Pancreatic Adenocarcinoma, Pancreatic Ductal Adenocarcinoma, Pancreatic Intraductal Papillary-Mucinous Neoplasm, Stage II Pancreatic Cancer AJCC v6 and v7, Stage I Pancreatic Cancer AJCC v6 and v7
Conditions
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.
Interventions
RADIATION3-Dimensional Conformal Radiation Therapy
Undergo 3-dimensional conformal radiation therapy
PROCEDUREBiospecimen Collection
Undergo blood and tissue sample collection
DRUGCapecitabine
Given PO
DRUGChemotherapy
Given combination chemotherapy
PROCEDUREComputed Tomography
Undergo CT
DRUGErlotinib Hydrochloride
Given PO
DRUGFluorouracil
Given IV
DRUGGemcitabine Hydrochloride
Given IV
RADIATIONIntensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
OTHERQuality-of-Life Assessment
Ancillary studies
PROCEDUREX-Ray Imaging
Undergo x-ray imaging
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. Five-year rates are reported here. | 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. |
| Overall Survival (Percentage of Participants Alive) by Baseline Fatigue Group | From enrollment (step 1) to death or last follow-up. Maximum follow-up at time of the phase III analysis was 13.2 years, measured from enrollment. Two- and five-year rates are reported here. | Overall survival is estimated by the Kaplan-Meier method. Survival time is measured from enrollment (step 1) 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. Combining treatment arms, patients with low fatigue at baseline (FACIT-F score \> 30) will be compared to patients with high fatigue at baseline (FACIT-F scores ≤ 30). |
Countries
Belgium, Canada, Israel, United States
Contacts
PRINCIPAL_INVESTIGATORRoss A Abrams
NRG Oncology
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) Patients receive either gemcitabine hydrochloride or \[starting 06-28-2016\] 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. | 163 |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) \[Closed to accrual 2-28-2014.\] 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. | 159 |
| Arm III (Chemotherapy) Patients receive the same treatment as in arm I or arm II for one 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. | 174 |
| Arm IV (Chemotherapy, Chemoradiotherapy) Patients receive the same treatment as in arm I or arm II for one 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. | 180 |
| Total | 676 |
Baseline characteristics
| Characteristic | Total | Arm IV (Chemotherapy, Chemoradiotherapy) | Arm III (Chemotherapy) | Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) |
|---|---|---|---|---|---|
| Adjuvant Systemic Treatment (Phase III only) FOLFIRINOX or mFOLFIRINOX | 0 Participants | 0 Participants | 0 Participants | — | — |
| Adjuvant Systemic Treatment (Phase III only) Gemcitabine alone | 236 Participants | 120 Participants | 116 Participants | — | — |
| Adjuvant Systemic Treatment (Phase III only) Gemcitabine + Erlotinib | 100 Participants | 50 Participants | 50 Participants | — | — |
| Adjuvant Systemic Treatment (Phase III only) Non-oxaliplatin gemcitabine combinations | 18 Participants | 10 Participants | 8 Participants | — | — |
| Age, Customized Phase II Analysis ≤ 49 | 35 Participants | — | — | 18 Participants | 17 Participants |
| Age, Customized Phase II Analysis 50 - 59 | 79 Participants | — | — | 42 Participants | 37 Participants |
| Age, Customized Phase II Analysis 60 - 69 | 116 Participants | — | — | 57 Participants | 59 Participants |
| Age, Customized Phase II Analysis 70 - 79 | 76 Participants | — | — | 35 Participants | 41 Participants |
| Age, Customized Phase II Analysis ≥ 80 | 16 Participants | — | — | 11 Participants | 5 Participants |
| Age, Customized Phase III analysis ≤ 49 | 33 Participants | 16 Participants | 17 Participants | — | — |
| Age, Customized Phase III analysis 50 - 59 | 88 Participants | 44 Participants | 44 Participants | — | — |
| Age, Customized Phase III analysis 60 - 69 | 135 Participants | 72 Participants | 63 Participants | — | — |
| Age, Customized Phase III analysis 70 - 79 | 83 Participants | 40 Participants | 43 Participants | — | — |
