. 2021 Mar 1;50(3):441-467. doi: 10.1097/MPA.0000000000001763. No abstract available.
Results Reference
derived

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Liposomal Irinotecan, Fluorouracil and Leucovorin in Treating Patients With Refractory Advanced High Grade Neuroendocrine Cancer of Gastrointestinal, Unknown, or Pancreatic Origin

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