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

• ClinicalTrials.gov Identifier: NCT04233866
• Recruitment Status: Recruiting
• First Posted: January 18, 2020
• Last Update Posted: April 3, 2023
• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

Tracking Information

• First Submitted Date: January 16, 2020
• First Posted Date: January 18, 2020
• Last Update Posted Date: April 3, 2023
• Actual Study Start Date: June 18, 2020
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 16, 2020)

Overall survival (OS) [ Time Frame: Up to 2 years post treatment ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 16, 2020)

Instrumental Activities of Daily Living (IADL) [ Time Frame: Up to 2 years post treatment ]

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.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: January 16, 2020)

• Progression-free survival (PFS) [ Time Frame: Up to 2 years post treatment ]
• Objective tumor response [ Time Frame: Up to 2 years post treatment ]
• Co-morbidities as a predictor of chemotherapy tolerance [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
• Depression as a predictor of chemotherapy tolerance [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
• Nutrition as a predictor of chemotherapy tolerance [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
• Cognition as a predictor of chemotherapy tolerance [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
• Change in functional status [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association between changes in functional status using a geriatric assessment, which will include the number of falls, cumulative illness rating scale, body mass index, weight loss and scores, such as the geriatric depression scale, and the blessed orientation memory concentration test. These will be treated as continuous measures as predictors of chemotherapy tolerance and will be assessed using a paired t-test. Longitudinal analyses will be conducted to evaluate the trajectory of patient-reported outcomes over time for each arm and to compare across the arms. Will explore the possibility that geriatric assessments at baseline that are prognostic for subsequent adverse events of interest, and will perform regression models for key adverse events (logistic, Poisson or linear regression as appropriate) to assess the relative predictive ability of the proposed geriatric assessments over those traditionally used to identify patients at risk.
• Comprehensive Geriatric Assessment (CGA) domains [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the correlation between CGA domains and overall survival by treatment arm.
• Quality of life scores [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will be assessed as a continuous variable by the Functional Assessment of Cancer Treatment - Hepatitis version 4 between baseline measures and assessment during treatment course by treatment arms.
• Incidence of toxicities in older patients [ Time Frame: Up to 2 years post treatment ]
  Will include peripheral neuropathy grade 2 or higher, fatigue grade 3 or higher, falls, emergency room visits, hospitalization, treatment modification and discontinuation. These data will be obtained and recorded by the study nurse while conducting the patient's toxicity evaluation using the National Cancer Institute Common Terminology Criteria for Adverse Events.
• Rate of grade 3 or higher chemotherapy toxicity experienced on treatment [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association between skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and rate of grade 3 or higher chemotherapy toxicity. In a preliminary analysis, the longitudinal course of SMI and IMAT will be examined graphically and use longitudinal regression modeling to account for correlations due to the repeated assessments. The main analysis will utilize logistic regression modeling. Models will be fitted first with only the baseline values of SMI and IMAT and subsequently will be elaborated to include both baseline and change from baseline. The models will control for sociodemographic and clinical status measures at baseline and will also consider interactions between the two imaging-based markers
• OS [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association between SMI and IMAT and OS. In a preliminary analysis, the longitudinal course of SMI and IMAT will be examined graphically and use Cox regression modeling to account for correlations due to the repeated assessments. The main analysis will utilize logistic regression modeling. Models will be fitted first with only the baseline values of SMI and IMAT and subsequently will be elaborated to include both baseline and change from baseline. The models will control for sociodemographic and clinical status measures at baseline and will also consider interactions between the two imaging-based markers.
• Geriatric assessment scores [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association between skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and geriatric assessment scores evaluating functional status. In a preliminary analysis, the longitudinal course of SMI and IMAT will be examined graphically and linear regression modeling to account for correlations due to the repeated assessments. The main analysis will utilize logistic regression modeling. Models will be fitted first with only the baseline values of SMI and IMAT and subsequently will be elaborated to include both baseline and change from baseline. The models will control for sociodemographic and clinical status measures at baseline and will also consider interactions between the two imaging-based markers
• Toxicity and biomarkers of aging (CRP and IL-6) [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association between biomarkers of aging (CRP and IL-6) and rates of grade 3 or higher chemotherapy toxicity. Will be analyzed as continuous variables and correlated with clinical outcomes. Analysis of interaction with treatment arm will be performed but power for these effects is lower as the study is not designed to detect interactions. Logistic regression will be used to determine if levels of these biomarkers serve as predictors of toxicity or binary measures of efficacy (response).
• Changes in levels of CRP and IL-6 and toxicity [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association correlation between changes in levels of CRP and IL-6 and rates of grade 3 chemotherapy toxicity. Will be analyzed as continuous variables and correlated with clinical outcomes. Analysis of interaction with treatment arm will be performed but power for these effects is lower as the study is not designed to detect interactions. Logistic regression will be used to determine if levels of these biomarkers serve as predictors of toxicity or binary measures of efficacy (response).
• OS and biomarkers of aging (CRP and IL-6) [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association correlation between changes in levels of CRP and IL-6 and overall survival. Will be analyzed as continuous variables and correlated with clinical outcomes. Analysis of interaction with treatment arm will be performed but power for these effects is lower as the study is not designed to detect interactions. Standard time to event analyses (Kaplan-Meier curves and Cox models) will be used to determine association of biomarkers with PFS and OS.
• Geriatric assessment scores and biomarkers of aging (CRP and IL-6) [ Time Frame: Baseline up to time of disease evaluation, assessed up to 2 years ]
  Will evaluate the association correlation between levels of CRP and IL-6 and geriatric assessments scores evaluation functional status. Will be analyzed as continuous variables and correlated with clinical outcomes. Analysis of interaction with treatment arm will be performed but power for these effects is lower as the study is not designed to detect interactions. Logistic regression will be used to determine if levels of these biomarkers serve as predictors of toxicity or binary measures of efficacy (response).