| Age, Customized Phase III analysis ≥ 80 | 15 Participants | 8 Participants | 7 Participants | — | — |
| Carbohydrate antigen 19-9 (CA19-9) Level Phase II analysis ≤ 90 | 300 Participants | — | — | 152 Participants | 148 Participants |
| Carbohydrate antigen 19-9 (CA19-9) Level Phase II analysis >90-180 | 22 Participants | — | — | 11 Participants | 11 Participants |
| Carbohydrate antigen 19-9 (CA19-9) Level Phase III analysis ≤ 90 | 340 Participants | 177 Participants | 163 Participants | — | — |
| Carbohydrate antigen 19-9 (CA19-9) Level Phase III analysis >90-180 | 14 Participants | 3 Participants | 11 Participants | — | — |
| Ethnicity (NIH/OMB) Phase II analysis Hispanic or Latino | 18 Participants | — | — | 10 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Phase II analysis Not Hispanic or Latino | 286 Participants | — | — | 143 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Phase II analysis Unknown or Not Reported | 18 Participants | — | — | 10 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Phase III analysis Hispanic or Latino | 24 Participants | 14 Participants | 10 Participants | — | — |
| Ethnicity (NIH/OMB) Phase III analysis Not Hispanic or Latino | 320 Participants | 162 Participants | 158 Participants | — | — |
| Ethnicity (NIH/OMB) Phase III analysis Unknown or Not Reported | 10 Participants | 4 Participants | 6 Participants | — | — |
| Histologic Type Phase II analysis Adenocarcinoma | 307 Participants | — | — | 154 Participants | 153 Participants |
| Histologic Type Phase II analysis Intraductal papillary mucinous neoplasm with invasive adenocarcinoma | 15 Participants | — | — | 9 Participants | 6 Participants |
| Histologic Type Phase III analysis Adenocarcinoma | 338 Participants | 172 Participants | 166 Participants | — | — |
| Histologic Type Phase III analysis Intraductal papillary mucinous neoplasm with invasive adenocarcinoma | 16 Participants | 8 Participants | 8 Participants | — | — |
| Number of Positive Lymph Nodes Phase II analysis 0 | 85 Participants | — | — | 45 Participants | 40 Participants |
| Number of Positive Lymph Nodes Phase II analysis 1-3 | 154 Participants | — | — | 76 Participants | 78 Participants |
| Number of Positive Lymph Nodes Phase II analysis >3 | 83 Participants | — | — | 42 Participants | 41 Participants |
| Number of Positive Lymph Nodes Phase III analysis 0 | 91 Participants | 49 Participants | 42 Participants | — | — |
| Number of Positive Lymph Nodes Phase III analysis 1-3 | 174 Participants | 79 Participants | 95 Participants | — | — |
| Number of Positive Lymph Nodes Phase III analysis >3 | 89 Participants | 52 Participants | 37 Participants | — | — |
| Pathologic N-Stage Phase II analysis N0 | 85 Participants | — | — | 45 Participants | 40 Participants |
| Pathologic N-Stage Phase II analysis N1 | 237 Participants | — | — | 118 Participants | 119 Participants |
| Pathologic N-Stage Phase III analysis N0 | 91 Participants | 49 Participants | 42 Participants | — | — |
| Pathologic N-Stage Phase III analysis N1 | 263 Participants | 131 Participants | 132 Participants | — | — |
| Pathologic T-Stage Phase II analysis T1 | 15 Participants | — | — | 7 Participants | 8 Participants |
| Pathologic T-Stage Phase II analysis T2 | 55 Participants | — | — | 30 Participants | 25 Participants |
| Pathologic T-Stage Phase II analysis T3 | 252 Participants | — | — | 126 Participants | 126 Participants |
| Pathologic T-Stage Phase III analysis T1 | 14 Participants | 12 Participants | 2 Participants | — | — |
| Pathologic T-Stage Phase III analysis T2 | 52 Participants | 25 Participants | 27 Participants | — | — |
| Pathologic T-Stage Phase III analysis T3 | 288 Participants | 143 Participants | 145 Participants | — | — |
| Race (NIH/OMB) Phase II analysis American Indian or Alaska Native | 1 Participants | — | — | 0 Participants | 1 Participants |
| Race (NIH/OMB) Phase II analysis Asian | 8 Participants | — | — | 4 Participants | 4 Participants |
| Race (NIH/OMB) Phase II analysis Black or African American | 32 Participants | — | — | 10 Participants | 22 Participants |
