Clinical Trials /

Vaccine Therapy and Pembrolizumab in Treating Patients With Solid Tumors That Have Failed Prior Therapy

NCT02432963

Description:

This phase I trial studies the side effects of vaccine therapy and pembrolizumab in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment, that have failed prior therapy, and that cannot be removed by surgery. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving vaccine therapy together with pembrolizumab may be a better treatment in patients with solid tumors.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Vaccine Therapy and Pembrolizumab in Treating Patients With Solid Tumors That Have Failed Prior Therapy
  • Official Title: A Phase I Study of a p53MVA Vaccine in Combination With Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: 15002
  • SECONDARY ID: NCI-2015-00653
  • SECONDARY ID: 15002
  • NCT ID: NCT02432963

Conditions

  • Adult Solid Neoplasm
  • Bladder Carcinoma
  • Colon Carcinoma
  • Estrogen Receptor Negative
  • Head and Neck Squamous Cell Carcinoma
  • Hepatocellular Carcinoma
  • HER2/Neu Negative
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Carcinoma
  • Progesterone Receptor Negative
  • Rectal Carcinoma
  • Renal Cell Carcinoma
  • Soft Tissue Sarcoma
  • Triple-Negative Breast Carcinoma
  • TP53 Gene Mutation
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
Modified Vaccinia Virus Ankara Vaccine Expressing p53MVA-p53 Vaccine, MVAp53 VaccineTreatment (p53MVA, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (p53MVA, pembrolizumab)

Purpose

This phase I trial studies the side effects of vaccine therapy and pembrolizumab in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment, that have failed prior therapy, and that cannot be removed by surgery. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving vaccine therapy together with pembrolizumab may be a better treatment in patients with solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of combined p53MVA vaccine (modified vaccinia
      virus Ankara vaccine expressing p53) and pembrolizumab that are well-tolerated in patients
      with refractory, tumor protein 53 (p53) over expressing cancer.

      SECONDARY OBJECTIVES:

      I. To evaluate clinical response and anti-p53 T cell immune responses.

      OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes followed by
      modified vaccinia virus Ankara vaccine expressing p53 subcutaneously (SC) at least 30
      minutes later once in weeks 1, 4, and 7.

      Patients may receive additional doses of pembrolizumab in weeks 10, 13, 16, and 19, for a
      maximum of 7 doses if there are no signs of progressive disease. Treatment continues in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (p53MVA, pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes followed by modified vaccinia virus Ankara vaccine expressing p53 SC at least 30 minutes later once in weeks 1, 4, and 7. Patients may receive additional doses of pembrolizumab in weeks 10, 13, 16, and 19, for a maximum of 7 doses if there are no signs of progressive disease. Treatment continues in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Since p53 mutations occur in a wide variety of tumor types, this is a mixed histology
                 study for incurable tumors; subjects with the following solid tumors are eligible for
                 screening: non-small cell lung cancer, squamous cell carcinoma of the head and neck,
                 hepatocellular carcinoma, renal cell carcinoma, melanoma, bladder, soft tissue
                 sarcoma, triple-negative breast cancer, and colorectal carcinoma displaying
                 microsatellite instability and pancreatic cancer
    
              -  Advanced (unresectable) solid tumors: patients must have failed or been intolerant to
                 at least one line of standard therapy or refuse standard treatment
    
              -  Performance status: patients must have an Eastern Cooperative Oncology Group (ECOG)
                 =< 2 (Karnofsky >= 60%)
    
              -  Informed consent: all subjects must have the ability to understand and the
                 willingness to sign an Institutional Review Board (IRB) approved consent form
    
              -  Absolute neutrophil count: >= 1,500/ul
    
              -  Platelets >= 100,000/ul
    
              -  Hemoglobin level: must be greater than 9 g/dL
    
              -  Renal function: calculated or measured creatinine clearance >= 50 ml/min and/or serum
                 creatinine =< 1.6 mg/dl
    
              -  Total bilirubin =< 1.5 x institutional upper limit of normal
    
              -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 times
                 institutional upper normal level (AST and ALT =< 5 times institutional upper normal
                 level, if there is evidence of liver metastasis)
    
              -  Confirmed p53 involvement: patients with p53 over-expression by immunohistochemistry
                 (>= 10% of cells within the tumor staining positive) or those with a p53 mutation as
                 determined by mutational analysis of tumor tissue will be eligible; patients with
                 prior exposure to p53-based vaccines will be eligible
    
              -  Agreement to use adequate contraception: women of child-bearing potential must use
                 contraception prior to study entry and for six months after study participation; men
                 that are sexually active whose partners are women of childbearing age must use
                 condoms
    
            Exclusion Criteria:
    
              -  Patients may not be receiving any additional investigational agents or radiation
                 therapy
    
              -  Pregnancy: pregnant women are excluded from this study; should a woman become
                 pregnant or suspect that she is pregnant while participating on the trial, she should
                 inform her treating physician immediately; women who are pregnant or breastfeeding
                 are excluded
    
              -  Patients with known brain metastasis
    
              -  Radiotherapy within 4 weeks prior to entering the study
    
              -  Patients with previous exposure to anti-programmed cell death (PD)-1 or
                 anti-programmed cell death ligand 1 (PDL-1) will not be eligible
    
              -  History of allergy to egg proteins
    
              -  Patients who have not recovered from adverse events due to agents administered more
                 than 4 weeks earlier
    
              -  Concurrent use of systemic corticosteroids (nasal corticosteroids, inhaled steroids,
                 adrenal replacement steroids, and topical steroids are allowed)
    
              -  History of immunodeficiency or autoimmune disease: patients with a history of
                 immunodeficiency, including organ grafts and human immunodeficiency virus (HIV), will
                 not be eligible
    
              -  Patients with a history of autoimmune disease will also be excluded, specifically
                 those with any active autoimmune disease or a condition that requires systemic
                 corticosteroids; exceptions to this are subjects with vitiligo and type I diabetes
                 mellitus, who will be permitted to enroll
    
              -  Patients with a history of severe immune-mediated adverse reactions with ipilimumab:
                 this will be defined as any grade 4 toxicity requiring treatment with corticosteroids
                 (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks
    
              -  Patients with a history of cardiac disease are excluded; baseline electrocardiography
                 and assessment of serum troponin (I) are included the screening exams; subjects in
                 whom these assays are abnormal (electrocardiogram [EKG] excluding 1st degree bundle
                 branch block, sinus bradycardia, sinus tachycardia or non-specific T wave changes,
                 serum troponin >= grade 2) are ineligible
    
              -  Non-compliance: if it is the opinion of the investigator that a subject may be unable
                 to comply with the safety monitoring requirements of the study, they will be excluded
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Tolerability of combined modified vaccinia virus Ankara vaccine expressing p53 and pembrolizumab, using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.3
    Time Frame:Up to week 20
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure:Clinical responses, assessed by the modified Response Evaluation Criteria in Solid Tumors (RECIST)
    Time Frame:Up to week 19
    Safety Issue:
    Description:Evaluated using immune-related response criteria (irRECIST, irRC).
    Measure:T cell reactivity to p53, assessed by flow cytometry
    Time Frame:Up to week 19
    Safety Issue:
    Description:Immunosuppressive cell types (MDSC, Tregs) and other selected lymphocyte subsets and markers including PD-1, PDL-1 and PDL-2 will be quantified. The Wilcoxon rank-sum test will be used, and are based on residual re-sampling simulations based on historical AUC values (subtracting baseline) and a hypothesized increase in that AUC.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:City of Hope Medical Center

    Last Updated

    March 30, 2017