Gemcitabine Hydrochloride With or Without Erlotinib Hydrochloride Followed by the Same Chemotherapy Regimen With or Without Radiation Therapy and Capecitabine or Fluorouracil in Treating Patients With Pancreatic Cancer That Has Been Removed by Surgery

Phase 3

Active, not recruiting

Conditions: Pancreatic Adenocarcinoma
Stage II Pancreatic Cancer AJCC v6 and v7
Pancreatic Ductal Adenocarcinoma
Stage I Pancreatic Cancer AJCC v6 and v7
Pancreatic Intraductal Papillary-Mucinous Neoplasm

Interventions: Procedure: Biospecimen Collection
Radiation: 3-Dimensional Conformal Radiation Therapy
Drug: Chemotherapy
Drug: Erlotinib Hydrochloride
Procedure: Computed Tomography
Drug: Capecitabine
Drug: Gemcitabine Hydrochloride
Procedure: Magnetic Resonance Imaging
Other: Quality-of-Life Assessment
Drug: Fluorouracil
Procedure: X-Ray Imaging
Radiation: Intensity-Modulated Radiation Therapy

Registration Number: NCT01013649

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II-R/III trial studies gemcitabine hydrochloride with or without erlotinib hydrochloride followed by the same chemotherapy regimen with or without radiation therapy and capecitabine or fluorouracil in treating patients with pancreatic cancer that was removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, capecitabine, and fluorouracil, 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. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells. Giving chemotherapy together with or without erlotinib hydrochloride and/or radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether chemotherapy is more effective when given with or without erlotinib hydrochloride and/or radiation therapy in treating pancreatic cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine whether the addition of erlotinib (erlotinib hydrochloride) to gemcitabine (gemcitabine hydrochloride) adjuvant chemotherapy shows a signal for improved survival as compared to gemcitabine alone following R0 or R1 resection of head of pancreas adenocarcinoma (including adenocarcinoma of the head, neck, and uncinate process). (Phase II-R) II. To determine whether the use of concurrent fluoropyrimidine and radiotherapy following adjuvant gemcitabine based chemotherapy or non-gemcitabine based chemotherapy such as modified fluorouracil-leucovorin-irinotecan-oxaliplatin regimen (FOLFIRINOX) further enhances survival for such patients who are without evidence of progressive disease after 5 months of adjuvant chemotherapy. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate disease-free survival of adjuvant chemotherapy followed by radiotherapy and concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who are disease free after 5 months of adjuvant chemotherapy.

II. To evaluate disease-free survival of standard adjuvant gemcitabine chemotherapy with and without erlotinib for patients with resected head of pancreas adenocarcinoma.

III. To evaluate adverse events with and without erlotinib for patients with resected head of pancreas adenocarcinoma.

IV. To evaluate adverse events of adjuvant chemotherapy with or without radiation therapy and concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who are disease free after adjuvant chemotherapy.

V. To evaluate preoperative cross-sectional imaging of the primary head of pancreas adenocarcinoma in order to determine the frequency with which objective criteria of resectability are present.

VI. To determine if patients reporting low baseline fatigue, as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, predicts survival and to explore correlations between baseline fatigue, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS), and survival.

OUTLINE: Patients without disease progression after treatment in arm I or II are randomized to 1 of 2 additional treatment arms (arm III or IV).

ARM I: Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months.

ARM II (closed to accrual 4/2/14): Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride orally (PO) once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive the same treatment as in arm I for 1 month.

ARM IV: Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO twice daily (BID) 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed.

Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.

After completion of study treatment, patients are followed up every 3-6 months for up to 4 years, then yearly.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 546

