Pancreas Ductal Adenocarcinoma, Pancreatic Adenocarcinoma, Pancreatic Cancer
Conditions
Keywords
Stereotactic Body Radiation Therapy, Perioperative Therapy, Resectable Pancreas Ductal Adenocarcinoma, Borderline Resectable Pancreas Ductal Adenocarcinoma, Nab-paclitaxel, Abraxane, Gemcitabine, Neoadjuvant Therapy, Adjuvant Therapy
Brief summary
The objective of this study is to estimate the R0 resection rate in patients with Resectable Pancreatic Ductal Adenocarcinoma (R-PDAC) as well as those with Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) independently in response to neoadjuvant sequential therapy of combination nab-paclitaxel and gemcitabine followed by stereotactic body radiotherapy (SBRT).
Detailed description
Patients in both cohorts will receive a total of 3 cycles of neoadjuvant combination chemotherapy of nab-paclitaxel and gemcitabine, followed by re-staging CT scan, if re-staging CT does not show evidence of metastatic disease. Patients will receive SBRT and definitive surgical resection. Subsequently, patients will receive 3 cycles of adjuvant combination chemotherapy of nab-paclitaxel and gemcitabine. Each cycle of combination chemotherapy will be a total of 4 weeks. Patients will be evaluated for response at completion of the 3 cycles of neoadjuvant combination chemotherapy with CT scans of chest, abdomen and pelvis. Patients will undergo surveillance CT scan at 3-month intervals until evidence of disease progression.
Interventions
DRUGNab paclitaxel
Nab-paclitaxel and gemcitabine, for R-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.
DRUGGemcitabine
Nab-paclitaxel and gemcitabine, for BR-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.
Sponsors
Celgene Corporation
Criterium, Inc.
University of Colorado, Denver
Academic Thoracic Oncology Medical Investigators Consortium
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 101 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed resectable or borderline resectable pancreatic adenocarcinoma. 2. No evidence of distant metastasis representing stage IV metastatic disease. 3. R-PDAC: No evidence of distant metastasis and tumor mass showing no extension to superior mesenteric artery (SMA) and hepatic artery. There must be a clearly defined fat plane between SMA and celiac axis. Patent superior mesenteric vein (SMV/portal vein (PV) with no distortion of venous architecture. 4. BR-PDAC: defined as localized PDAC with 1 or more of the following features: a) an interface between the primary tumor and superior mesenteric vein (SMV)-portal vein (PV) measuring 180o or greater of the circumference of the vein wall, and/or b) short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction and/or c) short-segment interface of any degree between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and arterial reconstruction and/or d) an interface between the tumor and SMA or celiac trunk measuring less than 180o of the circumference of the artery wall. 5. Age \> 18 years old 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. Patients must have adequate bone marrow function: * Platelets \>100,000 cells/mm3 * Hemoglobin \> 9.0 g/dL * Absolute Neutrophil Count \> 1,500 cells/mm3 8. Patients must have adequate liver function: * aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) \< 2.5 X upper limit of normal * Alkaline phosphatase \< 2.5 X upper limit of normal, unless bone metastasis is present in the absence of liver metastasis * Total bilirubin \< 1.5 mg/dL 9. Patients must have adequate renal function: creatinine \<1.5 mg/dL is recommended; however, institutional norms are acceptable. Creatinine within institutional limits of normal or creatinine clearance (CrCl) \> 50 mL/min calculated using the Cockcroft-Gault equation. 10. Women of childbearing potential and sexually active males must use an effective contraception method during treatment and for three months after completing treatment. 11. Negative serum or urine β-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of childbearing potential. 12. Patients must have \< Grade 2 pre-existing peripheral neuropathy (per CTCAE 4.03). 13. Ability to understand and willingness to sign a written informed consent.
