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
Conditions
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.
Interventions
DRUGFluorouracil
Given IV
DRUGLeucovorin
Given IV
DRUGLiposomal Irinotecan
Given IV
PROCEDUREQuality-of-Life Assessment
Correlative studies
Sponsors
Ipsen
Roswell Park Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Within 6 months of treatment initiation | Will be summarized using frequencies and relative frequencies; with the ORR (= CR+PR / N) estimated using an 80% confidence interval obtained using Jeffrey's prior method. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Assessed by RECIST 1.1 | 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 95% confidence intervals. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Time-to Treatment Failure | 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. |
| Proportion of Patients Achieving an Objective Response Based on Prior Response to Platinum Etoposide | Up to 3 years | The objective response rate (ORR) is as described in the primary analysis. Here it is reported in the subset of patients that received prior platinum etoposide therapy. |
| Overall Survival | 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 95% confidence intervals. |
| Quality of Life (QOL) as Assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) | From treatment initiation until treatment completion/progression (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. The overall QoL rating ranges from 0 (poor) to 10 (good). |
| Incidence of Grade 3+ Treatment Related Adverse Events (TRAE) | 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. |
| Clinical Benefit Response | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Fluorouracil: Given IV
Leucovorin: Given IV
Liposomal Irinotecan: Given IV
Quality-of-Life Assessment: Correlative studies | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 66.0 years STANDARD_DEVIATION 10.7 |
| Number of Prior Chemotherapy Regimens 1 Prior Regimen | 7 Participants |
| Number of Prior Chemotherapy Regimens 2 Prior Regimens | 3 Participants |
| Number of Prior Chemotherapy Regimens No Prior Regimens | 0 Participants |
| Number of Prior Chemotherapy Regimens Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 6 / 11 |
Outcome results
Primary
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 (= CR+PR / N) estimated using an 80% confidence interval obtained using Jeffrey's prior method. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: Within 6 months of treatment initiation
Population: 2 patients were not evaluable for response.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Objective Response (CR+PR) | 1 Participants |
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | No Objective Response (SD+PD) | 8 Participants |
80% CI: [0.033, 0.301]
Secondary
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.
Time frame: Up to 3 years
Population: The appropriate data to identify patient clinical benefit status (as defined above) was not adequately obtained (no available data) and analysis can not be conducted for this outcome measure.
Secondary
Incidence of Grade 3+ Treatment Related Adverse Events (TRAE)
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
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Incidence of Grade 3+ Treatment Related Adverse Events (TRAE) | No Grade 3+ TRAE | 4 Participants |
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Incidence of Grade 3+ Treatment Related Adverse Events (TRAE) | Grade 3+ TRAE | 7 Participants |
Secondary
Overall Survival
Will be summarized using standard Kaplan-Meier methods; where estimates of the median time will be obtained with 95% 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Overall Survival | 8.3 months |
Secondary
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 95% confidence intervals. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dosing of study treatment combination to disease progression, assessed up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Progression-free Survival Assessed by RECIST 1.1 | 3.9 months |
Secondary
Proportion of Patients Achieving an Objective Response Based on Prior Response to Platinum Etoposide
The objective response rate (ORR) is as described in the primary analysis. Here it is reported in the subset of patients that received prior platinum etoposide therapy.
Time frame: Up to 3 years
Population: Only 4 patients received prior platinum etoposide.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Proportion of Patients Achieving an Objective Response Based on Prior Response to Platinum Etoposide | No Objective Response | 3 Participants |
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Proportion of Patients Achieving an Objective Response Based on Prior Response to Platinum Etoposide | Objective Response | 1 Participants |
Secondary
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. The overall QoL rating ranges from 0 (poor) to 10 (good).
Time frame: From treatment initiation until treatment completion/progression (up to 3 years).
Population: There are 11 patients that have QoL data at baseline (pre-treatment). There are only 8 patients with end of treatment QoL assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Quality of Life (QOL) as Assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) | Pre Treatment QoL | 5.9 units on a scale | Standard Deviation 1.4 |
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Quality of Life (QOL) as Assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) | End of Treatment QoL | 5.5 units on a scale | Standard Deviation 1.7 |
Comparison: Comparing the pre-treatment and end of treatment QoL scores.p-value: 0.289Sign test
Secondary
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.
Time frame: From enrollment to discontinuation of treatment, assessed up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Liposomal Irinotecan, Leucovorin, Fluorouracil) | Time-to Treatment Failure | 3.9 months |