S1505: Combination Chemotherapy or Gemcitabine Hydrochloride and Paclitaxel Albumin-Stabilized Nanoparticle Formulation Before Surgery in Treating Patients With Pancreatic Cancer That Can Be Removed by Surgery

Phase 2

Completed

Conditions: Pancreatic Adenocarcinoma
Resectable Pancreatic Carcinoma

Interventions: Drug: Gemcitabine Hydrochloride
Drug: Fluorouracil
Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation
Drug: Irinotecan Hydrochloride
Procedure: Pancreatectomy
Drug: Oxaliplatin

Registration Number: NCT02562716

Lead Sponsor: SWOG Cancer Research Network

Brief Summary: This randomized phase II trial studies how well fluorouracil, irinotecan hydrochloride, and oxaliplatin (combination chemotherapy) works and compares to gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation before surgery in treating patients with pancreatic cancer that can be removed by surgery. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride, oxaliplatin, gemcitabine hydrochloride, and paclitaxel albumin-stabilized nanoparticle formulation, 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 more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective than gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation before surgery in treating pancreatic cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To assess 2-year overall survival in each treatment arm (fluorouracil, irinotecan hydrochloride, and oxaliplatin \[modified (m)FOLFIRINOX\] and gemcitabine \[gemcitabine hydrochloride\]/nab-paclitaxel \[paclitaxel albumin-stabilized nanoparticle formulation\]) in patients with resectable pancreatic cancer.

II. If the stated threshold is met in one or both arms: to choose the better regimen with respect to 2-year overall survival.

SECONDARY OBJECTIVES:

I. To estimate, for all patients and within treatment arms: frequency and severity of adverse events associated with chemotherapy in the perioperative setting.

II. To estimate, for all patients and within treatment arms: proportion of patients going to surgery for resection after preoperative chemotherapy.

III. To estimate, for all patients and within treatment arms: proportion of patients achieving macroscopically complete tumor removal with negative microscopic surgical margins (R0) resection after preoperative chemotherapy.

IV. To estimate, for all patients and within treatment arms: overall response rate following preoperative chemotherapy, including confirmed and unconfirmed, complete and partial response, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

V. To estimate, for all patients and within treatment arms: pathologic response rates after R0 or macroscopically complete tumor removal with any positive microscopic surgical margin (R1) resection.

VI. To estimate, for all patients and within treatment arms: patterns of recurrence (loco-regional, distant) after R0 or R1 resection.

VII. To estimate, for all patients and within treatment arms: disease-free survival from the time of R0 or R1 resection.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive fluorouracil IV over 46 hours on days 1-3 and 15-17. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of oxaliplatin, irinotecan hydrochloride, and fluorouracil treatment in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride treatment in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 2 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 147

Inclusion Criteria

Patients must have histologically or cytologically proven pancreatic adenocarcinoma; histologies other than adenocarcinoma, or any mixed histologies, will NOT be eligible
Patients must have measurable disease in the pancreas; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess measurable disease must have been completed within 28 days prior to registration; all disease must be assessed and documented on the baseline tumor assessment form
Patients must have resectable primary tumor based on contrast-enhanced CT or MRI (CT or MRI without contrast as part of positron emission tomography [PET]/CT or PET/MRI is NOT acceptable; CT or MRI with contrast as part of PET/CT or PET/MRI is acceptable) of the chest, abdomen, and pelvis, where resectable is defined as:
- No involvement of the celiac artery, common hepatic artery, and superior mesenteric artery (and, if present, replaced right hepatic artery)
- No involvement, or < 180° interface between tumor and vessel wall, of the portal vein and/or superior mesenteric vein; and patent portal vein/splenic vein confluence
- No evidence of metastatic disease
- Note: for tumors of the body and tail of the pancreas, involvement of the splenic artery and vein of any degree is considered resectable disease
CT scans or MRIs used to assess disease at baseline must be submitted for central review
Patients must have surgical consult to verify patient is a surgical candidate within 21 days prior to registration
Patients must not have received prior surgery, radiation therapy, chemotherapy, targeted therapy, or any investigational therapy for pancreatic cancer
Patients must have a Zubrod performance status of 0-1
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 9 g/dL
Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN
Serum albumin >= 3 g/dL
Serum creatinine =< IULN within 14 days prior to registration
Patients with 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 will NOT be eligible
No prior malignancy is allowed except for adequately treated basal (or squamous cell) skin cancer, in situ cervical cancer, in situ breast (ductal or lobular) cancer, or other cancer for which the patient has been disease and treatment-free for two years
Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method for up to 3 months after the final administered dose of chemotherapy; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures
Sites must seek additional patient consent for the future use of specimens
Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (gemcitabine, nab-paclitaxel, and surgery)	Gemcitabine Hydrochloride	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride treatment in the absence of disease progression or unacceptable toxicity.
Arm II (gemcitabine, nab-paclitaxel, and surgery)	Paclitaxel Albumin-Stabilized Nanoparticle Formulation	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride treatment in the absence of disease progression or unacceptable toxicity.
Arm II (gemcitabine, nab-paclitaxel, and surgery)	Pancreatectomy	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride treatment in the absence of disease progression or unacceptable toxicity.
Arm I (mFOLFIRINOX, surgery)	Pancreatectomy	Patients receive oxaliplatin IV over 2 hours and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive 5-fluorouracil IV over 46 hours on days 1-3 and 15-17. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of oxaliplatin, irinotecan hydrochloride, and fluorouracil treatment in the absence of disease progression or unacceptable toxicity.
Arm I (mFOLFIRINOX, surgery)	Fluorouracil	Patients receive oxaliplatin IV over 2 hours and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive 5-fluorouracil IV over 46 hours on days 1-3 and 15-17. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of oxaliplatin, irinotecan hydrochloride, and fluorouracil treatment in the absence of disease progression or unacceptable toxicity.
Arm I (mFOLFIRINOX, surgery)	Irinotecan Hydrochloride	Patients receive oxaliplatin IV over 2 hours and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive 5-fluorouracil IV over 46 hours on days 1-3 and 15-17. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of oxaliplatin, irinotecan hydrochloride, and fluorouracil treatment in the absence of disease progression or unacceptable toxicity.
Arm I (mFOLFIRINOX, surgery)	Oxaliplatin	Patients receive oxaliplatin IV over 2 hours and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive 5-fluorouracil IV over 46 hours on days 1-3 and 15-17. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of oxaliplatin, irinotecan hydrochloride, and fluorouracil treatment in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Up to 4 years for the estimates of median overall survival. Up to 2 years for Statistical Analysis 1 and 2, comparing the observed 2-year overall survival (OS) to the null hypothesis of 40%, in each arm.	OS is the length of time between protocol registration and patient death

