Epacadostat, Pembrolizumab, and CRS-207 with or without Cyclophosphamide and a Vaccine (GVAX Pancreas Vaccine) in Treating Patients with Metastatic Pancreatic Cancer

Status: Active

Description

This phase II trial studies the side effects and best dose of epacadostat and to see how well it works when given together with pembrolizumab and CRS-207 with or without cyclophosphamide and GVAX pancreas vaccine in treating patients with pancreatic cancer that has spread to other places in the body. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CRS-207 may cause the immune system to attack cells with mesothelin, which may then kill 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. Proteins in GVAX pancreas vaccine may help to activate the immune system cells (the body’s system to fight infection or disease) to recognize and attack cancer cells. It is not yet known whether given epacadostat, pembrolizumab, and CRS-207 with cyclophosphamide and GVAX pancreas vaccine works better in treating patients with pancreatic cancer.

Eligibility Criteria

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 progressed after previous systemic chemotherapy given in a neoadjuvant, adjuvant, locally advanced or metastatic setting (progressive disease not required in the dose escalation cohort). Neoadjuvant and adjuvant therapy can only be counted if distant metastases occurred within 6 months of completing systemic chemotherapy. Radiosensitizing doses of chemotherapy are not considered systemic chemotherapy
  • 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 (measurable disease not required in dose escalation cohort)
  • Patients’ 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) (biopsies not required in the dose escalation cohort)
  • 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
  • Absolute 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
  • Albumin >= 3.0 g/dL
  • Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula)
  • 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])
  • Both women and men of childbearing potential must agree to use adequate method of contraception from the screening visit through 120 days after the last dose of study treatment
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • Known history or evidence of brain metastases
  • 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
  • Surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
  • Has received a live vaccine within 30 days of study treatment. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, typhoid, and the intranasal flu vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed
  • History of prior treatment with anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD- L2 antibodies or with IDO inhibitor
  • Use of 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
  • Use of 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
  • Known allergy to both penicillin and sulfa
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Known or suspected hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any study drug component
  • Have current or prior history of infection or clinically significant adverse events (AEs) associated with an exogenous implant(s) or device(s) that 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 or radiographic ascites. Trace or small amounts of radiographic ascites without prior concern for malignant ascites or not associated with peritoneal carcinomatosis may be approved by the protocol chair
  • 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)
  • New pulmonary embolism, extremity deep venous thromboembolism, or portal vein thrombosis within 2 months of study enrollment (asymptomatic, incidental 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
  • 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
  • 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
  • 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 undetectable viral load at screening)
  • Pulse oximetry of < 92% on room air
  • Need for supplemental home oxygen
  • Unhealed surgical wound
  • 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
  • Valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis
  • Insufficient peripheral venous access to permit completion of the study dosing and compliance with study phlebotomy regimen
  • Regular use at the time of consent (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
  • Unwillingness or inability 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])
  • Presence of a gastrointestinal condition that may affect drug absorption
  • Use of monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening
  • Any history of serotonin syndrome (SS) after receiving serotonergic drugs
  • History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening corrected QT (QTc) interval > 480 milliseconds is excluded. In the event that a single QTc is > 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 480 milliseconds. For subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds), the corrected JT (JTc) interval may be used in place of the QTc with sponsor approval. The JTc must be < 340 milliseconds if JTc is used in place of the QTc. Subjects with left bundle branch block are excluded. Note: QTc prolongation due to pacemaker may enroll if the JTc is normal
  • Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
  • History of organ transplant that requires use of immunosuppressive therapy
  • Use of warfarin
  • Any condition that would jeopardize the safety of the subject or compliance with the protocol
  • History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis

Locations & Contacts

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Dung Thi Le
Phone: 443-287-0002
Email: dle2@jhmi.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended dose of epacadostat in combination with pembrolizumab, live-attenuated listeria encoding human mesothelin vaccine CRS-207 (CRS-207), cyclophosphamide (CY) and autologous GM-CSF-secreting lethally irradiated pancreatic cancer vaccine (GVAX pancreas vaccine). (Part 1)

II. To determine the 6 month survival rate in previously treated metastatic pancreatic cancer patients receiving epacadostat, pembrolizumab, and CRS-207 with or without CY and GVAX pancreas vaccine. (Part 2)

SECONDARY OBJECTIVES:

I. To assess safety and characterize toxicities of anti-programmed death-1 (PD-1), indoleamine 2,3-dioxygenase 1 (IDO1) blockade, and CRS-207 with or without CY/GVAX pancreas vaccine.

II. To assess overall survival (OS), progression-free survival (PFS), objective response rate (ORR), best overall response (BOR), duration of response (DOR), duration of clinical benefit (DCB), time to objective response (TTOR), and disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as well as by immune related response criteria (irPFS, irORR, irBOR, irDOR, irDCB, irTTOR, irDCR) in each arm.

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

EXPLORATORY OBJECTIVES:

I. To collect baseline and longitudinal peripheral blood mononuclear cells (PBMC), plasma, and serum to identify potential therapeutic targets, biomarkers, and predictors of response and autoimmune toxicity.

II. To collect archived tissue and pre- and on-treatment biopsies to test for predictors of response (OS, PFS and BOR) and future targets for combinatorial therapy.

III. To collect stool samples pre- and on-treatment to identify candidate gut microbial biomarkers and predictors of response (OS, PFS and BOR).

OUTLINE: This is a dose-escalation study of epacadostat. Patients are randomized to 1 of 2 arms.

ARM A: Patients receive epacadostat orally (PO) twice daily (BID) and pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also receive cyclophosphamide IV over 30 minutes on day 1 and GVAX pancreas vaccine via six intradermal injections on day 2 of cycles 1 and 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 epacadostat PO BID, pembrolizumab IV over 30 minutes on day 1, and CRS-207 IV over 1 hour on day 2. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 90 days and every 12 weeks.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Dung Thi Le

Trial IDs

Primary ID J16173
Secondary IDs NCI-2019-00172, CRMS-65666, IRB00118520
Clinicaltrials.gov ID NCT03006302