Patient case: 49-year-old female with Pancreatic adenocarcinoma. Genetic variant: KRAS, TP53. Other conditions: None.

Clinical trial: High or Standard Intensity Radiation Therapy After Gemcitabine Hydrochloride and Nab-paclitaxel in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery

Summary: This randomized phase II trial studies how well high or standard intensity radiochemotherapy after gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) work compared with gemcitabine hydrochloride and nab-paclitaxel alone in treating patients with pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and nab-paclitaxel, 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as capecitabine, may make tumor cells more sensitive to radiation therapy. Giving radiation therapy in different ways and adding chemotherapy may kill more tumor cells. It is not yet known whether high intensity radiochemotherapy after gemcitabine hydrochloride and nab-paclitaxel is more effective than standard intensity radiochemotherapy after gemcitabine hydrochloride and nab-paclitaxel or gemcitabine hydrochloride and nab-paclitaxel alone in treating pancreatic cancer.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine if intensified radiochemotherapy following gemcitabine (gemcitabine hydrochloride) and nab-paclitaxel in patients with unresectable pancreatic cancer will show a signal for improved 2-year overall survival (OS) from 10% to 22.5% as compared to chemotherapy with gemcitabine and nab-paclitaxel alone.
  II. To determine if standard radiochemotherapy, following gemcitabine and nab-paclitaxel, in patients with unresectable pancreatic cancer will show a signal for improved 2-year OS from 10% to 22.5% as compared to chemotherapy with gemcitabine and nab-paclitaxel alone.
  SECONDARY OBJECTIVES:
  I. To evaluate patterns of failure (local and systemic progression) by SMAD family member 4 (SMAD4) status and intensity of radiation therapy.
  II. To evaluate the impact of radiochemotherapy on OS for the subset of SMAD4 intact patients.
  III. To evaluate adverse events associated with the treatments. IV. To evaluate correlation between SMAD4 status determined by immunohistochemistry (IHC) and genetic SMAD4 status.
  OUTLINE: Patients are randomized to 1 of 3 treatment arms.
  ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 4 weeks for *3 courses in the absence of disease progression or unacceptable toxicity. Beginning 3-5 weeks later, patients undergo high-dose intensity-modulated radiation therapy (IMRT) 5 days a week for 6 weeks (28 fractions) and receive concurrent capecitabine orally (PO) twice daily (BID) 5 days a week for 6 weeks.
  ARM II: Patients receive gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation as in Arm I. Beginning 3-5 weeks later, patients undergo standard-dose 3-dimensional conformal radiation therapy (3D-CRT) or IMRT 5 days a week for 6 weeks (28 fractions) and receive capecitabine as in Arm I.
  ARM III: Patients receive gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  NOTE: *In Arms I and II, 2-6 weeks after completion of radiation therapy, patients resume receiving gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation until disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up at 1 month and then every 3 months.

Eligibility: Inclusion Criteria:
  -  Histologically or cytologically proven diagnosis of adenocarcinoma of the pancreas prior to registration
  -  Tumor diameter =< 7 cm
  -  Unresectable by radiographic criteria (pancreas protocol computed tomography [CT] or magnetic resonance imaging [MRI]) or exploration within 30 days prior to registration
  -  A cell block or core biopsy must be submitted for central review and analysis of SMAD4 status as soon as possible following step 1 registration
  -  No distant metastases, based upon the following minimum diagnostic workup:
  -  History/physical examination within 30 days prior to registration
  -  Whole body fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT within 30 days prior to registration
  -  NOTE: if whole-body FDG-PET/CT is not performed, CT of the chest and CT (or MRI) of abdomen and pelvis must be obtained (imaging of abdomen and pelvis need not be repeated if already included in pancreas protocol study)
  -  Zubrod performance status 0-1 within 30 days prior to registration
  -  Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
  -  Platelets >= 100,000 cells/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)
  -  Cancer antigen 19-9 (CA19-9); NOTE: in the event that a stent has been placed and biliary obstruction has been relieved, the CA19-9 should be drawn post stent placement
  -  Creatinine < 2 mg/dl; glomerular filtration rate (GFR) > 50 mL/min (Cockroft and Gault formula)
  -  Bilirubin < 1.5 x upper limit of normal (ULN)
  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
  -  Activated partial thromboplastin time (aPTT) =< 1.2 x ULN
  -  Prothrombin time (PT) =< 1.2 x ULN
  -  Patient must provide study specific informed consent prior to study entry
  -  Women of childbearing potential and male participants must practice adequate contraception during protocol treatment and for at least 6 months following treatment
  -  For females of child-bearing potential, negative serum pregnancy test within 30 days prior to registration
  Exclusion Criteria:
  -  More than one primary lesion
  -  Prior invasive malignancy (unless disease free for a minimum of 1095 days [3 years]); non-melanomatous skin cancer and previous early prostate cancer that had a non-rising prostate-specific antigen (PSA) are eligible
  -  Prior systemic anti-cancer therapy for pancreatic cancer; note that prior chemotherapy for a different cancer is allowable
  -  Prior radiation therapy to the abdomen that would result in overlap of radiation therapy fields
  -  Severe, active co-morbidity, defined as follows:
  -  Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  -  Transmural myocardial infarction within the last 6 months
  -  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 within 30 days before registration
  -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
  -  Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients
  -  Pregnancy or women of childbearing potential, women who cannot discontinue breastfeeding and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  -  Prior allergic reaction to the study drug(s) involved in this protocol
  -  Pre-existing grade 2 or greater neuropathy
  -  Distant metastases

Relevance to patient case: not relevant