Clinical Trials /

Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer

NCT03300843

Description:

Background: Exomes are the parts of deoxyribonucleic acid (DNA) that make proteins. Researchers are finding a way to read the letters in the exome. Incorrect letters are called mutations. Tumors contain specific mutations. Researchers can find these mutations in tumors to make treatments. Researchers want to use pieces of participants tumors to find the tumor-specific mutations. They also will take participants white blood cells to make a vaccine that they hope will shrink the tumors. Objectives: To see if dendritic vaccine tumor-fighting cells are safe and can cause certain cancer tumors to shrink. Eligibility: Adults ages 18-70 who have metastatic melanoma or metastatic epithelial cancer Design: The first part of this study was done under protocol 03-C-0277. In that study, white blood cells and pieces of participants' tumors were taken to make a vaccine. In this study, participants will get a vaccine every 2 weeks for 8 weeks. It will be given both in a vein and under the skin. At each visit, participants will have a physical exam and have blood taken. They will talk about any side effects they have. After treatment ends, participants will have many follow-up visits for the first year, then once each year after that. Visits will last up to 2 days each. They will include lab tests, imaging studies, and a physical exam. Blood will be taken at each visit. At the first follow-up visit, participants may have leukapheresis, which they also had as part of protocol 03-C-0277. Participants may not have to return to the Clinical Center for these visits.

Related Conditions:
  • Carcinoma
  • Melanoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer
  • Official Title: A Phase II Trial to Evaluate the Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer

Clinical Trial IDs

  • ORG STUDY ID: 170177
  • SECONDARY ID: 17-C-0177
  • NCT ID: NCT03300843

Conditions

  • Melanoma
  • Gastrointestinal Cancer
  • Breast Cancer
  • Ovarian Cancer
  • Pancreatic Cancer

Interventions

DrugSynonymsArms
Peptide loaded dendritic cell vaccine1/Experimental Therapy

Purpose

Background: Exomes are the parts of DNA that make proteins. Researchers are finding a way to read the letters in the exome. Incorrect letters are called mutations. Tumors contain specific mutations. Researchers can find these mutations in tumors to make treatments. Researchers want to use pieces of participants tumors to find the tumor-specific mutations. They also will take participants white blood cells to make a vaccine that they hope will shrink the tumors. Objectives: To see if dendritic vaccine tumor-fighting cells are safe and can cause certain cancer tumors to shrink. Eligibility: Adults ages 18-70 who have metastatic melanoma or metastatic epithelial cancer Design: The first part of this study was done under protocol 03-C-0277. In that study, white blood cells and pieces of participants' tumors were taken to make a vaccine. In this study, participants will get a vaccine every 2 weeks for 8 weeks. It will be given both in a vein and under the skin. At each visit, participants will have a physical exam and have blood taken. They will talk about any side effects they have. After treatment ends, participants will have many follow-up visits for the first year, then once each year after that. Visits will last up to 2 days each. They will include lab tests, imaging studies, and a physical exam. Blood will be taken at each visit. At the first follow-up visit, participants may have leukapheresis, which they also had as part of protocol 03-C-0277. Participants may not have to return to the Clinical Center for these visits.

Detailed Description

      Background:

        -  Therapeutic vaccination against cancer has proven very challenging with little clinical
           benefit.

        -  Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer
           testis antigens, and overexpressed antigens. However negative selection in the thymus
           against these normal nonmutated antigens severely limits the ability to generate high
           avidity anti-cancer T cells. Such depletion can impair their antitumor activity and
           limit tumor elimination.

        -  The National Cancer Institute Surgery Branch (NCI SB ) has developed a pipeline for the
           identification of immunogenic T cell epitopes derived from neoantigens.

        -  In recent studies, we identified the neoantigens recognized by TIL that mediated
           regression in patients with metastatic cancer. Using whole exome sequencing of a
           resected metastatic nodule followed by high throughput immunologic screening, we were
           able to demonstrate that tumor regressions were associated with the recognition by the
           administered TIL of unique somatic mutations that occurred in the cancer.

        -  We, therefore, aim to use this pipeline to identify immunogenic neoantigens from
           epithelial cancer patients and to use these defined epitopes for a personalized
           therapeutic dendritic cell (DC) vaccine.

      Objectives:

      -Primary objectives:

      --To determine the clinical response rate in patients with metastatic melanoma or epithelial
      cancer who receive this DC vaccine

      Eligibility:

        -  Age greater than or equal to 18 and less than or equal to 70 years

        -  ECOG 0 - 2

        -  Evaluable metastatic melanoma or epithelial cancer refractory to standard treatment

        -  Metastatic melanoma or epithelial cancer lesion(s) that is resectable for TIL or in
           selected cases, available PBMC.