| Race (NIH/OMB) Phase II analysis More than one race | 0 Participants | — | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase II analysis Native Hawaiian or Other Pacific Islander | 1 Participants | — | — | 1 Participants | 0 Participants |
| Race (NIH/OMB) Phase II analysis Unknown or Not Reported | 7 Participants | — | — | 4 Participants | 3 Participants |
| Race (NIH/OMB) Phase II analysis White | 273 Participants | — | — | 144 Participants | 129 Participants |
| Race (NIH/OMB) Phase III analysis American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants | — | — |
| Race (NIH/OMB) Phase III analysis Asian | 12 Participants | 8 Participants | 4 Participants | — | — |
| Race (NIH/OMB) Phase III analysis Black or African American | 46 Participants | 27 Participants | 19 Participants | — | — |
| Race (NIH/OMB) Phase III analysis More than one race | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase III analysis Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase III analysis Unknown or Not Reported | 6 Participants | 3 Participants | 3 Participants | — | — |
| Race (NIH/OMB) Phase III analysis White | 286 Participants | 139 Participants | 147 Participants | — | — |
| Sex: Female, Male Phase II analysis Female | 138 Participants | — | — | 75 Participants | 63 Participants |
| Sex: Female, Male Phase II analysis Male | 184 Participants | — | — | 88 Participants | 96 Participants |
| Sex: Female, Male Phase III analysis Female | 159 Participants | 85 Participants | 74 Participants | — | — |
| Sex: Female, Male Phase III analysis Male | 195 Participants | 95 Participants | 100 Participants | — | — |
| Surgical margins Phase II analysis Negative | 269 Participants | — | — | 136 Participants | 133 Participants |
| Surgical margins Phase II analysis Positive | 53 Participants | — | — | 27 Participants | 26 Participants |
| Surgical margins Phase III analysis Negative | 295 Participants | 151 Participants | 144 Participants | — | — |
| Surgical margins Phase III analysis Positive | 59 Participants | 29 Participants | 30 Participants | — | — |
| Tumor size largest dimension Phase II analysis | 3.0 centimeters | — | — | 3.0 centimeters | 3.0 centimeters |
| Tumor size largest dimension Phase III analysis | 3.0 centimeters | 3.0 centimeters | 3.0 centimeters | — | — |
| Type of surgery (phase III only) Phase II analysis Classic Pancreaticoduodenectomy (Whipple) | 240 Participants | — | — | 123 Participants | 117 Participants |
| Type of surgery (phase III only) Phase II analysis Other | 2 Participants | — | — | 0 Participants | 2 Participants |
| Type of surgery (phase III only) Phase II analysis Pylorus preserving pancreaticoduodenectomy | 80 Participants | — | — | 40 Participants | 40 Participants |
| Type of surgery (phase III only) Phase III analysis Classic Pancreaticoduodenectomy (Whipple) | 260 Participants | 139 Participants | 121 Participants | — | — |
| Type of surgery (phase III only) Phase III analysis Other | 1 Participants | 0 Participants | 1 Participants | — | — |
| Type of surgery (phase III only) Phase III analysis Pylorus preserving pancreaticoduodenectomy | 93 Participants | 41 Participants | 52 Participants | — | — |
| Zubrod Performance Status Phase II analysis 0 | 143 Participants | — | — | 65 Participants | 78 Participants |
| Zubrod Performance Status Phase II analysis 1 | 179 Participants | — | — | 98 Participants | 81 Participants |
| Zubrod Performance Status Phase III analysis 0 | 155 Participants | 83 Participants | 72 Participants | — | — |
| Zubrod Performance Status Phase III analysis 1 | 199 Participants | 97 Participants | 102 Participants | — | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 103 / 160 | 100 / 158 | 136 / 174 | 134 / 180 |
| other Total, other adverse events | 158 / 160 | 157 / 158 | 173 / 174 | 179 / 180 |
| serious Total, serious adverse events | 38 / 160 | 45 / 158 | 33 / 174 | 31 / 180 |
Outcome results
Primary
Overall Survival (Percentage of Participants Alive) [Phase II]
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.
