I. Evaluate the clinical response to nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen
vaccine (Arm 1) versus (vs.) nab-paclitaxel + MEDI4736 (durvalumab) (Arm 2) in patients with
metastatic triple negative breast cancer (TNBC).
I. Evaluate the safety of nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen vaccine vs.
nab-paclitaxel + MEDI4736 (durvalumab) in patients with metastatic TNBC.
I. Assess the immune response induced by nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen
vaccine vs. nab-paclitaxel + MEDI4736 (durvalumab) in patients with metastatic TNBC.
II. Biomarkers of response to therapy will be assessed based on the research biopsies
performed at baseline, following the chemotherapy run-in (Part A) and following
nab-paclitaxel + MEDI4736 +/- neoantigen vaccine (Part B).
PART A: Participants receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and
carboplatin IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses
in the absence of disease progression or unacceptable toxicity. Participants with progression
of disease within the first 18 weeks may switch and receive nab-paclitaxel IV over 30 minutes
on days 1, 8, and 15 of each remaining course.
PART B: Participants are randomized to 1 of 2 arms.
ARM I: Participants receive personalized synthetic long peptide vaccine and poly-ICLC
subcutaneously (SC) on days 1, 4, 8, 15, 22, 50, and 78 in the absence of disease progression
or unacceptable toxicity. Participants also receive durvalumab IV over 60 minutes on day 1
and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. courses repeat every 28 days in
the absence of disease progression or unacceptable toxicity.
ARM II: Participants receive durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV
over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, participants are followed up for 52 weeks.
- Patients must have a histologically confirmed diagnosis of metastatic invasive triple
negative breast cancer.
- Estrogen receptor (ER) and progesterone receptor (PR) less than Allred score of 3 OR
less than 1% positive staining cells in the invasive component of the tumor.
- HER2 negative by fluorescence in situ hybridization (FISH) or immunohistochemistry
(IHC) staining 0 or 1+.
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
nonnodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam.
- A tumor specimen obtained from relapsed metastatic or locally advanced disease (if
applicable) must be submitted. Acceptable samples include core needle biopsies for
deep tumor tissue (minimum 4 cores) or excisional, incisional, punch, or forceps
biopsies for cutaneous, subcutaneous, or mucosal lesions. Formalin-fixed,
paraffin-embedded (FFPE) tumor specimens in paraffin blocks are preferred. Fine-needle
aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage
samples are not acceptable.
- No prior therapy for metastatic TNBC. Patients who have received taxane-based adjuvant
therapy are required to have a disease-free interval of at least 12 months after
completion of taxane therapy.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%).
- Body weight > 30 kg.
- Must have a life expectancy of at least 12 weeks.
- Absolute neutrophil count >= 1,500/mcL.
- Platelets >= 100,000/mcL.
- Hemoglobin >= 9.0 g/dL.
- Serum bilirubin =< 1.5 x institutional upper limit of normal.
- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase
(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =<
2.5 x institutional upper limit of normal unless liver metastases are present, in
which case it must be =< 5 x institutional upper limit of normal.
- Measured creatinine clearance > 40 mL/min.
- Calculated creatinine clearance > 40 mL/min by the Cockcroft-Gault formula or by
24-hour urine collection for determination of creatinine clearance.
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. 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
- The effects of MEDI4736 (durvalumab) and neoantigen vaccine on the developing human
fetus are unknown. For this reason and because these agents may be teratogenic, women
of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation, and through 180 days after the last dose of durvalumab. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.
- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
- Ability to understand and the willingness to sign a written informed consent document.
- Patients who have had chemotherapy, radiotherapy (to more than 30% of the bone
marrow), or biologic therapy within 30 days (42 days for nitrosoureas or mitomycin C)
prior to entering the study.
- Patients who have received prior immunotherapy for metastatic disease.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736 (durvalumab).
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1).
- Patients who are receiving any other investigational agents or who have 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 MEDI4736 (durvalumab).
- Major surgical procedure within 28 days prior to the first dose of MEDI4736
(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 MEDI4736 (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 central nervous system (CNS) disease, except for treated asymptomatic CNS
metastases. Patients with known brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
- Leptomeningeal disease.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MEDI4736 (durvalumab). Known allergy, or history of serious adverse
reaction to vaccines, such as anaphylaxis, hives or respiratory difficulty.
- 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).
- 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 situations that would limit
compliance with study requirements.
- Pregnant women are excluded from this study because MEDI4736 (durvalumab) has the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with MEDI4736 (durvalumab), breastfeeding should be discontinued if the mother
is treated with MEDI4736 (durvalumab). These potential risks may also apply to other
agents used in this study. A negative serum pregnancy test is required no more than 7
days before study entry.
- Human immunodeficiency virus (HIV)-positive patients are ineligible because of the
potential inability to generate an immune response to vaccines.
- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- 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 (positive test for hepatitis B virus (HBV) surface
antigen (HBsAg)), or hepatitis C (positive test for hepatitis C virus ribonucleic acid
(HCV RNA) indicating acute or chronic infection.
- The patient with a previous history of non-breast malignancy is eligible for this
study only if the patient meets the following criteria for a cancer survivor. A cancer
survivor is eligible provided the following criteria are met:
- Patient has undergone potentially curative therapy for all prior malignancies.
- Patients have been considered disease free for at least 1 year (with the
exception of basal cell or squamous cell carcinoma of the skin or
carcinoma-in-situ of the cervix).
- Patients with a strong likelihood of non-adherence (such as difficulties in adhering
to follow-up schedule due to geographic distance from the treatment facility) should
not be knowingly registered.
- Patients with a history of prior allogeneic stem cell or solid organ transplantation.