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.
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
Drug | Synonyms | Arms |
---|
Fluorouracil | 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 | Treatment (liposomal irinotecan, leucovorin, fluorouracil) |
Leucovorin | Folinic acid | Treatment (liposomal irinotecan, leucovorin, fluorouracil) |
Liposomal Irinotecan | Irinotecan Liposome, MM-398, nal-IRI, Nanoliposomal Irinotecan, Nanoparticle Liposome Formulation of Irinotecan, Onivyde, PEP02 | Treatment (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
Name | Type | Description | Interventions |
---|
Treatment (liposomal irinotecan, leucovorin, fluorouracil) | Experimental | 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. | - 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 other known or unknown primary site 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 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
May 4, 2021