Inclusion Criteria

Histologic proof of primary head of pancreas invasive adenocarcinoma managed with a potentially curative resection (i.e., removal of all gross tumor) involving a classic pancreaticoduodenectomy (Whipple) or a pylorus preserving pancreaticoduodenectomy; patients with invasive adenocarcinoma that also contains a component of intraductal papillary mucinous neoplasm (IPMN) are eligible
- The operating surgeon must document in the operative note that a complete gross excision of the primary tumor was achieved; the pathology report must include documentation of the margin status and the size of the tumor; the pathology report must also include the status of the three major margins-bile duct, pancreatic parenchyma, and retroperitoneal (uncinate)
For patients who have not started their chemotherapy prior to registration, the interval between definitive tumor-related surgery and 1st step registration must be between 21-70 days; for patients entering on the study who have already received up to 3 months of adjuvant chemotherapy as per the treating institution, the interval between definitive tumor-related surgery and day one of adjuvant chemotherapy must be between 21-77 days
Patients will be staged according to the 6th edition American Joint Committee on Cancer (AJCC) staging system with pathologic stage T1-3, N0-1, M-0 being eligible. Pathologic reporting using the College of American Pathologists (CAPS) format is strongly encouraged
Age >= 18
Zubrod performance status 0 or 1
Complete history and physical examination including weight and Zubrod status within 31 days of study entry (or within 31 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)
Before starting therapy the patient should be able to maintain adequate oral nutrition of >= 1500 calories estimated caloric intake per day and be free of significant nausea and vomiting
Complete blood count (CBC)/differential obtained within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelets >= 100,000/mm^3
Hemoglobin >= 8.0 g/dL (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
Post resection serum cancer antigen (CA)19-9 =< 180 units/mL AND prior to any systemic treatment
Serum total bilirubin =< twice the institutional upper limit of normal (ULN) within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)
Creatinine levels =< twice the institutional upper limit of normal within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)
Serum glutamic oxaloacetic transaminase (SGOT) must be =< 2.5 x the institutional upper limit of normal within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)
Negative serum pregnancy test for women of childbearing potential within 14 days of study registration
Abdominal/pelvic CT scan with contrast is preferred; abdominal CT alone is acceptable only if insurance restrictions are experienced; chest CT/x-ray (CT of chest preferred) within 31 days of registration on study (or within 31 days prior to day 1 of chemo post-surgery for those patients having started chemotherapy prior to first step registration); patients allergic to IV contrast can have MRI of the abdomen/pelvis instead
Signed study-specific informed consent
Consultation, agreement, and documentation in the patient's chart by a radiation oncologist that patient is suitable to receive radiotherapy per this protocol
Women of childbearing potential and male participants must practice adequate contraception
Patients with active human immunodeficiency virus (HIV) infection are eligible if their cluster of differentiation (CD)4 count is > 499/cu mm and their viral load is < 50 copies/ml; use of highly active antiretroviral treatment (HAART) is allowed

Exclusion Criteria

Patients with non-adenocarcinomas, adenosquamous carcinomas, islet cell (neuroendocrine) tumors, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile duct, and ampullary carcinomas; patients with tumors that are largely intraductal papillary mucinous neoplasms (IPMN) with a minimal or minor component of invasive carcinoma are not eligible; patients with acinar carcinomas are not eligible; patients with IPMN's that contain some secondary (minor) foci of adenocarcinoma are also not eligible
Patients managed with a total pancreatectomy, a distal pancreatectomy, or central pancreatectomy
Patients entering on the study after pancreaticoduodenectomy, who have not already started chemotherapy must not have had prior systemic chemotherapy for pancreas cancer; note that prior chemotherapy for a different cancer is allowable; for patients entering on the study who have already received up to 3 months of adjuvant chemotherapy as per the treating institution, patients must not have received adjuvant chemotherapy with agents other than gemcitabine, nab-paclitaxel, oxaliplatin, fluoropyrimidine, or irinotecan for the current pancreatic cancer; prior chemotherapy for a different cancer is allowable
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
Previous history of invasive malignancy (except non-melanoma skin cancer) unless the patient has been disease free for at least 2 years prior to study entry (or first day of chemotherapy for patients having started chemotherapy prior to first step registration); patients with a previous history of carcinoma in situ are eligible
Severe, active co-morbidity, defined as follows per time points indicated below (or per time points indicated below prior to the first day of chemotherapy for patients having started chemotherapy prior to first step registration):
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- Transmural myocardial infarction within the 3 months of study registration
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
Pregnant or lactating women
Women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
If surgical margin status cannot be determined after consultation with the operating surgeon and the institutional pathologist, the patient will be ineligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (gemcitabine hydrochloride or combination chemotherapy)	Gemcitabine Hydrochloride	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	Erlotinib Hydrochloride	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	Gemcitabine Hydrochloride	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm III (chemotherapy)	Gemcitabine Hydrochloride	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Gemcitabine Hydrochloride	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm I (gemcitabine hydrochloride or combination chemotherapy)	Chemotherapy	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm III (chemotherapy)	Quality-of-Life Assessment	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm I (gemcitabine hydrochloride or combination chemotherapy)	Biospecimen Collection	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm I (gemcitabine hydrochloride or combination chemotherapy)	Computed Tomography	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm I (gemcitabine hydrochloride or combination chemotherapy)	Magnetic Resonance Imaging	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm I (gemcitabine hydrochloride or combination chemotherapy)	Quality-of-Life Assessment	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm I (gemcitabine hydrochloride or combination chemotherapy)	X-Ray Imaging	Patients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	Biospecimen Collection	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	Computed Tomography	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm III (chemotherapy)	X-Ray Imaging	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	Magnetic Resonance Imaging	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	Quality-of-Life Assessment	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)	X-Ray Imaging	Patients receive gemcitabine hydrochloride IV over 30 minutes once a week for 3 weeks then off 1 week and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline. (closed to accrual 4/2/14)
Arm III (chemotherapy)	Biospecimen Collection	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm III (chemotherapy)	Chemotherapy	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm III (chemotherapy)	Computed Tomography	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm III (chemotherapy)	Magnetic Resonance Imaging	Patients receive the same treatment as in arm I for 1 month. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	3-Dimensional Conformal Radiation Therapy	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Biospecimen Collection	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Capecitabine	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Chemotherapy	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Computed Tomography	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Fluorouracil	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Intensity-Modulated Radiation Therapy	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Magnetic Resonance Imaging	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	Quality-of-Life Assessment	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.
Arm IV (chemotherapy, chemoradiotherapy)	X-Ray Imaging	Patients receive the same treatment as in arm I for 1 month. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed. Patients undergo CT, MRI, and/or x-ray imaging throughout the trial. Patients also undergo blood sample collection during screening and follow-up and undergo tissue sample collection at baseline.