      Design:

        -  Patients with metastatic melanoma or epithelial cancer will undergo surgical resection
           of tumor followed by exome and RNA sequencing to identify expressed mutations (CONDUCTED
           UNDER THE nci sb COMPANION PROTOCOL 03-c-0277).

        -  Patients will undergo apheresis and DC will be cryopreserved for vaccine preparation.

        -  Immunogenic neoantigens will be identified from TIL and PBMC by high throughput
           immunologic screening using long peptides and tandem minigenes covering all mutated
           epitopes.

        -  Patient will be vaccinated with autologous mature dendritic cells loaded with long
           peptides and minimal epitopes from defined neoantigens or highly expressed mutations in
           tumor suppressor or driver genes.

        -  DC will be administered intravenously and subcutaneously for four cycles at biweekly
           intervals.

        -  Blood samples will be taken every two weeks, and patients will be monitored for the
           quantity and quality of circulating neoantigen-specific T cells.
    

Trial Arms

NameTypeDescriptionInterventions
1/Experimental TherapyExperimentalPeptide loaded dendritic cell vaccine on days 0, 14, 28, and 42
  • Peptide loaded dendritic cell vaccine

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Metastatic melanoma or epithelial cancer with at least one lesion that is resectable
             or in selected cases, available PBMCs

          -  Measurable and evaluable metastatic disease per RECIST 1.1 criteria

          -  Confirmation of the diagnosis of metastatic cancer by the Laboratory of Pathology of
             NCI.

          -  All patients must be refractory to approved standard systemic therapy.

          -  Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
             asymptomatic are eligible. Lesions that have been treated with stereotactic
             radiosurgery must be clinically stable for one month after treatment for the patient
             to be eligible. Patients with surgically resected brain metastases are eligible.

          -  Greater than or equal to 18 years of age and less than or equal to 70 years of age.

          -  Clinical performance status of ECOG 0, 1, 2

          -  Patients of both genders must be willing to practice birth control from the time of
             enrollment on this study and for up to four months after treatment.

          -  Serology:

               -  Seronegative for HIV antibody. (The experimental treatment being evaluated in
                  this protocol depends on an intact immune system. Patients who are HIV
                  seropositive can have decreased immune-competence and thus are less responsive to
                  the experimental treatment and more susceptible to its toxicities.)

               -  Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.
                  If hepatitis C antibody test is positive, then the patient must be tested for the
                  presence of antigen by RT-PCR and be HCV RNA negative.

          -  Hematology

               -  Absolute neutrophil count greater than 1000/mm^3 without the support of
                  filgrastim

               -  WBC greater than or equal to 3000/mm^3

               -  Platelet count greater than or equal to 100,000/mm^3

               -  Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.

               -  CD4 count > 200/uL

          -  Chemistry:

               -  Serum ALT/AST less than 5.0 x ULN

               -  Serum Creatinine less than or equal to 1.6 mg/dl

               -  Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
                  Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0
                  mg/dl.

          -  More than four weeks must have elapsed since any prior systemic therapy at the time
             the patient receives the vaccine, and patients toxicities must have recovered to a
             grade 1 or less (except for toxicities such as alopecia or vitiligo).

        Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as
        long as all toxicities have recovered to grade 1 or less.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

          -  Subjects must be co-enrolled On protocol 03-C-0277.

        EXCLUSION CRITERIA:

          -  Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the treatment on the fetus or infant.

          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          -  Concurrent opportunistic infections (The experimental treatment being evaluated in
             this protocol depends on an intact immune system. Patients who have decreased immune
             competence may be less responsive to the experimental treatment and more susceptible
             to its toxicities).

          -  Active systemic infections (requiring anti-infective treatment), coagulation disorders
             or any other active or uncompensated major medical illnesses.

          -  Patients who are receiving any other investigational agents.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:2 weeks after 4th vaccine (Day 56), then 1 month after Day 56, then every 1-2 months for the 1st year, then annually or as clinically indicated by the PI
Safety Issue:
Description:Percentage of patients who have a clinical response to treatment

Secondary Outcome Measures

Measure:Quantity and quality of circulating antigen-specific T cells
Time Frame:Approximately 6 years after cell infusion
Safety Issue:
Description:Eliza and Elispot assays assessing reactivity to the mutated peptidecompared to the non-mutated peptide
Measure:Frequency of treatment related adverse
Time Frame:Until time of second follow-up evaluation
Safety Issue:
Description:Aggregate of all adverse events and their frequency

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Cell Therapy
  • Immunotherapy
  • Vaccines

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