Vaccine Therapy with or without Nivolumab or Urelumab before and after Surgery in Treating Patients with Stage I-IIB Pancreatic Cancer That Can Be Removed by Surgery

Status: Active

Description

This randomized phase I / II trial studies how well vaccine therapy with or without nivolumab or urelumab before and after surgery works in treating patients with stage I-IIB pancreatic cancer that can be removed by surgery. Vaccines, such as GVAX pancreatic cancer vaccine, made from gene-modified tumor cells may help the body build an immune response to kill tumor cells. Monoclonal antibodies, such as nivolumab and urelumab, may block tumor growth in different ways by targeting certain cells. Giving vaccine therapy with or without nivolumab or urelumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving vaccine therapy with or without nivolumab or urelumab after surgery may kill any remaining tumor cells. It is not yet known if vaccine therapy is more effective with or without nivolumab or urelumab before and after surgery in treating patients with pancreatic cancer.

Eligibility Criteria

Inclusion Criteria

  • Have a newly diagnosed, biopsy-proven adenocarcinoma of the head, neck and uncinate of the pancreas, and is a candidate for a pancreaticoduodenectomy; if the biopsy is not sufficient for diagnosis, the patient can be considered to meet eligibility if the study team agrees that clinically the patient’s tumor is suspected to be adenocarcinoma
  • Patient’s tumor must be deemed resectable by the study team prior to registration; borderline resectable patients will be excluded
  • Ability to understand and willingness to sign a written informed consent document
  • Agree to undergo a core biopsy of the pancreatic tumor for both research and diagnosis purposes if a prior core biopsy is not performed or the core biopsy specimen is not available for the research purpose of this study
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • White blood cell count (WBC) >= 2000/uL
  • Neutrophils >= 1500/uL
  • Absolute lymphocyte count (ALC) >= 500/uL
  • Platelets >= 100 x 10^3/uL
  • Hemoglobin >= 9.0 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula)
  • Aspartate aminotransferase (AST) =< 3.5 x ULN
  • Alanine aminotransferase (ALT) =< 3.5 x ULN
  • Amylase =< 2 X ULN
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) * WOCBP must agree to follow instructions for highly effective method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total of 23 weeks post treatment completion * Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion * Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception * Women must not be breastfeeding * At least one barrier method of contraception must be employed by all sexually active patients (male and female), regardless of other methods, to prevent the transfer of body fluids
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Have a surgically resected (R0 or R1) American Joint Committee on Cancer (AJCC) pathologic stage I or stage II adenocarcinoma of the head, neck, or uncinate of the pancreas; (following study treatment #1, if the patient’s tumor is found intraoperatively to be limited to the distal portion (body or tail) of the pancreas and is resected by distal pancreatectomy, the patient may continue to receive study treatments but will be considered non-evaluable for the primary and efficacy endpoints and will be followed for additional endpoints;) the patients with an R2 resection will not be eligible for the continuation of the study; patients with intraoperative findings of metastatic disease will not be eligible for the continuation of the study
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: ECOG performance 0-1
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Absolute neutrophil count (ANC) >= 1500/mm^3
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Platelet count >= 100,000/mm^3
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Hemoglobin >= 9 gm/dl
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Total bilirubin =< 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin =< 2.0 x ULN)
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: AST and ALT =< 2 X upper level of normal
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Alkaline phosphatase (alk phos) =< 5 X upper level of normal
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Serum creatinine =< 2 mg/dl
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Absolute lymphocyte count >= 500/mm^3
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) * WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total of 23 weeks post treatment completion * Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion * At least one barrier method of contraception must be employed by all sexually active patients (male and female), regardless of other methods, to prevent the transfer of body fluids

Exclusion Criteria

  • History of any autoimmune disease, including but not limited to: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis); patients with Graves or Hashimoto’s disease, vitiligo, and type I diabetes mellitus will be allowed
  • Systemic steroid therapy or immunosuppressive therapy within 14 days before vaccine administration
  • Major active medical or psychosocial problems that could be exacerbated by the study treatment
  • Evidence of active infections
  • Have received any type of cancer immunotherapy including the same pancreatic cancer vaccine
  • Have received any anti-pancreatic cancer therapy (symptomatic therapies are allowed)
  • Pregnant or breastfeeding
  • Have been diagnosed with another cancer or myeloproliferative disorder in the past 5 years except for superficial bladder cancer, non-melanoma skin cancers, or a low grade prostate cancer not requiring therapy
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other component of GVAX pancreas vaccine
  • Have received a diagnosis of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (patients who are hepatitis C antibody positive may be enrolled if they are confirmed with negative viral load at screening)
  • Patient has a pulse oximetry of < 92% on room air
  • Patient is on supplemental home oxygen
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Radiographic evidence of pancreatic cancer recurrence
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Not able to receive the vaccination within 10 weeks following the surgery secondary to a delayed recovery from the surgery
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Major active medical or psychosocial problems that could be exacerbated by this treatment
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: History of any autoimmune disease, including but not limited to: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis); patients with Graves or Hashimoto’s disease, vitiligo, and type I diabetes mellitus will be allowed
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Systemic steroid or immunosuppressive therapy within 14 days before vaccine administration
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Evidence of active infections
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Pregnant or breastfeeding
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Have been diagnosed with another cancer or myeloproliferative disorder in the past 5 years except for superficial bladder cancer, non-melanoma skin cancers, or a low grade prostate cancer not requiring therapy
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: History of severe hypersensitivity reaction to any monoclonal antibody
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other component of GVAX pancreas vaccine
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Have received a diagnosis of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (patients who are hepatitis C antibody positive may be enrolled if they are confirmed with negative viral load at screening)
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Patient has a pulse oximetry of < 92% on room air
  • ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Patient is on supplemental home oxygen

Locations & Contacts

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Lei Zheng
Phone: 410-502-6214
Email: lzheng6@jhmi.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To compare interleukin-17A (IL17A) expression in vaccine-induced lymphoid aggregates between resected pancreatic ductal adenocarcinomas (PDAs) from patients treated with the combination of GVAX pancreatic cancer vaccine (GVAX) with low dose cyclophosphamide (Cy) and anti-programmed cell death (PD-1) blockade antibody versus (vs.) the treatment of GVAX with low dose Cy alone vs. the combination of GVAX, low dose Cy, anti-PD-1 blockade antibody, and anti-CD137 agonist antibody.

