Pancreatic Cancer
Conditions
Keywords
adenocarcinoma of the pancreas, stage I pancreatic cancer, stage II pancreatic cancer
Brief summary
PURPOSE: This phase II trial is studying how well gemcitabine and erlotinib work when given before and after surgery in treating patients with pancreatic cancer that can be removed by surgery. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine and erlotinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these drugs after surgery may kill any tumor cells that remain after surgery.
Detailed description
This is a single arm, non-randomized phase II study. Eligible, fully registered patients will receive preoperative chemotherapy consisting of gemcitabine plus erlotinib. Preoperative chemotherapy will be followed by exploratory laparotomy and pancreaticoduodenectomy. Patients will then receive postoperative chemotherapy consisting of gemcitabine plus erlotinib. Up to 123 patients will be accrued to this study, with the expectation that 78 patients will remain fully eligible and evaluable for the primary endpoint. The primary and secondary objectives for the study are listed below. Primary Objective: To estimate the proportion of patients alive at two years from the date of registration Secondary Objectives: 1. To determine the resection rate (defined as the fraction of patients who proceed to planned surgery with removal of primary tumor \[R0/R1\]) following induction treatment with gemcitabine plus erlotinib 2. To estimate the time to disease progression/relapse 3. To evaluate the rate of R0, R1, and R2 resections (defined as per the 6th edition of the AJCC Cancer Staging Manual) in patients treated with preoperative gemcitabine plus erlotinib chemotherapy 4. To evaluate the toxicity profile of preoperative gemcitabine plus erlotinib and the feasibility of postoperative gemcitabine plus erlotinib 5. To evaluate response rates to preoperative chemotherapy for patients treated with preoperative gemcitabine and erlotinib 6. To identify molecular predictors of pancreatic cancer response to gemcitabine combined with erlotinib 7. To identify genetic profiles of pancreatic adenocarcinoma that may be associated with response to neoadjuvant therapy After completion of postoperative chemotherapy treatment, patients are followed every 3 months for 2 years and then every 6 months for 2 years.
Interventions
DRUGerlotinib hydrochloride
oral administration
DRUGgemcitabine hydrochloride
Intravenous administration
PROCEDUREtherapeutic conventional surgery
Sponsors
National Cancer Institute (NCI)
OSI Pharmaceuticals
Astellas Pharma Inc
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria: 1. Cytologic or histologic proof of adenocarcinoma of the pancreatic head or uncinate process. NOTE: Patients with tumors of the pancreatic neck, body or tail are not eligible. Patients with evidence of neuroendocrine tumors, duodenal adenocarcinoma, or ampullary adenocarcinoma are not eligible. 2. Localized, potentially resectable tumors as defined below. All patients must be staged with a chest X-ray or CT, and abdominal CT (contrast-enhanced, helical thin-cut) or MRI. Radiological resectability is defined by the following criteria on abdominal imaging: * No evidence of tumor extension to the celiac axis, hepatic artery, or superior mesenteric artery * No evidence of tumor encasement or occlusion of the superior mesenteric vein (SMV) or the SMV/portal vein confluence * No evidence of visceral or peritoneal metastases NOTE: Patients with borderline resectable or marginally resectable pancreatic cancer are not eligible. Patients must meet all objective imaging criteria outlined above. 3. ≥ 18 years of age 4. ECOG/Zubrod performance status of 0 or 1 5. Baseline weight loss ≤ 15% of premorbid weight 6. Patient must have adequate hematologic, renal, and hepatic function as defined by: * WBC ≥ 2,000 cells/mm³ * ANC ≥ 1,500 cells/mm³ * Platelets ≥ 100,000 cells/mm³ * Serum bilirubin ≤ 2.5 mg/dL * Serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of ≥ 50 ml/min (24 hour urine collection) * ALT \< 2.5 times upper limit of normal (ULN) * AST \< 2.5 times ULN * Albumin ≥ 3.2 g/dl 7. No history of the following: * Prior EGFR targeted therapy or therapy for pancreatic cancer * Active infection requiring intravenous antibiotics at the time of registration 8. Non-pregnant and non-breast feeding. Female participants of child bearing potential must have a negative urine or serum pregnancy test prior to registration. Perimenopausal participants must be amenorrheic ≥ 12 months to be considered not of childbearing potential. All patients of reproductive potential must agree to use an effective method of birth control while receiving study therapy. 