Combination Chemotherapy and Stereotactic Body Radiation Therapy before Surgery Followed by Combination Chemotherapy in Treating Patients with Pancreatic Cancer That Can Be Removed by Surgery
This phase II clinical trial studies how well combination chemotherapy and stereotactic body radiation therapy before surgery followed by combination chemotherapy works in treating patients with pancreatic cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride, 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. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and stereotactic body radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed, and giving paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride after surgery may kill any remaining tumor cells.
- Histologically confirmed resectable or borderline resectable pancreatic adenocarcinoma; pathology report form
- No evidence of distant metastasis representing stage IV metastatic disease
- Resectable pancreatic ductal adenocarcinoma (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
- Borderline resectable pancreatic ductal adenocarcinoma (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 180 degrees 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 180 degrees of the circumference of the artery wall
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Platelets > 100,000 cells/mm^3
- Hemoglobin > 9.0 g/dL
- Absolute neutrophil count >= 1,500 cells/mm^3
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal
- Alkaline phosphatase =< 2.5 x upper limit of normal
- Total bilirubin =< 1.5 mg/dL
- 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
- Women of childbearing potential and sexually active males must use an effective contraception method during treatment and for three months after completing treatment
- Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of childbearing potential
- Patients must have < grade 2 pre-existing peripheral neuropathy (per Common Terminology Criteria for Adverse Events 4.03 [CTCAE 4.03])
- Ability to understand and willingness to sign a written informed consent
- Patients with locally advanced surgically unresectable PDAC
- Patients with evidence of distant metastatic PDAC
- Prior chemotherapy or radiation therapy of any kind for treatment of pancreas adenocarcinoma
- Prior major surgery within 4 weeks of starting study drug administration
- 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
- 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
- Recent or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, bleeding, inflammation, emesis, diarrhea > grade 1)
- Patients with clinically significant cardiac disease (e.g. congestive heart failure New York Heart Association class III or IV, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication), or myocardial infarction within the previous six months
- Serious, uncontrolled, concurrent infection(s)
- Pregnant or breastfeeding women; positive pregnancy test within 7 days of starting treatment
- Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer
- Participation in any investigational drug study within 4 weeks preceding the start of study treatment
- Patients with external biliary drains
Locations & Contacts
Contact: Tanios Sam Bekaii-Saab
Contact: Aaron James Scott
Contact: Wells A. Messersmith
Contact: Colin Dexter Weekes
Contact: Elliot Newman
Trial Objectives and Outline
I. To estimate the microscopically margin-negative (R0) resection rate in patients with resectable pancreatic ductal adenocarcinoma (PDAC) as well as those with borderline resectable PDAC independently in response to neoadjuvant sequential therapy of combination gemcitabine and nab-paclitaxel followed by stereotactic body radiation therapy (SBRT).
I. To assess safety and feasibility of perioperative therapy with neoadjuvant gemcitabine and nab-paclitaxel (nab-paclitaxel) (paclitaxel albumin-stabilized nanoparticle formulation) chemotherapy followed by stereotactic radiotherapy before surgery in addition to adjuvant gemcitabine and nab-paclitaxel.
II. Estimation of objective response rate in response to neoadjuvant therapy.
III. Estimation of overall survival: overall survival, defined as the time from study treatment initiation until death from any cause.
IV. Estimation of progression-free survival: progression-free survival (PFS), defined as the time from study treatment initiation to the first occurrence of documented disease progression, as determined by the principal investigator (PI) review of tumor assessments using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or death from any cause during the study.
V. Estimation of disease-free survival: disease-free survival, defined as the time from first postoperative computed tomography (CT) scan demonstrating no evidence of malignancy to the time of documented disease progression, as determined by the PI review of tumor assessments using RECIST v1.1, or death from any cause during the study.
VI. Estimation of the histopathologic response rate to neoadjuvant therapy and correlate it to survival outcomes.
I. Correlate the post therapeutic macropinocytosis with other exploratory markers and estimates of clinical outcomes.
II. Correlate pathologic response after neoadjuvant therapy with PFS stratified by ability to undergo surgical resection.
III. Correlate dynamic changes in stromal elasticity associated with chemotherapy administration and clinical outcomes.
IV. Correlate changes in serum cancer antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) levels in response to therapy will be correlated with outcomes.
V. To correlate basal and dynamic changes in biomarkers of tissue secreted protein acidic and rich in cysteine (SPARC), mothers against decapentaplegic homolog 4 (SMAD4) deletion, circulating deoxyribonucleic acid (DNA) analysis of v-Ki-RAS2 Kirsten rat sarcoma 2 viral oncogene homolog gene (KRAS) and gene expression analysis with clinical outcomes.
Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30-40 minutes and gemcitabine hydrochloride IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Within 21-35 days after completion of chemotherapy, patients undergo SBRT on 5 consecutive days over 1-2 weeks for a total of 5 fractions. Within 4-6 weeks after completion of SBRT, patients undergo pancreaticoduodenectomy or distal pancreatectomy. Within 6-12 weeks after surgery, patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes and gemcitabine hydrochloride IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.
Trial Phase & Type
University of Colorado Hospital
Wells A. Messersmith
Secondary IDs NCI-2016-00745, s15-00236
Clinicaltrials.gov ID NCT02723331