SECONDARY OBJECTIVES:

I. To assess the safety of nivolumab with or without urelumab when given in combination with a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting pancreatic vaccine as neoadjuvant and adjuvant treatments.

II. To assess overall survival (OS) and disease free survival (DFS) of patients treated with the combination of GVAX with cyclophosphamide and anti-PD-1 blockade antibody vs. the treatment of GVAX with low dose cyclophosphamide alone vs. the combination of GVAX, low dose Cy, anti-PD-1 blockade antibody, and anti-CD137 agonist antibody.

III. To assess the effects of anti-PD-1 antibody in combination with Cy/GVAX vs. the combination of Cy/GVAX, anti-PD-1antibody, and anti-CD137 antibody on PD-L1/PD-1 associated pathways, vaccine-induced immune regulatory signatures, and peripheral and intratumoral antigen specific T cell responses.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A:

NEOADJUVANT IMMUNOTHERAPY: Patients receive cyclophosphamide intravenously (IV) over 30 minutes on day 0 and GVAX pancreatic cancer vaccine intradermally (ID) on day 1.

SURGERY: Patients undergo standard of care pancreaticoduodenectomy 2 weeks after vaccination.

POST-OPERATIVE IMMUNOTHERAPY: Within 6-10 weeks following surgery, patients receive cyclophosphamide IV over 30 minutes on day 0 and GVAX pancreatic cancer vaccine ID on day 1.

ADJUVANT CHEMORADIATION: Patients then receive standard of care fluorouracil, capecitabine, and gemcitabine hydrochloride and undergo radiation therapy over 26-28 weeks.

POST-CHEMORADIATION VACCINATION: Within 4-8 weeks after completion of chemoradiation, patients receive cyclophosphamide IV over 30 minutes on day 0 and GVAX pancreatic cancer vaccine ID on day 1. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

EXTENDED STUDY DRUG ADMINISTRATION PHASE: Beginning 4 weeks after post-chemoradiation vaccination, patients receive cyclophosphamide IV over 30 minutes on day 0 and GVAX pancreatic cancer vaccine ID on day 1. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

ARM B:

NEOADJUVANT IMMUNOTHERAPY: Patients receive GVAX pancreatic cancer vaccine intradermally and cyclophosphamide IV as in Arm A, and nivolumab IV over 60 minutes on day 0.

SURGERY: Patients undergo standard of care pancreaticoduodenectomy 2 weeks after vaccination.

POST-OPERATIVE IMMUNOTHERAPY: Patients receive cyclophosphamide and GVAX pancreatic cancer vaccine intradermally and cyclophosphamide IV as in Arm A, and nivolumab IV over 60 minutes on day 0.

ADJUVANT CHEMORADIATION: Patients then receive standard of care chemoradiation as in Arm A.

POST-CHEMORADIATION VACCINATION: Patients receive cyclophosphamide and GVAX pancreatic cancer vaccine intradermally as in Arm A and nivolumab IV over 60 minutes on day 0. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

EXTENDED STUDY DRUG ADMINISTRATION PHASE: Beginning 4 weeks after post-chemoradiation vaccination, patients receive cyclophosphamide IV over 30 minutes the day 0 and GVAX pancreatic cancer vaccine on day 1. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV every 4 weeks for 3 doses in the absence of disease progression or unacceptable toxicity.

ARM C:

NEOADJUVANT IMMUNOTHERAPY: Patients receive GVAX pancreatic cancer vaccine intradermally and cyclophosphamide IV as in Arm A, and nivolumab IV as in Arm B, followed by urelumab IV over 60 minutes on day 0.

SURGERY: Patients undergo standard of care pancreaticoduodenectomy 2 weeks after vaccination.

POST-OPERATIVE IMMUNOTHERAPY: Patients receive GVAX pancreatic cancer vaccine intradermally, cyclophosphamide IV as in Arm A, nivolumab IV as in Arm B, followed by urelumab IV over 60 minutes on day 0.

ADJUVANT CHEMORADIATION: Patients then receive standard of care chemoradiation as in Arm A.

POST-CHEMORADIATION VACCINATION: Patients receive cyclophosphamide and GVAX pancreatic cancer vaccine intradermally as in Arm A and nivolumab IV as in Arm B followed by urelumab IV over 60 minutes on day 0. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

EXTENDED STUDY DRUG ADMINISTRATION PHASE: Beginning 4 weeks after post-chemoradiation vaccination, patients receive cyclophosphamide IV over 30 minutes on day 0 and GVAX pancreatic cancer vaccine on day 1. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive of nivolumab IV and of urelumab every 4 weeks for 3 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, every 3 months for 24 months and then every 6 months for 12 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Lei Zheng

Trial IDs

Primary ID J1568
Secondary IDs NCI-2016-00268, IRB00050517, CRMS-61622
Clinicaltrials.gov ID NCT02451982