Clinical Trials /

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

NCT03736720

Description:

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.

Related Conditions:
  • Gastrointestinal Neuroendocrine Tumors
  • Neuroendocrine Carcinoma of Unknown Primary
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: i 64518
  • SECONDARY ID: NCI-2018-02122
  • SECONDARY ID: i 64518
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT03736720

Conditions

  • 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

Interventions

DrugSynonymsArms
Fluorouracil5-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-2-9757Treatment (liposomal irinotecan, leucovorin, fluorouracil)
LeucovorinFolinic acidTreatment (liposomal irinotecan, leucovorin, fluorouracil)
Liposomal IrinotecanIrinotecan Liposome, MM-398, nal-IRI, Nanoliposomal Irinotecan, Nanoparticle Liposome Formulation of Irinotecan, Onivyde, PEP02Treatment (liposomal irinotecan, leucovorin, fluorouracil)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (liposomal irinotecan, leucovorin, fluorouracil)ExperimentalPatients 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.
  • Fluorouracil
  • Leucovorin
  • Liposomal Irinotecan

Eligibility 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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame:Within 6 months of treatment initiation
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Measure: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
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Measure:Time-to treatment failure
Time Frame:From enrollment to discontinuation of treatment, assessed up to 3 years
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 90% confidence intervals.
Measure:Proportion of patients achieving an objective response based on prior response to platinum etoposide
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Clinical benefit response
Time Frame:Up to 3 years
Safety Issue:
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.
Measure: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
Safety Issue:
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.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

July 7, 2020