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Nivolumab, Paricalcitol, and Combination Chemotherapy Before and After Surgery for the Treatment of Resectable Pancreatic Cancer

Trial Status: Active

This early phase I trial studies the effect of nivolumab, paricalcitol, and combination chemotherapy before and after surgery in treating patients with pancreatic cancer that can be removed by surgery (resectable). Nivolumab is a cancer therapy that activates the immune system to attack tumor cells by “turning off the brakes” of the immune system. Paricalcitol is the active form of vitamin D and used in the prevention and treatment of hyperparathyroidism (over-active parathyroid, a gland which controls the amount of calcium in blood and in bones) associated with chronic kidney disease. Chemotherapy drugs, such as gemcitabine, nab-paclitaxel, and cisplatin, 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. Giving nivolumab, paricalcitol, and combination chemotherapy before and after surgery may work better than combination chemotherapy alone in treating patients with pancreatic cancer.

Inclusion Criteria

  • Previously untreated, apparently resectable (defined in section 4.5) adenocarcinoma of the pancreas at registration. Histologic confirmation of adenocarcinoma must be obtained before chemotherapy is initiated
  • A tumor biopsy must be obtained before the initiation of treatment for characterization of the tumor subtype (epithelial versus [vs] quasi-mesenchymal [QM]) – unless the patient has usable baseline tissue obtained previously. (Note that patients who meet these inclusion criteria, and have tissue sent for analysis may have treatment initiated with chemotherapy while tissue analysis is completed.)
  • Age greater than or equal to 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Standard laboratory criteria for hematologic, biochemical, and urinary indices within a range that, in the opinion of the physician, clinically supports enrollment of the subject on the trial * Note: subjects must have: creatinine =< 1.5 x upper limit of normal (ULN) AND estimated glomerular filtration Rate (eGFR) >= 50 by Cockcroft-Gault equation, neutrophils > 1.5 x 10^9/L, total bilirubin =< 1.5 x ULN (3 x ULN if due to biliary obstruction), aspartate aminotransferase (AST) =< 3 x ULN (5 x ULN if due to biliary obstruction), alanine aminotransferase (ALT) =< 3 x ULN (5 x ULN if due to biliary obstruction), and platelets > 100,000/mm^3
  • Ability to provide written informed consent
  • Willing and eligible to undergo paired MRI examinations

Exclusion Criteria

  • Subjects with hypercalcemia (blood levels greater than 11.5 mg/dL). In subjects with creatinine clearance 50-60 mL/min, blood calcium levels must be 9.5 mg/dL or lower
  • Subjects who are currently pregnant, planning to become pregnant, or breast-feeding * Females participants of child-bearing potential are required to use an effective contraception method or abstain from intercourse during treatment and for at least 5 months following the last dose * Males participants with partners of child-bearing potential are required to use an effective contraception method or abstain from intercourse during treatment and for at least 7 months following the last dose
  • Subjects who, in the opinion of the physician, would not be clinically appropriate for receipt of the therapy regimen associated with participation
  • Subjects with contraindications to immune checkpoint therapy, as follows: * Interstitial lung disease that is symptomatic or may interfere with the detection and management of suspected drug-related pulmonary toxicity * Prior organ allograft or allogeneic bone marrow transplantation * Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication * Active autoimmune disease, except for vitiligo, type 1 diabetes mellitus, asthma, atopic dermatitis, or endocrinopathies manageable by hormone replacement; other autoimmune conditions may be allowable at the discretion of the principal investigator * Condition requiring systemic treatment with either corticosteroids ** Systemic steroids at physiologic doses (equivalent to dose of oral prednisone 10 mg) are permitted. Steroids as anti-emetics for chemotherapy are strongly discouraged ** Intranasal, inhaled, topical, intra-articular, and ocular corticosteroids with minimal systemic absorption are permitted

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: ACTIVE
Contact: Peter James O'Dwyer
Phone: 215-662-7606

PRIMARY OBJECTIVE:

I. To determine the effect of neoadjuvant targeting of the immune microenvironment with checkpoint blockade and chemotherapy with or without vitamin D in subjects with epithelial-subtype resectable pancreatic cancer through an assessment of (a) tumor fibrosis, (b) profiling of circulating lymphocytes and tumor-infiltrating lymphocytes, (c) expression of vitamin D-regulated genes, and (d) circulating cytokine profiles, and (e) stromal imaging features using dynamic contrast-enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance imaging (MRI).

SECONDARY OBJECTIVES:

I. To describe the effect of gemcitabine/cisplatin/nab-paclitaxel/nivolumab with or without vitamin D on tumor response to neoadjuvant chemotherapy in the primary tumor in epithelial-subtype resectable pancreatic cancer.

II. To determine the safety of this perioperative approach by defining the adverse effects in each arm of the study.

III. To determine the feasibility of this perioperative approach.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A:

CYCLES 1-3: Patients receive nab-paclitaxel intravenously (IV) over 30 minutes, gemcitabine IV over 30-100 minutes, and cisplatin IV over 60 minutes on days 1 and 8. Beginning in cycle 2, patients also receive nivolumab IV over 30 minutes on day 1 and paricalcitol IV on days 1, 8, and 15 (and weekly up until the day prior to surgery). Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: After completion of cycles 1-3, patients undergo standard of care surgical resection.

CYCLES 4-9: Beginning 4-12 weeks after completion of surgical resection, patients receive nab-paclitaxel IV over 30 minutes, gemcitabine IV over 30 minutes, and cisplatin IV over 60 minutes on days 1 and 8. Patients also receive nivolumab IV over 30 minutes on day 1 and paricalcitol IV on days 1, 8, and 15. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM B:

CYCLES 1-3: Patients receive nab-paclitaxel IV over 30 minutes, gemcitabine IV over 30-100 minutes, and cisplatin IV over 60 minutes on days 1 and 8. Beginning in cycle 2, patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: After completion of cycles 1-3, patients undergo standard of care surgical resection.

CYCLES 4-9: Beginning 4-12 weeks after completion of surgical resection, patients receive nab-paclitaxel IV over 30 minutes, gemcitabine IV over 30 minutes, and cisplatin IV over 60 minutes on days 1 and 8. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2-6 weeks, every 6 months for 1 year, and then annually for 4 years.

Trial Phase Phase O

Trial Type Treatment

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Peter James O'Dwyer

  • Primary ID UPCC 22217
  • Secondary IDs NCI-2020-13532
  • Clinicaltrials.gov ID NCT03519308