Clinical Trials /

Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy

NCT03199040

Description:

This is a single institution, open-label randomized phase 1 trial of neoantigen DNA vaccine alone vs. neoantigen DNA vaccine plus durvalumab in triple negative breast cancer (TNBC) patients following standard of care therapy. Patients with newly diagnosed clinical stage II-III TNBC are eligible for enrollment. Patients will receive standard of care therapy including chemotherapy, surgery and radiation therapy as clinically indicated. Following standard of care therapy, patients will be randomized to receive either a neoantigen DNA vaccine alone, or a neoantigen DNA vaccine + durvalumab.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy
  • Official Title: A Randomized Phase 1 Trial of Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy

Clinical Trial IDs

  • ORG STUDY ID: 201710109
  • NCT ID: NCT03199040

Conditions

  • Triple Negative Breast Cancer
  • Triple Negative Breast Neoplasms
  • TNBC - Triple-Negative Breast Cancer
  • Triple-negative Breast Carcinoma

Interventions

DrugSynonymsArms
DurvalumabImfinziNeoantigen DNA vaccine + Durvalumab
Neoantigen DNA vaccineNeoantigen DNA vaccine + Durvalumab

Purpose

This is a single institution, open-label randomized phase 1 trial of neoantigen DNA vaccine alone vs. neoantigen DNA vaccine plus durvalumab in triple negative breast cancer (TNBC) patients following standard of care therapy. Patients with newly diagnosed clinical stage II-III TNBC are eligible for enrollment. Patients will receive standard of care therapy including chemotherapy, surgery and radiation therapy as clinically indicated. Following standard of care therapy, patients will be randomized to receive either a neoantigen DNA vaccine alone, or a neoantigen DNA vaccine + durvalumab.

Trial Arms

NameTypeDescriptionInterventions
Neoantigen DNA vaccine + DurvalumabExperimentalThe first neoantigen DNA vaccine injection will take place up to 90 days following the completion of standard of care therapy. The day of the first vaccine injection will be referred to as Day 1 The schedule of vaccination is Day 1, Day 29 ± 7, Day 57 ± 7, Day 85 ± 7, Day 113 ± 7, and Day 141 ± 7 with at least 21 days between injection days For patients who are randomized to the neoantigen DNA vaccine plus durvalumab arm, the neoantigen-specific T cell response will be assessed at Day 57. If a neoantigen-specific T cell response is present, durvalumab will be started on Day 85, and will be administered Q4W at a dose of 1500 mg over the course of 60 minutes.
  • Durvalumab
Neoantigen DNA vaccineExperimentalThe first neoantigen DNA vaccine injection will take place up to 90 days following the completion of standard of care therapy. The day of the first vaccine injection will be referred to as Day 1 The schedule of vaccination is Day 1, Day 29 ± 7, Day 57 ± 7, Day 85 ± 7, Day 113 ± 7, and Day 141 ± 7 with at least 21 days between injection days

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Histologically confirmed diagnosis of invasive breast cancer.
    
              -  ER and PR less than Allred score of 3 or less than 1% positive staining cells in the
                 invasive component of the tumor
    
              -  HER2 negative by FISH or IHC staining 0 or 1+.
    
              -  Consented for genome sequencing and dbGAP-based data sharing
    
              -  Clinical stage T1c-T4c, any N, M0 primary tumor by AJCC 7th edition clinical staging
                 prior to neoadjuvant chemotherapy.
    
              -  At least 18 years of age.
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status ≥1.
    
              -  Adequate organ and marrow function no more than 14 days prior to registration as
                 defined below:
    
                   -  absolute neutrophil count ≥1,500/μL
    
                   -  platelets ≥100,000/μL
    
                   -  hemoglobin ≥ 9.0 g/dL
    
                   -  serum bilirubin ≤ 1.5 X institutional upper limit of normal
    
                   -  AST/ALT ≤2.5 X institutional upper limit of normal
    
                   -  serum creatinine clearance >40 mL/min by the Cockcroft-Gault formula or by
                      24-hour urine collection for determination of creatinine clearance
    
              -  Body weight > 30 kg.
    
              -  Evidence of post-menopausal status or negative urine or serum pregnancy test for
                 female pre-menopausal subjects. Women will be considered post-menopausal if they have
                 been amenorrheic for 12 months without an alternative medical cause. The following
                 age-specific requirements apply:
    
                   -  Women < 50 years of age would be considered post-menopausal if they have been
                      amenorrheic for 12 months or more following cessation of exogenous hormonal
                      treatments and if they have luteinizing hormone and follicle-stimulating hormone
                      levels in the post-menopausal range for the institution or underwent surgical
                      sterilization (bilateral oophorectomy or hysterectomy).
    
                   -  Women ≥ 50 years of age would be considered post-menopausal if they have been
                      amenorrheic for 12 months or more following cessation of all exogenous hormonal
                      treatments, had radiation-induced menopause with last menses > 1 year ago, had
                      chemotherapy-induced menopause with last menses > 1 year ago, or underwent
                      surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or
                      hysterectomy).
    
              -  Able to understand and willing to sign an IRB-approved written informed consent
                 document.
    
            Exclusion Criteria:
    
              -  Received chemotherapy, radiotherapy (to more than 30% of the bone marrow or with a
                 wide field of radiation), or biologic therapy within the last 30 days.
    
              -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
    
              -  Concurrent enrollment in another clinical study, unless it is an observational
                 (non-interventional) clinical study or during the follow-up period of an
                 interventional study.
    
              -  Receiving any other investigational agent(s) or has received an investigational agent
                 within the last 30 days.
    
