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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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ClinicalTrials.gov Identifier: NCT03736720
Recruitment Status : Recruiting
First Posted : November 9, 2018
Last Update Posted : July 1, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Ipsen
Information provided by (Responsible Party):
Roswell Park Cancer Institute

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.

Condition or disease Intervention/treatment Phase
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 Drug: Fluorouracil Drug: Leucovorin Drug: Liposomal Irinotecan Procedure: Quality-of-Life Assessment Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 17, 2019
Estimated Primary Completion Date : September 5, 2021
Estimated Study Completion Date : September 5, 2022


Arm Intervention/treatment
Experimental: Treatment (liposomal irinotecan, leucovorin, fluorouracil)
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.
Drug: Fluorouracil
Given IV
Other Names:
  • 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

Drug: Leucovorin
Given IV
Other Name: Folinic acid

Drug: Liposomal Irinotecan
Given IV
Other Names:
  • Irinotecan Liposome
  • MM-398
  • nal-IRI
  • Nanoliposomal Irinotecan
  • Nanoparticle Liposome Formulation of Irinotecan
  • Onivyde
  • PEP02

Procedure: Quality-of-Life Assessment
Correlative studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Within 6 months of treatment initiation ]
    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 :
  1. Overall survival [ Time Frame: From first dosing of study treatment combination to time of death or imitation of a new therapy, assessed up to 3 years ]
    Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.

  2. Progression-free survival assessed by RECIST 1.1 [ Time Frame: From first dosing of study treatment combination to disease progression, assessed up to 3 years ]
    Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.

  3. Time-to treatment failure [ Time Frame: From enrollment to discontinuation of treatment, assessed up to 3 years ]
    Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.

  4. Proportion of patients achieving an objective response based on prior response to platinum etoposide [ Time Frame: Up to 3 years ]
  5. Clinical benefit response [ Time Frame: Up to 3 years ]
    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.

  6. Quality of life (QOL) as assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) [ Time Frame: Up to 3 years ]
    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.

  7. Incidence of adverse events [ Time Frame: Up to 3 years ]
    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.


Other Outcome Measures:
  1. molecular profiling for mutations, immune-oncology Will be conducted on all pre-study tumor samples and will be compared to patient treatment outcome. [ Time Frame: Up to 3 years ]
    Genetic profiling

  2. molecular profiling for select protein expression biomarker ERCC1 [ Time Frame: Up to 3 years ]
    Genetic profiling for mutations

  3. molecular profiling for select protein expression biomarker MGMT [ Time Frame: Up to 3 years ]
    Genetic profiling for mutations

  4. Molecular profiling for select protein expression biomarker PD-L1 [ Time Frame: Up to 3 years ]
    Genetic profiling for mutations

  5. Molecular profiling for select protein expression biomarker TOP2A [ Time Frame: Up to 3 years ]
    Genetic profiling for mutations



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma of the gastrointestinal (GI) tract, or of unknown primary that has been previously treated with platinum etoposide or temozolomide and capecitabine: 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 or legal representative 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.
  • Participants must NOT have previous or concurrent malignancy: exceptions are made for patients who meet any of the following conditions:

    • Non-melanoma skin cancer.
    • In situ cervical cancer.
    • Superficial bladder cancer.
    • Breast cancer in situ.
    • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03736720


Locations
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United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Renuka V. Iyer    716-845-8195    Renuka.Iyer@roswellpark.org   
Principal Investigator: Renuka V. Iyer         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Ipsen
Investigators
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Principal Investigator: Renuka Iyer Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT03736720     History of Changes
Other Study ID Numbers: i 64518
NCI-2018-02122 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
i 64518 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: November 9, 2018    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: June 2019

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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

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Neuroendocrine
Carcinoma, Islet Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Irinotecan
Fluorouracil
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs