Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy
Condition: Triple Negative Breast Cancer; Triple Negative Breast Neoplasms; TNBC - Triple-Negative Breast Cancer; Triple-negative Breast Carcinoma
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Durvalumab; Neoantigen DNA vaccine; TDS-IM system (Inchor Medical Systems); Peripheral blood draw
Intervention description: -Human monoclonal antibody; -The vaccine will be given by the TDS-IM system; -At each vaccination time point, patients will receive two injections at separate sites.; -Baseline, following completion of standard of care therapy, Day 1, Day 57, Day 113, Day 159, and 1 year after initiation of neoantigen DNA vaccine therapy
Intervention MeSH terms: Durvalumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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. Patients not meeting this pathology criteria, but
             have been clinically treated as having TNBC, may be enrolled at treating physician's
             discretion.

          -  HER2 negative by FISH or IHC staining 0 or 1+.

          -  Consented for genome sequencing

          -  Clinical stage T1c-T4c, any N, M0 primary tumor by AJCC 7th edition clinical staging
             prior to neoadjuvant chemotherapy, with residual invasive breast cancer after
             neoadjuvant therapy.

          -  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

               -  total 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.

          -  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, inhaled, and
             intra-articular 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 1 year 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, or chronic seizure disorder which is well
             controlled by medication with no seizures within the last 2 years

          -  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.