Pancreatic Cancer
Conditions
Keywords
pancreas, pancreatic, cancer, resectable
Brief summary
This study is to determine the efficacy of bevacizumab and gemcitabine in combination with radiation therapy in the preoperative treatment of potentially-resectable subjects with pancreatic cancer.
Detailed description
This is a 2 stage phase II study of bevacizumab (10 mg/kg) and fixed dose rate (FDR) gemcitabine (1500 mg/m2 at 10 mg/kg/min) in combination with sequential rapid fractionation radiotherapy (30 Gy total) in the preoperative treatment of potentially-resectable subjects with adenocarcinoma of the pancreas. The purpose of this study is to determine the rate of margin negative surgical resection (R0 resection rate) and the rate of complete pathological response in patients with resected pancreas cancer. The overall goal of this study is to determine the merit of this novel regimen for further study in a Phase III trial examining time to progression and overall survival. Based on the need for 48 evaluable subjects to evaluate the primary endpoints, the study will be opened with a target accrual of 60 subjects given an expected 20% rate of attrition observed in prior studies of subjects with pancreas cancer at UPCI.
Interventions
10 mg/kg, days 1, 15, 29 and 43
On days 1, 15, and 29, subjects will receive gemcitabine 1500 mg/m2 IV over 150 minutes at the fixed-dose rate (10 mg/m2/min).
RADIATIONexternal beam radiotherapy
3 Gy/fraction utilizing a 95% isodose field over 10 consecutive weekdays, Monday to Friday, for a total of 30 Gy
Sponsors
Amer Zureikat
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic proof of pancreatic adenocarcinoma. * Subjects with biopsy-proven adenocarcinoma of the pancreas which is potentially resectable by preoperative imaging. Subjects will be considered potentially resectable using criteria defined by Pisters (Pisters et al., 2001): * if imaging detects no evidence of extrapancreatic disease; * no evidence of tumor extension to the superior mesenteric artery (SMA) or celiac axis (intact fat plane between the tumor and the adjacent visceral artery), * patent superior mesenteric-portal vein confluence * no encasement of portal or superior mesenteric vein. * Karnofsky performance status ≥ 80. * No active second malignancy except for basal cell carcinoma of the skin * Normal renal, hepatic, and hematologic function at the time of enrollment as evidenced by: * Serum creatinine level ≤1.6 mg/dl ( Calculated Creat clearance \>50) * Serum total bilirubin level ≤1.5 X ULN * Urine protein excretion ≤ 1+ by urine dipstick * White blood cell count ≥ 3.5x109/ml per ml and platelet count ≥ 100x109 per ml * Age \>18 years. * Children are excluded because of toxic effects of bevacizumab and gemcitabine on growth and development during preclinical studies. * For subjects with obstructive jaundice, the biliary tract must be drained with a temporary plastic or a short permanent metallic biliary stent. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Disease-Specific Exclusions * Subjects who have received chemotherapy within 12 months prior to study entry. * Prior use of radiotherapy or investigational agents for pancreatic cancer. * Subjects who have undergone laparotomy for pancreas cancer within 6 weeks * Any evidence of metastasis to distant organs (liver, lung, peritoneum). * Symptomatic or endoscopic evidence of gastric outlet obstruction • Endoscopic findings suggesting tumor erosion into the gastrointestinal mucosa. * Concurrent malignancies with evidence of active or measurable disease except basal cell carcinoma of the skin. * General Medical Exclusions * Inability to adhere to study and/or follow-up procedures * History of allergic reactions or hypersensitivity to the study drugs (bevacizumab, gemcitabine, and proton pump inhibitors). * Other concurrent experimental therapy. * Because subjects with immune deficiency are at increased risk for lethal infections when treated with marrow-suppressive therapy, HIV-positive subjects receiving combination anti-retroviral therapy are excluded from the study. * Bevacizumab-Specific Exclusions * Subjects who have had recent surgery (prior 6 weeks) * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment * Subjects with the following co-morbid medical conditions: * History of myocardial infarction or unstable angina within 12 months prior to study enrollment. * Ascites * Pregnancy/lactation - The effects of the study drugs on the developing human fetus are unknown. For this reason and because bevacizumab, gemcitabine, and radiation therapy used in this trial are known to be teratogenic in animal studies, women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of study entry until 6 months after the completion of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A serum pregnancy test for those females of childbearing potential must be done prior to their receiving study drugs. Due to the combined effects of chemotherapy and radiation, breastfeeding is not allowed for 6 months after the completion of study participation. * Regular aspirin use \> 325 mg per day * Regular NSAID use * Bleeding diathesis, coagulopathy, need for full-dose anticoagulation or INR \> 1.5 * Known central nervous system metastasis * Previous cerebrovascular accident, transient ischemic attack, or seizure (within 6 months) * Serious non-healing wound, ulcer, or bone fracture * History of abdominal fistula, gastrointestinal perforation, diverticulitis, or intra-abdominal abscess within 6 months prior to study enrollment. * Recent hemoptysis, * Uncontrolled hypertension (defined as systolic blood pressure \>150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications) * Any prior history of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) grade 2 or greater congestive heart failure (see Appendix I) * Prior deep venous thrombosis or pulmonary embolism * Urine protein excretion 2+ or ≥ 1 g per 24 hours * Peripheral vascular disease such as lower extremity claudication and rest pain or prior lower extremity vascular surgery for arterial insufficiency * Dyspnea requiring supplemental oxygen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Margin Negative Surgical Resection (R0 Resection Rate) | Up to 48 months | Number of participants who underwent laparoscopy and pancreatic resections that were margin negative/total number of participants who underwent laparoscopy and pancreatic resections. |