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Comparing Two Treatment Combinations, Gemcitabine and Nab-Paclitaxel With 5-Fluorouracil, Leucovorin, and Liposomal Irinotecan for Older Patients With Pancreatic Cancer That Has Spread
• Official Title: 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)
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Pancreatic Adenocarcinoma
• Stage IV Pancreatic Cancer AJCC v8

Intervention

• Drug: Fluorouracil
  Given IV
  Other Names:

  • 5 Fluorouracil
  • 5 Fluorouracilum
  • 5 FU
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • 5FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757
• Drug: Gemcitabine
  Given IV
  Other Names:

  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine
• Drug: Gemcitabine Hydrochloride
  Given IV
  Other Names:

  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011
• Drug: Leucovorin
  Given IV
  Other Name: Folinic acid
• Drug: Leucovorin Calcium
  Given IV
  Other Names:

  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • Citrovorum Factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin
• Drug: Liposomal Irinotecan
  Given IV
  Other Names:

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

  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • Paclitaxel Albumin
  • paclitaxel albumin-stabilized nanoparticle formulation
  • protein-bound paclitaxel
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

• Experimental: Arm A (gemcitabine, nab-paclitaxel)
  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.
  Interventions:

  • Drug: Gemcitabine
  • Drug: Gemcitabine Hydrochloride
  • Drug: Nab-paclitaxel
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Arm B (fluorouracil, leucovorin, liposomal irinotecan)
  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.
  Interventions:

  • Drug: Fluorouracil
  • Drug: Leucovorin
  • Drug: Leucovorin Calcium
  • Drug: Liposomal Irinotecan
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 16, 2020): 184
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2023
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 70 Years and older (Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Efrat Dotan, MD; 215-728-2500; Efrat.Dotan@fccc.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04233866
• Other Study ID Numbers: EA2186; NCI-2019-08286 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA2186 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA2186 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )
• Original Responsible Party: Same as current
• Current Study Sponsor: ECOG-ACRIN Cancer Research Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Efrat Dotan; ECOG-ACRIN Cancer Research Group

• PRS Account: Eastern Cooperative Oncology Group
• Verification Date: June 2022