Primary Outcome Measures

Name	Time	Method
Overall Survival (Percentage of Participants Alive) [Phase II]	From step 1 randomization (gemcitabine vs. gemcitabine/erlotinib) to death or last follow-up. Maximum follow-up at the time of the phase II analysis was 6.2 years.	Overall survival is estimated by the Kaplan-Meier method. Survival time is measured from step 1 randomization to date of death from any cause or last known follow-up (censored). Analysis was to occur after 200 deaths were reported.
Overall Survival (Percentage of Participants Alive) [Phase III]	From step 2 randomization (chemotherapy vs. chemotherapy followed by chemoradiation) to the date of death or last follow-up. Maximum follow-up at time of the phase III analysis was 12.8 years, measured from step 2 randomization.	Overall survival (OS) is estimated by the Kaplan-Meier method. Survival time is measured from step 2 randomization to date of death from any cause or last known follow-up (censored). Analysis was to occur at the earlier of 316 reported deaths or when all patients have five years potential follow-up from step 2 randomization.

Secondary Outcome Measures

Name	Time	Method
Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase II]	From step1 randomization (gemcitabine vs. gemcitabine/erlotinib) to disease event, death, or last follow-up. Maximum follow-up at the time of the phase II analysis was 6.2 years.	Disease-free survival is estimated by the Kaplan-Meier method. Disease-free survival time is measured from step 1 randomization to the first date of local or regional disease, distant metastases, second primary tumor, death due to any cause, or last known follow-up (censored). Analysis was to occur after 200 deaths were reported.
Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase III]	From step 2 randomization (chemotherapy vs. chemotherapy followed by chemoradiation) to disease event, death, or last follow-up. Maximum follow-up at time of the phase III analysis was 12.8 years, measured from step 2 randomization.	Disease-free survival is estimated by the Kaplan-Meier method. Disease-free survival time is measured from step 2 randomization to the first date of local or regional disease, distant metastases, second primary tumor, death due to any cause, or last known follow-up (censored). Analysis was to occur at the earlier of 316 reported deaths or when all participants have five years potential follow-up from second step randomization.
Number of Participants by Highest Grade Adverse Event Reported (Phase II)	From step 1 randomization (gemcitabine vs. gemcitabine/erlotinib) to death or last follow-up. Maximum follow-up at the time of the phase II analysis was 6.2 years.	Assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 which grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Number of Participants by Highest Grade Adverse Event Reported (Phase III)	From step 2 randomization (chemotherapy vs. chemotherapy followed by chemoradiation) to death or last follow-up. Maximum follow-up at time of the phase III analysis was 12.8 years, measured from step 2 randomization.	Assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 which grades adverse event severity from 1=mild to 5=death.
Frequency of Objective Criteria of Resectability as Measured by Preoperative Imaging	Baseline
Overall Survival by Baseline Fatigue Group	From enrollment to death or last follow-up.	Overall survival is estimated by the Kaplan-Meier method. Survival time is measured from step 1 randomization to date of death from any cause or last known follow-up (censored). Baseline fatigue is measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACT-F) questionnaire which has a range of 0 to 52 with a higher score indicating less fatigue. Patients with low fatigue at baseline (FACIT-F score \> 30) will be compared to patients with high fatigue at baseline (FACIT-F scores ≤ 30). The analysis population is all enrolled eligible participants who consented to the quality of life study component and who have baseline FACT-F data.

Trial Locations

Locations (688): Providence Hospital
🇺🇸
Mobile, Alabama, United States
Alaska Breast Care and Surgery LLC
🇺🇸
Anchorage, Alaska, United States
Alaska Women's Cancer Care
🇺🇸
Anchorage, Alaska, United States
Katmai Oncology Group
🇺🇸
Anchorage, Alaska, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
🇺🇸
Auburn, California, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸
Burbank, California, United States
Mills-Peninsula Medical Center
🇺🇸
Burlingame, California, United States
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
🇺🇸
Cameron Park, California, United States
Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
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Providence Hospital
🇺🇸Mobile, Alabama, United States