| Rate of Pathologic Complete Response (pCR) | Up to 48 months | Rate of pathologic complete response (pCR) is no residual invasive tumor, in situ carcinoma can be present, and no residual lymph node metastasis. Rate of pCR is the number of participants who underwent laparoscopy and pancreatic resections that experienced complete pathologic response/total number of participants who underwent laparoscopy and pancreatic resections. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Surgical Resection | Up to 48 months | Number of participants that underwent resection / per the total number of evaluable participants |
| Overall Survival (OS) | Up to 48 months | — |
| Ca 19-9 Level (in Serum) - Biomarker Response | Baseline and up to 48 months | Percentage decrease in Ca 19-9 level (in serum) |
| Radiographic Tumor Response | Up to 48 months | CT scans evaluated for response using Response Evaluation Criteria in Solid Tumors (RECIST) |
| Progression-free Survival (PFS) | Up to 48 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FDR GEM + BEV +/- BEV/RT Participants received fixed-dose rate (FDR) gemcitabine (GEM) (1,500 mg/m\^2) plus bevacizumab (BEV) (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin, +/- laparoscopy and resection after day 85. | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Change in health insurance | 1 |
Baseline characteristics
| Characteristic | FDR GEM + BEV +/- BEV/RT |
|---|---|
| Age, Continuous | 60 years |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 50 / 59 |
| serious Total, serious adverse events | 10 / 59 |
Outcome results
Primary
Rate of Margin Negative Surgical Resection (R0 Resection Rate)
Number of participants who underwent laparoscopy and pancreatic resections that were margin negative/total number of participants who underwent laparoscopy and pancreatic resections.
Time frame: Up to 48 months
Population: Participants who underwent laparoscopy and pancreatic resection.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Rate of Margin Negative Surgical Resection (R0 Resection Rate) | 88 percentage of participants |
Primary
Rate of Pathologic Complete Response (pCR)
Rate of pathologic complete response (pCR) is no residual invasive tumor, in situ carcinoma can be present, and no residual lymph node metastasis. Rate of pCR is the number of participants who underwent laparoscopy and pancreatic resections that experienced complete pathologic response/total number of participants who underwent laparoscopy and pancreatic resections.
Time frame: Up to 48 months
Population: Participants who underwent laparoscopy and pancreatic resections.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Rate of Pathologic Complete Response (pCR) | 2.3 percentage of participants |
Secondary
Ca 19-9 Level (in Serum) - Biomarker Response
Percentage decrease in Ca 19-9 level (in serum)
Time frame: Baseline and up to 48 months
Population: Participants that did NOT demonstrate metastatic progression upon restaging CT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Ca 19-9 Level (in Serum) - Biomarker Response | 25 percentage decrease in serum Ca19-9 leve | Standard Deviation 80 |
Secondary
Overall Survival (OS)
Time frame: Up to 48 months
Population: Includes entire study cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Overall Survival (OS) | 16.8 months |
Secondary
Overall Survival (OS)
Time frame: Up to 48 months
Population: Includes participants who underwent laparoscopy and pancreatic resection.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Overall Survival (OS) | 19.7 months |
Secondary
Progression-free Survival (PFS)
Time frame: Up to 48 months
Population: Includes participants who underwent laparoscopy and pancreatic resection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Progression-free Survival (PFS) | 12.9 months |
Secondary
Progression-free Survival (PFS)
Time frame: Up to 48 months
Population: Includes entire study cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Progression-free Survival (PFS) | 6.6 months |
Secondary
Radiographic Tumor Response
CT scans evaluated for response using Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: Up to 48 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Radiographic Tumor Response | metastatic progression (at restaging) | 4 Participants |
| FDR GEM + BEV +/- BEV/RT | Radiographic Tumor Response | stable disease | 39 Participants |
| FDR GEM + BEV +/- BEV/RT | Radiographic Tumor Response | partial response | 5 Participants |
| FDR GEM + BEV +/- BEV/RT | Radiographic Tumor Response | progressive disease | 10 Participants |
Secondary
Rate of Surgical Resection
Number of participants that underwent resection / per the total number of evaluable participants
Time frame: Up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FDR GEM + BEV +/- BEV/RT | Rate of Surgical Resection | 74 percentage of participants |