Clinical Trials /

Gut Microbiome Modulation to Enable Efficacy of Checkpoint-based Immunotherapy in Pancreatic Adenocarcinoma

NCT03891979

Description:

A multi-institutional, single arm pilot study of antibiotics and pembrolizumab for the treatment of surgically resectable pancreatic cancer. The primary purpose of this study is to determine the change in immune activation in pancreatic tumor tissue following treatment with antibiotics and pembrolizumab.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Suspended

Phase:

Phase 4

Trial Eligibility

Document

Title

  • Brief Title: Gut Microbiome Modulation to Enable Efficacy of Checkpoint-based Immunotherapy in Pancreatic Adenocarcinoma
  • Official Title: A Pilot Study of Gut Microbiome Modulation to Enable Efficacy of Checkpoint-based Immunotherapy in Pancreatic Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 18-00137
  • NCT ID: NCT03891979

Conditions

  • Pancreatic Cancer

Interventions

DrugSynonymsArms
Antibiotics and PembrolizumabPembrolizumab + Antibiotics

Purpose

A multi-institutional, single arm pilot study of antibiotics and pembrolizumab for the treatment of surgically resectable pancreatic cancer. The primary purpose of this study is to determine the change in immune activation in pancreatic tumor tissue following treatment with antibiotics and pembrolizumab.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + AntibioticsExperimentalPembrolizumab will be given for two doses every 3 weeks starting on day 8 (ie days 8 and 29). Antibiotics will continue throughout the entire four week pre-operative period.
  • Antibiotics and Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed pancreatic adenocarcinoma. Histologies other than
             adenocarcinoma, or any mixed histologies, will NOT be eligible. *Note: histology must
             be confirmed prior to study treatment, however, participants may be consented to study
             based on imaging results consistent with pancreatic adenocarcinoma and then undergo
             diagnostic and research biopsy simultaneously.

          -  Clinical stage I and II disease (per AJCC 8th ed)

          -  Resectable pancreatic cancer as defined by NCCN Guidelines 1.2018 and based on
             pancreatic protocol dual-phase CT imaging. Multi-detector computed tomography (MDCT)
             angiography, performed by acquiring thin, preferably sub-millimeter, axial sections
             using a dual-phase pancreatic protocol, with images obtained in the pancreatic and
             portal venous phase of contrast enhancement, is required.

          -  No arterial tumor contact (celiac axis [CA], superior mesenteric artery [SMA], or
             common hepatic artery [CHA])

          -  No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or ≤180°
             contact without vein contour irregularity

          -  Patients must agree to pre-treatment biopsy and definitive surgical resection

          -  ECOG performance status of 0 or 1

          -  No prior treatment for diagnosis of pancreatic cancer

          -  Normal organ and marrow function

          -  Absolute neutrophil count (ANC) ≥1500/µL

          -  Platelets ≥100 000/µL

          -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

          -  Renal Creatinine OR Measured or calculated by creatinine clearance (GFR can also be
             used in place of creatinine or CrCl) ≤1.5 × ULN OR

             ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN

          -  Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total
             bilirubin levels >1.5 × ULN

          -  AST (SGOT) and ALT (SGPT) ≤2.5 × ULN

          -  Coagulation International normalized ratio (INR) OR prothrombin time (PT)

          -  Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is
             receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
             intended use of anticoagulants

          -  ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST
             (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);
             GFR=glomerular filtration rate; ULN=upper limit of normal.

          -  Criteria must be met without erythropoietin dependency and without packed red blood
             cell (pRBC) transfusion within last 2 weeks.

          -  Creatinine clearance (CrCl) should be calculated per institutional standard. Note:
             This table includes eligibility-defining laboratory value requirements for treatment;
             laboratory value requirements should be adapted according to local regulations and
             guidelines for the administration of specific chemotherapies.

          -  Ability to understand and sign a written informed consent document. Participant must
             have willingness and ability to comply with scheduled visits, treatment plans,
             laboratory tests and other study procedures.

          -  A female participant is eligible to participate if she is not pregnant (see Appendix
             1), not breastfeeding, and at least one of the following conditions applies:

          -  Not a woman of childbearing potential (WOCBP) as defined in Appendix 1 OR

          -  A WOCBP who agrees to follow the contraceptive guidance in Appendix 1 during the
             treatment period and for at least 120 days plus 30 days (a menstruation cycle) after
             the last dose of study treatment.

          -  Males who are sexually active with WOCBP must agree to follow instructions for
             method(s) of contraception (see Appendix 1) for the duration of treatment with study
             treatment(s) and for a total of 180 days posttreatment completion. In addition, male
             participants must be willing to refrain from sperm donation during this time.

        Exclusion Criteria:

          -  Borderline resectable, locally advanced or distant metastatic disease

          -  Any medical condition which makes definitive surgical resection of the pancreatic
             cancer contraindicated due to high risk of morbidity/mortality

          -  Has active autoimmune disease that has required systemic treatment in past 2 years
             (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive
             drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic treatment.