9. No prior malignancy within 5 years of registration (Exceptions: non-melanoma skin cancer, in-situ cancers)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at 2 Years | At 2 years post-registration | The primary endpoint of this trial is 2-year overall survival, which will be evaluated as the proportion of treatment successes. A treatment success is defined to be an evaluable patient who is alive at two years from the date of registration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Resection Rate | Up to 4 years postoperative chemotherapy treatment | The resection rate is defined as the fraction of patients that proceed to planned surgery with removal of primary tumor (R0/R1) following neoadjuvant treatment with gemcitabine plus erlotinib.The resection rate will be estimated by the binomial point estimate, i.e. as the number of patients that undergo the planned surgery with removal of the primary tumor following neoadjuvant treatment with gemcitabine plus erlotinib divided by the number of evaluable patients. This quantity will also be estimated with a 95% binomial confidence interval. Curative resection (R0) is defined as macroscopically and microscopically complete resection (with microscopic surgical margin assessment according to AJCC Staging Principles). An R1 resection is defined as macroscopically complete tumor removal with any positive microscopic surgical margin (bile duct, pancreatic parenchyma, or SMA margins). |
| Relapse/Progression-free Survival | At 2 years post-registration | Relapse/progression-free survival is defined as the time from date of registration to the date of documentation of disease recurrence/progression. If a patient dies without documentation of disease recurrence/progression, the patient will be considered to have had disease recurrence/progression at the time of their death unless there is sufficient documented evidence to conclude no recurrence/progression occurred prior to death. If a patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation occurred. If a patient is lost to follow-up, s/he will be censored at the data of last contact. The distribution of disease-free survival will be estimated using the method of Kaplan and Meier. |
| Number of Participants Experiencing Grade 3 or Higher Adverse Events as Graded by the NCI's Common Toxicity Criteria for Adverse Events | Up to 4 years postoperative chemotherapy treatment | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. These patterns will be summarized with descriptive statistics. The number of patients reporting grade 3 or higher adverse events as graded by the NCI's Common Toxicity Criteria (CTCAE) Version 4 are reported here. A complete list of all reported adverse events is reported in the Adverse Events section of this report. |
| Response Rate | Up to 4 years postoperative chemotherapy treatment | The response rates to preoperative chemotherapy for patients treated with preoperative gemcitabine and erlotinib and rates of accurate pathologic assessment of the resected tumor specimen according to College of American Pathology guidelines will be estimated with a binomial point estimate and corresponding 95% confidence intervals. |
Countries
Canada, United States
Participant flow
Pre-assignment details
123 patients enrolled to this study. 4 patients cancelled prior to treatment and were not included in any analysis.
Participants by arm
| Arm | Count |
|---|---|
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy Neoadjuvant Therapy:
As part of neoadjuvant therapy, patients receive 1000 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 29, 36, and 43 and 100 mg oral erlotinib hydrochloride once daily on days 1-43 in the absence of disease progression or unacceptable toxicity.
Surgery:
Within 3-6 weeks after completion of neoadjuvant therapy, patients are reevaluated for eligibility for pancreaticoduodenectomy.
Adjuvant Therapy:
Patients that receive pancreaticoduodenectomy according to protocol are given 1000 mg/m2 gemcitabine hydrochloride IV on days 1, 8, 15, 29, 36, and 43 and 100 mg erlotinib hydrochloride as in neoadjuvant therapy within 5-10 weeks post-surgery. | 119 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 5 |
Baseline characteristics
| Characteristic | Neoadjuvant Therapy + Surgery + Adjuvant Therapy |
|---|---|
| Age, Continuous | 66 years |
| Region of Enrollment Canada | 19 Participants |
| Region of Enrollment United States | 100 Participants |
| Sex: Female, Male Female | 58 Participants |
| Sex: Female, Male Male | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 118 / 119 |
| serious Total, serious adverse events | 37 / 119 |
Outcome results
Primary
Overall Survival at 2 Years
The primary endpoint of this trial is 2-year overall survival, which will be evaluated as the proportion of treatment successes. A treatment success is defined to be an evaluable patient who is alive at two years from the date of registration.
