Comparing Two Treatment Combinations, Gemcitabine and Nab-Paclitaxel With 5-Fluorouracil, Leucovorin, and Liposomal Irinotecan for Older Patients With Pancreatic Cancer That Has Spread

Study Overview
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Brief Summary
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This phase II trial compares two treatment combinations: gemcitabine hydrochloride and nab-paclitaxel, or fluorouracil, leucovorin calcium, and liposomal irinotecan in older patients with pancreatic cancer that has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as gemcitabine hydrochloride, nab-paclitaxel, fluorouracil, leucovorin calcium, and liposomal irinotecan, 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. This study may help doctors find out which treatment combination is better at prolonging life in older patients with metastatic pancreatic cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. Overall survival. SECONDARY OBJECTIVES: I. Progression-free survival. II. Objective tumor response. III. Comprehensive Geriatric Assessment (CGA)/quality of life (QOL) related objectives: IIIa. Hypothesize that lower scores in functional status assessment tool - instrumental activities of daily living (IADL) will correlate with higher rates of grade 3 or higher chemotherapy toxicity. IV. CGA/QOL related exploratory objectives: IVa. Evaluation of other pre-treatment CGA domains including co-morbidities, depression, nutrition and cognition as predictors of chemotherapy tolerance. IVb. Evaluation of the association between change in functional status during treatment course (comparison between activities of daily living [ADL] and IADL score pre-treatment and at time of disease evaluation) as predictors of chemotherapy tolerance. IVc. Evaluation of the correlation between CGA domains and overall survival by treatment arm. IVd. Evaluation of the difference in QOL scores (Functional Assessment of Cancer Therapy - Hepatitis [FACT-Hep] version 4) between baseline measures and assessment during treatment course between by treatment arms. V. Focused evaluation of toxicities that are of interest for older patients including: peripheral neuropathy, fatigue, falls, emergency room visits, hospitalization, treatment modification and discontinuation. VI. Imaging correlative study objectives: VIa. Evaluate the association between baseline and change during treatment of skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and rates of grade 3 or higher chemotherapy toxicity experienced on treatment. VIb. Evaluate the association between baseline and change during treatment of skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and overall survival among older patients with metastatic pancreatic cancer. VIc. Evaluate the association between baseline and change during treatment of skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and geriatric assessment scores evaluating functional status. VII. Laboratory correlative study objectives: VIIa. Evaluation of the correlation between base line levels of biomarkers of aging (CRP and IL-6) and rates of grade 3 or higher chemotherapy toxicity during therapy. VIIb. Evaluation of the correlation between changes in levels of CRP and IL-6 during therapy and rates of grade 3 chemotherapy toxicity. VIIc. Evaluation of the correlation between baseline levels of biomarkers of aging (CRP and IL-6) and overall survival among older patients with metastatic pancreatic cancer. VIId. Evaluation of the correlation between levels of baseline biomarkers of aging (CRP and IL-6) and geriatric assessments scores evaluation functional status. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive gemcitabine intravenously (IV) over 30 minutes and nab-paclitaxel IV over 30 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive fluorouracil IV over 46 hours starting on day 1. Patients also receive leucovorin IV over 90-120 minutes and liposomal irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
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A Randomized Phase II Study of Gemcitabine and Nab-Paclitaxel Compared With 5-Fluorouracil, Leucovorin, and Liposomal Irinotecan in Older Patients With Treatment Naïve Metastatic Pancreatic Cancer (GIANT)

Conditions
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Metastatic Pancreatic Adenocarcinoma, Stage IV Pancreatic Cancer AJCC v8

Intervention / Treatment
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* Drug: Fluorouracil
* Drug: Gemcitabine
* Drug: Gemcitabine Hydrochloride
* Drug: Leucovorin
* Drug: Leucovorin Calcium
* Drug: Liposomal Irinotecan
* Drug: Nab-paclitaxel
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided radiation therapy is completed at least 2 weeks prior to registration and adjuvant therapy was administered more than 6 months prior to registration. Patients with the following histology are excluded: acinar cell; adenosquamous carcinoma Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patient is an English speaker with the ability to understand and complete the informed consent and questionnaires Leukocytes >= 3,000/mcL (obtained within 4 weeks of registration) Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks of registration) Platelets >= 100,000/mcL (obtained within 4 weeks of registration) Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks of registration) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 4 weeks of registration) Creatinine =< institutional ULN unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of registration) Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of registration) Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this protocol. HIV positive (+) patients who are on ritonavir or/and cobicistat-based regimen must be switched to alternative anti-retroviral therapy (ART) For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Male patients must agree not to father children while on study Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this protocol, patients should be class 2B or better Patients must have measurable disease and scans must be done within 4 weeks of registration Patients classified to have mild-moderate abnormalities in any of the domains evaluated in the screening geriatric assessment and are classified as vulnerable are eligible. Patients classified without any abnormalities (fit) or with severe cognitive/functional impairment or high co-morbidity score (frail) on the screening geriatric assessment are ineligible Patients must agree not to take any medications or substances that are strong inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan treatment arm should avoid drugs that are UGT1A1 inhibitors

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (gemcitabine, nab-paclitaxel)<br>Patients receive gemcitabine IV over 30 minutes and nab-paclitaxel IV over 30 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: protein-bound paclitaxel;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm B (fluorouracil, leucovorin, liposomal irinotecan)<br>Patients receive fluorouracil IV over 46 hours starting on day 1. Patients also receive leucovorin IV over 90-120 minutes and liposomal irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: Liposomal Irinotecan<br>* Given IV<br>* Other names: PEP02;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will use a stratified log rank test with one-sided alpha of 0.05 and 90% power. A truncated O'Brien-Fleming boundary will be used to control type I error for efficacy testing and repeated confidence interval methodology on the OS hazard ratio will be used for futility analyses | Up to 2 years post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Instrumental Activities of Daily Living (IADL) | Will evaluate the association between functional status as recorded by the IADL assessment tool and rates of grade 3 or higher chemotherapy toxicity within treatment arm. Will use logistic regression and a 0.025 level one-sided test for the odds ratio. | Up to 2 years post treatment |