Time frame: 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.
Population: Eligible participants randomized at step 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Overall Survival (Percentage of Participants Alive) [Phase II] | 29.9 months |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Overall Survival (Percentage of Participants Alive) [Phase II] | 28.1 months |
Comparison: A total of 200 deaths between the arms will provide 80% power to detect a signal for an increase in median overall survival from 22 to 28.8 months and 90% power to detect a signal for an increase in median overall survival from 22 to 30.6 months (HRs of 0.76 and 0.72, respectively, in favor of the erlotinib arm) with the addition of erlotinib and a 1-sided alpha of 0.15p-value: 0.6295% CI: [0.79, 1.38]Log Rank
Primary
Overall Survival (Percentage of Participants Alive) [Phase III]
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.
Time frame: 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.
Population: Participants randomized at step 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Overall Survival (Percentage of Participants Alive) [Phase III] | 31.1 months |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Overall Survival (Percentage of Participants Alive) [Phase III] | 27.3 months |
Comparison: 316 deaths from step 2 randomized patients provides 80% power, with 0.05 1-sided alpha, to detect an OS increase (HR=0.76 in favor of arm IV), corresponding to increasing median OS from 17 to 22.5 months with the addition of RT. For analysis triggered by patients having 5 years potential follow-up from step 2 randomization, it is projected that at least 265 events will be observed, providing at least 72% power. The trigger used for the primary analysis was 5-years of follow-up (270 deaths).p-value: 0.3890% CI: [0.79, 1.18]Log Rank
Secondary
Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase II]
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.
Time frame: 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.
Population: Eligible participants randomized at step 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase II] | 12.7 months |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase II] | 12.4 months |
95% CI: [0.8, 1.31]
Secondary
Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase III]
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.
Time frame: 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.
Population: Participants randomized at step 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase III] | 12.4 months |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Disease-free Survival (Percentage of Participants Alive Without Disease) [Phase III] | 15.6 months |
90% CI: [0.68, 0.99]
Secondary
Frequency of Objective Criteria of Resectability as Measured by Preoperative Imaging
Time frame: Baseline
Secondary
Number of Participants by Highest Grade Adverse Event Reported (Phase II)
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.
Time frame: 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.
Population: Eligible participants randomized in Step 1 who started protocol treatment and were assessed for adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 2 | 20 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 4 | 32 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 3 | 100 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 5 | 2 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 1 | 6 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 5 | 3 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 1 | 3 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 2 | 24 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 3 | 101 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase II) | Grade 4 | 27 Participants |
Secondary
Number of Participants by Highest Grade Adverse Event Reported (Phase III)
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.
Time frame: 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.
Population: Participants randomized at step 2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 2 | 50 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 4 | 21 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 3 | 67 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 5 | 1 Participants |
| Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 1 | 22 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 5 | 1 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 1 | 16 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 2 | 56 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 3 | 79 Participants |
| Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride) | Number of Participants by Highest Grade Adverse Event Reported (Phase III) | Grade 4 | 23 Participants |
Secondary
Overall Survival by Baseline Fatigue Group
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.
Time frame: From enrollment to death or last follow-up.
Other Pre-specified
Determination of National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue and Overall Survival
Baseline PROMIS Fatigue scores will be analyzed to determine if there is a cut point (adjusting for multiple comparisons) that correlates with overall survival using the log-rank statistic. The analysis population is all enrolled eligible participants who consented to the quality of life study component and who have baseline PROMIS data.
Time frame: From enrollment to death or last follow-up.