Time frame: At 2 years post-registration
Population: All patients meeting the eligibility criteria who completed neoadjuvant therapy and underwent protocol surgery with R0 or R1 resection were evaluated for the primary endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy | Overall Survival at 2 Years | 0.54 proportion of patients |
Secondary
Number of Participants Experiencing Grade 3 or Higher Adverse Events as Graded by the NCI's Common Toxicity Criteria for Adverse Events
The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. These patterns will be summarized with descriptive statistics. The number of patients reporting grade 3 or higher adverse events as graded by the NCI's Common Toxicity Criteria (CTCAE) Version 4 are reported here. A complete list of all reported adverse events is reported in the Adverse Events section of this report.
Time frame: Up to 4 years postoperative chemotherapy treatment
Population: All patients that started protocol treatment and were assessed for adverse events were included in this endpoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy | Number of Participants Experiencing Grade 3 or Higher Adverse Events as Graded by the NCI's Common Toxicity Criteria for Adverse Events | Grade 4+ Adverse Event | 2 Participants |
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy | Number of Participants Experiencing Grade 3 or Higher Adverse Events as Graded by the NCI's Common Toxicity Criteria for Adverse Events | Grade 3+ Adverse Event | 27 Participants |
Secondary
Relapse/Progression-free Survival
Relapse/progression-free survival is defined as the time from date of registration to the date of documentation of disease recurrence/progression. If a patient dies without documentation of disease recurrence/progression, the patient will be considered to have had disease recurrence/progression at the time of their death unless there is sufficient documented evidence to conclude no recurrence/progression occurred prior to death. If a patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation occurred. If a patient is lost to follow-up, s/he will be censored at the data of last contact. The distribution of disease-free survival will be estimated using the method of Kaplan and Meier.
Time frame: At 2 years post-registration
Population: All patients meeting the eligibility criteria who completed neoadjuvant therapy and underwent protocol surgery with R0 or R1 resection were evaluated for the primary endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy | Relapse/Progression-free Survival | 11.9 months |
Secondary
Resection Rate
The resection rate is defined as the fraction of patients that proceed to planned surgery with removal of primary tumor (R0/R1) following neoadjuvant treatment with gemcitabine plus erlotinib.The resection rate will be estimated by the binomial point estimate, i.e. as the number of patients that undergo the planned surgery with removal of the primary tumor following neoadjuvant treatment with gemcitabine plus erlotinib divided by the number of evaluable patients. This quantity will also be estimated with a 95% binomial confidence interval. Curative resection (R0) is defined as macroscopically and microscopically complete resection (with microscopic surgical margin assessment according to AJCC Staging Principles). An R1 resection is defined as macroscopically complete tumor removal with any positive microscopic surgical margin (bile duct, pancreatic parenchyma, or SMA margins).
Time frame: Up to 4 years postoperative chemotherapy treatment
Population: All patients that completed neoadjuvant treatment and were eligible for surgery were included in this endpoint.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy | Resection Rate | 0.76 proportion of patients |
Secondary
Response Rate
The response rates to preoperative chemotherapy for patients treated with preoperative gemcitabine and erlotinib and rates of accurate pathologic assessment of the resected tumor specimen according to College of American Pathology guidelines will be estimated with a binomial point estimate and corresponding 95% confidence intervals.
Time frame: Up to 4 years postoperative chemotherapy treatment
Population: All patients that completed neoadjuvant treatment and were eligible for protocol surgery were included in this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Therapy + Surgery + Adjuvant Therapy | Response Rate | 0.06 proportion of patients |