Exclusion criteria
1. Patients with locally advanced surgically unresectable PDAC. 2. Patients with evidence of distant metastatic PDAC. 3. Prior chemotherapy or radiation therapy of any kind for treatment of pancreas adenocarcinoma. 4. Prior major surgery within 4 weeks of starting study drug administration. 5. Patient unable or not willing to perform all study related biopsies and blood draws for exploratory endpoints will not be enrolled on study as all study related procedures are mandatory. 6. Concomitant treatment with full dose warfarin (coumadin) is NOT allowed. However, treatment with low molecular weight heparin (LMWH) (such as enoxaparin or dalteparin) or rivaroxaban is allowed. Patients on full dose warfarin (coumadin) must be transitioned to either LMWH or rivaroxaban prior to administration of any study related drugs. 7. Recent or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, bleeding, inflammation, emesis, diarrhea \>grade 1). 8. Patients with clinically significant cardiac disease (New York Heart Association Classification III or IV and cardiac arrhythmias not well controlled with medication), or myocardial infarction within the previous six months. 9. Serious, uncontrolled, concurrent infection(s) requiring antibiotics. 10. Pregnant or breastfeeding women: positive pregnancy test within 7 days of starting treatment. 11. Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer. 12. Participation in any investigational drug study within 4 weeks preceding the start of study treatment. 13. Patients with external biliary drains.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| R0 Resection Rates in Each Cohort as Measured by Macroscopically Complete Tumor Removal With Negative Microscopic Surgical Margins | at the time of surgery | R0 resection rates will be measured in patients with resectable PDAC and with patients with borderline-resectable PDAC, independently in response to neoadjuvant sequential therapy of combination of nab-paclitaxel and gemcitabine and SBRT, as perioperative therapy. R0 resection is determined by macroscopically complete tumor removal with negative microscopic surgical margins in the bile duct, pancreatic parenchyma, and superior mesenteric artery (SMA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Related Adverse Events as Assessed by CTCAE v.4.03 | 24 months | — |
| Median Overall Survival | Up to 74 months | Overall survival will be assessed for all participants |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nab-paclitaxel and Gemcitabine for R-PDAC Nab-paclitaxel and gemcitabine, for R-PDAC patients enrolled in this trial, will be given in combination as neoadjuvant combination chemotherapy, followed by SBRT. This is will be followed up by surgical resection and an additional combination chemotherapy of nab-paclitaxel and gemcitabine as adjuvant chemotherapy.
Nab paclitaxel: Nab-paclitaxel and gemcitabine, for R-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.
Gemcitabine: Nab-paclitaxel and gemcitabine, for BR-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. | 19 |
| Nab-paclitaxel and Gemcitabine for BR-PDAC Nab-paclitaxel and gemcitabine, for BR-PDAC patients enrolled in this trial, will be given in combination as neoadjuvant combination chemotherapy, followed by SBRT. This is will be followed up by surgical resection and an additional combination chemotherapy of nab-paclitaxel and gemcitabine as adjuvant chemotherapy.
Nab paclitaxel: Nab-paclitaxel and gemcitabine, for R-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.
Gemcitabine: Nab-paclitaxel and gemcitabine, for BR-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. | 29 |
| Total | 48 |
Baseline characteristics
| Characteristic | Nab-paclitaxel and Gemcitabine for R-PDAC | Nab-paclitaxel and Gemcitabine for BR-PDAC | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 20 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 9 Participants | 14 Participants |
| Age, Continuous | 68.35 years STANDARD_DEVIATION 8.3 | 68.4 years STANDARD_DEVIATION 8.8 | 68.4 years STANDARD_DEVIATION 8.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 26 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 16 Participants | 24 Participants | 40 Participants |
| Region of Enrollment United States | 19 participants | 29 participants | 48 participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 26 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 19 | 26 / 29 |
| other Total, other adverse events | 19 / 19 | 29 / 29 |
| serious Total, serious adverse events | 10 / 19 | 17 / 29 |
Outcome results
Primary
R0 Resection Rates in Each Cohort as Measured by Macroscopically Complete Tumor Removal With Negative Microscopic Surgical Margins
R0 resection rates will be measured in patients with resectable PDAC and with patients with borderline-resectable PDAC, independently in response to neoadjuvant sequential therapy of combination of nab-paclitaxel and gemcitabine and SBRT, as perioperative therapy. R0 resection is determined by macroscopically complete tumor removal with negative microscopic surgical margins in the bile duct, pancreatic parenchyma, and superior mesenteric artery (SMA).
Time frame: at the time of surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nab-paclitaxel/Gemcitabine for R-PDAC | R0 Resection Rates in Each Cohort as Measured by Macroscopically Complete Tumor Removal With Negative Microscopic Surgical Margins | 9 participants with resectable PDAC |
| Nab-paclitaxel/Gemcitabine for BR-PDAC | R0 Resection Rates in Each Cohort as Measured by Macroscopically Complete Tumor Removal With Negative Microscopic Surgical Margins | 9 participants with resectable PDAC |
Secondary
Median Overall Survival
Overall survival will be assessed for all participants
Time frame: Up to 74 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nab-paclitaxel/Gemcitabine for R-PDAC | Median Overall Survival | 17.4 months |
| Nab-paclitaxel/Gemcitabine for BR-PDAC | Median Overall Survival | 15.5 months |
Secondary
Number of Participants With Treatment Related Adverse Events as Assessed by CTCAE v.4.03
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nab-paclitaxel/Gemcitabine for R-PDAC | Number of Participants With Treatment Related Adverse Events as Assessed by CTCAE v.4.03 | 19 Participants |
| Nab-paclitaxel/Gemcitabine for BR-PDAC | Number of Participants With Treatment Related Adverse Events as Assessed by CTCAE v.4.03 | 29 Participants |