              -  Receipt of live attenuated vaccination within 6 months prior to study entry or within
                 30 days of receiving durvalumab.
    
              -  Major surgical procedure within 28 days prior to the first dose of durvalumab. Local
                 surgery of isolated lesions for palliative intent is acceptable.
    
              -  Current use or prior use of immunosuppressive medication within 28 days before the
                 first dose of durvalumab, with the exceptions of intranasal and inhaled
                 corticosteroids or systemic corticosteroids at physiological doses which are not to
                 exceed 10 mg/day of prednisone or an equivalent corticosteroid.
    
              -  Known metastatic disease.
    
              -  Invasive cancer in the contralateral breast.
    
              -  Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis,
                 hives, or respiratory difficulty.
    
              -  History of hypersensitivity to durvalumab or any excipient.
    
              -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
                 calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart).
    
              -  Any unresolved toxicity NCI CTCAE grade ≥ 2 from previous anticancer therapy with the
                 exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
                 criteria. Subjects with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis
                 after consultation with the study physician. Subjects with irreversible toxicity not
                 reasonably expected to be exacerbated by treatment with durvalumab may be included
                 only after consultation with the study physician.
    
              -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
                 infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
                 angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
                 gastrointestinal conditions associated with diarrhea, evidence of any acute or chronic
                 viral illness or disease, or psychiatric illness/social situation that would limit
                 compliance with study requirements or compromise the ability of the subject to give
                 written informed consent.
    
              -  Active or prior documented autoimmune or inflammatory disorders (including
                 inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
                 the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
                 or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
                 arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
                 criterion:
    
                   -  Subjects with vitiligo or alopecia
    
                   -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                      hormone replacement
    
                   -  Any chronic skin condition that does not require systemic therapy
    
                   -  Subjects without active disease in the last 5 years may be included but only
                      after consultation with the study physician
    
                   -  Subjects with celiac disease controlled by diet alone
    
              -  History of pneumonitis or interstitial lung disease.
    
              -  History of active primary immunodeficiency.
    
              -  Active infection including tuberculosis (clinical evaluation that includes clinical
                 history, physical examination, and radiographic findings, and TB testing in line with
                 local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
                 hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects
                 with a past or resolved HBV infection (defined as the presence of hepatitis B core
                 antibody (anti-HBc) and absence of HBsAg) are eligible. Subjects positive for
                 hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
                 for HCV RNA.
    
              -  History of allogeneic organ transplantation.
    
              -  Pregnant or breastfeeding. A negative serum pregnancy test is required no more than 7
                 days before study entry.
    
              -  Subjects of reproductive potential who are not willing to employ effective birth
                 control from screening to 90 days after the last dose of durvalumab.
    
              -  History of another primary malignancy except for:
    
                   -  Malignancy treated with curative intent and with no known active disease ≥ 5
                      years before the first dose of study treatment and low potential for risk of
                      recurrence
    
                   -  Adequately treated non-melanoma skin cancer of lentigo maligna without evidence
                      of disease
    
                   -  Adequately treated carcinoma in situ without evidence of disease
    
              -  History of leptomeningeal carcinomatosis.
    
              -  Patient must have no active major medical or psychosocial problems that could be
                 complicated by study participation.
    
              -  Subjects with a strong likelihood of non-adherence such as difficulties in adhering to
                 follow-up schedule due to geographic distance from the Siteman Cancer Center should
                 not knowingly be registered.
    
              -  Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue
                 for eligible injection sites (left and right medial deltoid region) exceeds 40 mm.
    
              -  Individuals in whom the ability to observe possible local reactions at the eligible
                 injection sites (deltoid region) is, in the opinion of the investigator, unacceptably
                 obscured due to a physical condition or permanent body art.
    
              -  Therapeutic or traumatic metal implant in the skin or muscle of either deltoid region.
    
              -  Acute or chronic, clinically significant hematologic, pulmonary, cardiovascular, or
                 hepatic or renal functional abnormality as determined by the investigator based on
                 medical history, physical examination, EKG, and/or laboratory screening test
    
              -  Any chronic or active neurologic disorder, including seizures and epilepsy, excluding
                 a single febrile seizure as a child
    
              -  Syncopal episode within 12 months of screening
    
              -  Current use of any electronic stimulation device, such as cardiac demand pacemakers,
                 automatic implantable cardiac defibrillator, nerve stimulators, or deep brain
                 stimulators.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Safety of neoantigen DNA vaccines given alone or in combination with durvalumab as measured by number of adverse events experienced by patient
    Time Frame:30 days after completion of treatment (approximately day 171)
    Safety Issue:
    Description:Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Assessment of the safety of neoantigen DNA vaccines will include both clinical observation and laboratory evaluation. Safety will be closely monitored after injection with eight or more clinical and laboratory assessments in the first 24 weeks of the trial

    Secondary Outcome Measures

    Measure:Immune response to neoantigen DNA vaccines given alone or in combination with durvalumab as measured by luminex assay
    Time Frame:Up to 1 year
    Safety Issue:
    Description:-Peripheral blood will be collected at multiple time points before and after vaccination
    Measure:Immune response to neoantigen DNA vaccines given alone or in combination with durvalumab as measured by ELISPOT
    Time Frame:Up to 1 year
    Safety Issue:
    Description:-Peripheral blood will be collected at multiple time points before and after vaccination
    Measure:Immune response to neoantigen DNA vaccines given alone or in combination with durvalumab as measured by multiparametric flow cytometry
    Time Frame:Up to 1 year
    Safety Issue:
    Description:-Peripheral blood will be collected at multiple time points before and after vaccination

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Washington University School of Medicine

    Last Updated

    October 24, 2017