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CRS-207, Nivolumab, and Ipilimumab with or without A Vaccine (GVAX Pancreas Vaccine) and Cyclophosphamide in Treating Patients with Metastatic Pancreatic Ductal Cancer

Trial Status: Active

This phase II trial studies how well CRS-207, nivolumab, and ipilimumab with or without GVAX pancreas vaccine and cyclophosphamide work in treating patients with pancreatic ductal cancer that has spread to other places in the body. Vaccines made from inserting a laboratory-treated gene into a person's tumor cells, such as CRS-207, may help the body build an effective immune response to kill tumor cells that express mesothelin. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. GVAX pancreas vaccine is made by putting the GM-CSF gene into the pancreatic cancer cells. GM-CSF helps to activate immune system cells to recognize and attack their cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, 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. It is not yet known whether giving CRS-207, nivolumab, and ipilimumab with or without GVAX pancreas vaccine and cyclophosphamide will work better in treating patients with pancreatic ductal cancer.

Inclusion Criteria

  • Have histologically- or cytologically-proven ductal adenocarcinoma of the pancreas. Patients with mixed histology (> 30% non-adenocarcinoma component) will be excluded
  • Have metastatic disease
  • Have documented radiographic disease progression at the time of study enrollment, after previous systemic chemotherapy given in a neoadjuvant, adjuvant, locally advanced or metastatic setting
  • Presence of at least one lesion with measurable disease as defined by 10 mm in longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node by RECIST 1.1
  • Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Life expectancy of greater than 3 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Lymphocyte count >= 800/mcL
  • Platelets >= 100 x 10^3/uL
  • Hemoglobin >= 9.0 g/dL
  • Total bilirubin =< upper limit of normal (ULN) except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x ULN
  • Alkaline phosphatase =< 5.0 x ULN
  • Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min
  • Albumin >= 3.0 g/dL
  • 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 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 5 months 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 7 months 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
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • Patient has a known history or evidence of brain metastases
  • Patient who has had chemotherapy, radiation, or biological cancer therapy within 14 days prior to the first dose of study drug
  • Patient has received an investigational agent or used an investigational device within 28 days of the first dose of study drug
  • Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study
  • Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
  • Patients who have received any prophylactic vaccine within 14 days of first dose of study drug (7 days for the COVID vaccine) or received a live vaccine within 30 days of planned start of study therapy
  • Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibodies
  • Have used any systemic steroids within 14 days of study treatment
  • Use more than 2 g/day of acetaminophen
  • Patients on immunosuppressive agents (e.g., TNF pathway inhibitors, PI3 kinase inhibitors) within 7 days of study treatment
  • Patients receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration. Use of such agents while on study is also prohibited
  • Patient has a known allergy to both penicillin and sulfa
  • 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 or CRS-207 (e.g., glycerol)
  • Have current or prior history of infection or clinically significant adverse events (AEs) associated with an exogenous implant(s) or device(s) that has not and cannot be easily removed
  • Subjects who have implanted medical devices that pose high risks for colonization and cannot be easily removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic screw[s], metal plate[s]) if infection occurs. Other common devices such as venous access devices (e.g., Port-a-Cath or Mediport) may be permitted as well as arterial and venous stents and dental and breast implants
  • Evidence of clinical ascites. Trace or small amounts of radiographic ascites may be approved by the protocol chair
  • Have clinically significant and/or malignant pleural effusion (pleural effusions that are not clinically significant are allowed, defined as no more than 25% fluid level of the corresponding hemithorax and stable fluid level [non-progressive] over at least 6 weeks documented radiographically)
  • Have had a new pulmonary embolism, extremity deep venous thromboembolism, or portal vein thrombosis within 2 months of study enrollment (any thrombosis within 2 months of study enrollment may be approved by the protocol chair)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Subjects with active, known or suspected autoimmune disease. Subjects with Graves or Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
  • Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Instances where loss of the graft is not a clinical concern (such as dental bone grafts or skin grafts placed only to promote skin growth) can be approved by the protocol chair. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded
  • All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE], version 4.03) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long-lasting sequelae, such as neuropathy after chemotherapy, are permitted to enroll
  • 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
  • Patient has an unhealed surgical wound or ulcer, or a bone fracture considered non-healing
  • Patient has clinically significant heart disease (such as uncontrolled angina, myocardial infarction within the last 3 months or congestive heart failure of New York Heart Association III or IV)
  • Patient has valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis
  • Have insufficient peripheral venous access to permit completion of the study dosing and compliance with study phlebotomy regimen
  • Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
  • Patient is unwilling or unable to follow the study schedule for any reason
  • Patient is pregnant or breastfeeding
  • Have rapidly progressing disease, as judged by the investigator (e.g., rapid progression through prior treatment[s])

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Dung Thi Le
Phone: 443-287-0002
Email: dle@jhmi.edu

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR) using Response Evaluation Criteria for Solid Tumors (RECIST 1.1) in two cohorts of subjects with previously treated metastatic pancreatic cancer: Arm A treated with cyclophosphamide (CY)/nivolumab/ipilimumab/allogeneic GM-CSF-secreting lethally irradiated pancreatic tumor cell vaccine (GVAX pancreas vaccine) followed by nivolumab/ipilimumab/live-attenuated listeria encoding human mesothelin vaccine CRS-207 (CRS-207) and Arm B treated with nivolumab/ipilimumab/CRS-207.

SECONDARY OBJECTIVE:

I. To assess safety and characterize toxicities of each vaccine treatment regimen when combined with anti-PD-1 and anti-CTLA-4 blockade in subjects with metastatic pancreatic adenocarcinoma.

EXPLORATORY OBJECTIVES:

I. To assess the overall survival (OS).

II. To assess progression free survival (PFS), duration of response (DOR), and time to progression (TTP) by RECIST 1.1.

III. To measure tumor marker kinetics (CA 19-9) in subjects receiving treatment and correlate with OS, PFS, and best overall response.

IV. To assess the ORR, PFS, and DOR by immune-related response criteria (irRC).

V. To collect peripheral blood mononuclear cells (PBMC), plasma, and serum to identify potential therapeutic targets, biomarkers and predictors of response (OS, PFS and best overall response) and autoimmune toxicity.

VI. To collect archived tissue and pre- and post-treatment biopsies to test for predictors of response (OS, PFS, and best overall response) and future targets for combinatorial therapy.

VII. To collect stool and oral wash samples pre- and post-treatment to identify candidate gut microbial biomarkers and predictors of response (OS, PFS and best overall response).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab IV over 30 minutes on day 1. Patients also receive cyclophosphamide intravenously (IV) over 30 minutes on day 1 of cycles 1-2, ipilimumab IV over 30 minutes on day 1 of cycles 1, 3, and 5, GVAX pancreas vaccine intradermally (ID) on day 2 of cycles 1-2, and CRS-207 IV over 1 hour on day 2 of cycles 3-6. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nivolumab IV over 30 minutes on day 1. Patients also receive ipilimumab IV over 30 minutes on day 1 of cycles 1, 3, and 5 and CRS-207 IV over 1 hour on day 2 of cycles 1-6. Treatment repeats every 3 weeks for 6 cycles the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at day 100 and every 3 months thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Dung Thi Le

  • Primary ID J1790
  • Secondary IDs NCI-2018-03630, CRMS-66805, IRB00137389
  • Clinicaltrials.gov ID NCT03190265