             4. Medical history and concurrent disease as below:

             • Participants with a condition requiring systemic treatment with either
             corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
             medications within 14 days of study treatment administration except for adrenal
             replacement steroid doses > 10 mg daily prednisone equivalent in the absence of active
             autoimmune disease.

        Note: Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating
        study treatment is permitted. Participants with asthma that require intermittent use
        intermittent use of bronchodilators, inhaled steroids, or local steroid injections would
        not be excluded from the study.

          -  Interstitial lung disease that is symptomatic or may interfere with the detection or
             management of suspected treatment-related pulmonary toxicity.

          -  Uncontrolled or significant cardiovascular disease including, but not limited to, any
             of the following:

               -  Myocardial infarction or stroke/transient ischemic attack within the past 6
                  months

               -  Uncontrolled angina within the past 3 months

               -  Any history of clinically significant arrhythmias (such as ventricular
                  tachycardia, ventricular fibrillation, or torsades de pointes)

               -  History of other clinically significant heart disease (eg, cardiomyopathy,
                  congestive heart failure with New York Heart Association functional
                  classification III to IV, pericarditis, significant pericardial effusion, or
                  myocarditis)

               -  Cardiovascular disease-related requirement for daily supplemental oxygen therapy.

          -  Evidence of uncontrolled, active infection, requiring parenteral or oral
             anti-bacterial, anti-viral or anti-fungal therapy ≤ 28 days prior to screening on
             study.

          -  Participants with a condition requiring chronic systemic oral treatment with either
             antibiotics or anti-fungals

          -  Any uncontrolled inflammatory GI disease including Crohn's Disease and ulcerative
             colitis.

               -  Participants with active, known, or suspected autoimmune disease. Participants
                  with vitiligo, type I diabetes mellitus, residual hypothyroidism due to
                  autoimmune condition only requiring hormone replacement, euthyroid participants
                  with a history of Grave's disease (participants with suspected autoimmune thyroid
                  disorders must be negative for thyroglobulin and thyroid peroxidase antibodies
                  and thyroid stimulating immunoglobulin prior to first dose of study treatment),
                  psoriasis not requiring systemic treatment, or conditions not expected to recur
                  in the absence of an external trigger are permitted to enroll after discussing
                  with the Principal Investigator.

               -  Has received a live vaccine within 30 days prior to the first dose of study drug.
                  Examples of live vaccines include, but are not limited to, the following:
                  measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
                  Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines
                  for injection are generally killed virus vaccines and are allowed; however,
                  intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are
                  not allowed. *Note: for those participants who will be undergoing planned
                  splenectomy, vaccinations against S. pneumoniae, N. meningitidis, H. influenzae
                  type b and influenza virus should be administered at least 2 weeks after the
                  surgical intervention.

               -  Known human immunodeficiency virus (HIV), known active hepatitis A, or known
                  hepatitis B or C infection.

               -  History of acute diverticulitis within the last 6 months or current chronic
                  diarrhea

               -  Expected to require any other form of antineoplastic or surgical therapy while on
                  study

               -  Pregnant or lactating women

               -  A WOCBP who has a positive urine pregnancy test within 72 hours or no pregnancy
                  test prior to registration (see Appendix 1). If the urine test is positive or
                  cannot be confirmed as negative, a serum pregnancy test will be required.

        Note: in the event that >72 hours have elapsed between the screening pregnancy test and the
        first dose of study treatment, another pregnancy test (urine or serum) must be performed
        and must be negative in order for subject to start receiving study medication.

          -  WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of
             pregnancy (see Appendix 1) for the entire study period and 120 days plus 30 days (a
             menstruation cycle) after the last dose of study treatment. WOCBP who are continuously
             not heterosexually active are also exempt from contraceptive requirements, but still
             must undergo pregnancy testing as described in section 20.

          -  Sexually active fertile men not using effective birth control if their partners are
             WOCBP

          -  History of primary immunodeficiency

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  History of organ allograft or allogeneic bone marrow transplant.

          -  Any prior radiation therapy, immunotherapy, or biologic ('targeted') therapy for
             treatment of the patient's pancreatic tumor. Biliary stent is allowed.

          -  Treatment for other invasive carcinomas within the last two years who are at greater
             than 5% risk of recurrence at time of eligibility screening. Carcinoma in-situ and
             basal cell carcinoma/ squamous cell carcinoma of the skin are allowed.

          -  Participation in any investigational drug study within 4 weeks preceding the start of
             study treatment.

          -  Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment,
             without complete recovery.

          -  History of allergy to study treatments or any of its components
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in immune activation in pancreatic tumor tissue following treatment with antibiotics and pembrolizumab measured by activation of HLA-DR,
Time Frame:12 Weeks
Safety Issue:
Description:activation is defined as an increase of 20% or more over baseline in percentage of T cells expressing the marker.

Details

Phase:Phase 4
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:NYU Langone Health

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