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug	Duration of treatment and follow up until death or 4 years post registration.	Only adverse events that are possibly, probably or definitely related to preoperative and postoperative chemotherapy are reported.
Number of Patients Going to Surgery for Resection After Preoperative Chemotherapy.	Up to 8 months post registration (and within 4 to 8 weeks after the last dose of Cycle 3 preoperative chemotherapy).
Number of Participants With a Response Following Preoperative Chemotherapy, Including Confirmed and Unconfirmed, Complete and Partial Response, Per RECIST 1.1.	Up to 6 months post registration (and within 2 to 4 weeks after the last dose of Cycle 3 preoperative chemotherapy.).	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Number of Participants With Complete Response, Moderate Response, Minimal Response, and Poor or No Response After Resection.	Up to 8 months post registration (and within 4 to 8 weeks after the last dose of Cycle 3 preoperative chemotherapy).	Pathologic response was evaluated after the patient had surgery, and was based on local pathology review of the resected surgical specimen, according to the following Tumor Regression Grade definitions: 0: Complete response - no residual tumor 1. Moderate response - minimal residual cancer (single cells or small groups of cancer cells) 2. Minimal response - residual cancer outgrown by fibrosis 3. Poor or no response - no definite response identified (minimal or no tumor kill; extensive residual cancer)
Number of Participants With Loco-regional and Distant Recurrence After R0 or R1 Resection.	Up to 4 years	Loco-regional recurrence is defined as any evidence of new disease within the pancreatic tumor bed based on surveillance scans. The pancreatic tumor bed includes: 1. Superior mesenteric artery and vein lymph nodes 2. Lymph nodes in porta hepatis (bile duct, portal vein, hepatic artery lymph nodes) 3. Lymph nodes around left renal vein, inferior vena cava or aorta 4. Celiac axis lymph nodes. Distant Recurrence is defined as any evidence of new disease outside the primary tumor bed (liver, lungs, etc.) based on surveillance scans.
Disease-free Survival From the Time of R0 or R1 Resection.	Up to 4 years	Disease-free survival (DFS) is calculated for patients who undergo surgical resection (R0/R1). DFS will be measured from the date of surgical resection to date of first documentation of recurrence (loco-regional or distant) or death due to any cause. Patients last known to be alive and free of disease will be censored at date of last contact.
Number of Patients Achieving R0 Resection After Preoperative Chemotherapy.	Up to 8 months post registration (and within 4 to 8 weeks after the last dose of Cycle 3 preoperative chemotherapy).	R0 resection classification is defined as macroscopically complete tumor removal with negative microscopic surgical margins (bile duct, pancreatic parenchyma, and superior mesenteric artery margins).

Trial Locations

Locations (805): University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
University of South Alabama Mitchell Cancer Institute
🇺🇸
Mobile, Alabama, United States
Anchorage Associates in Radiation Medicine
🇺🇸
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
🇺🇸
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
🇺🇸
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
🇺🇸
Anchorage, Alaska, United States
Alaska Regional Hospital
🇺🇸
Anchorage, Alaska, United States
Alaska Women's Cancer Care
🇺🇸
Anchorage, Alaska, United States
Anchorage Oncology Centre
🇺🇸
Anchorage, Alaska, United States
Katmai Oncology Group
🇺🇸
Anchorage, Alaska, United States
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University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States