| Eligibility |
Patient inclusion criteria
1. Written informed consent for all study procedures according to local regulatory
requirements prior to beginning specific protocol procedures.
2. Female patients age =18 years at the time of informed consent.
3. Histologically confirmed diagnosis of non-metastatic primary invasive adenocarcinoma
of the breast, with all of the following characteristics:
- TNBC or luminal B-like/HER2-negative breast cancer.
- At least 1 lesion that can be accurately and serially measured in at least 1
dimension and for which the longest diameter is = 10 mm as measured by magnetic
resonance imaging (MRI).
- Breast cancer eligible for primary surgery
- In the case of a multifocal/multicentric tumor, the largest lesion must be = 15
mm and designated the "target" lesion for all subsequent tumor evaluations.
4. ER, PgR and HER2 tumor determination by ASCO/CAP guidelines locally assessed:
- TNBC defined as: ER and PR negative defined as IHC nuclear staining <1% AND HER2
negative.
- Luminal B-like/HER2 negative defined as:
- ER or PR positive defined as IHC nuclear staining =1% AND HER2 negative AND
local Ki-67 =20% or
5. Patient must have injectable and biopsiable disease (direct injection or ultrasound
guided).
6. Completed = 80% total dose of an anthracycline/taxane-based neoadjuvant regimen
recommended by the NCCN guidelines. The addition of carboplatin to a taxane is
allowed.
7. ECOG Performance Status of 0 or 1.
8. Adequate organ function determined within 14 days prior to enrollment, defined as
follows:
- Hematological
- Absolute neutrophil count (ANC) = 1.5 x 109/L
- Platelet count = 100 x 109/L
- Hemoglobin = 9 g/dL (red blood cell transfusion and/or erythropoietin
allowed)
- Renal
o Serum creatinine = 1.5 x upper limit of normal (ULN), or 24-hour creatinine
clearance = 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note:
Creatinine clearance does not need to be determined if the baseline serum
creatinine is within normal limits. Creatinine clearance should be calculated per
institutional standard).
- Hepatic
- serum bilirubin = 1.5 x ULN OR direct bilirubin = ULN for a subject with
total bilirubin level > 1.5 x ULN
- aspartate aminotransferase (AST) = 2.5 x ULN alanine aminotransferase (ALT)
= 2.5 x ULN
- Coagulation International normalization ratio (INR) or prothrombin time (PT)
= 1.5 x ULN
9. Partial thromboplastin time (PTT) or activated PTT (aPTT) = 1.5 x ULN
10. Absence of any psychological, familial, sociological or geographical situation
potentially hampering compliance with the study protocol and follow-up schedule; those
situations should be discussed with the patient before registration in the trial.
11. Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to enrollment. If urine pregnancy test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical
procedures to NCI CTCAE version 4.0 Grade = 1 (except alopecia or other toxicities not
considered a safety risk for the patient at investigator´s discretion).
Patient exclusion criteria
1. Inoperable locally advanced breast cancer after NAC.
2. Metastatic (Stage IV) breast cancer.
3. Bilateral invasive breast cancer.
4. Prior therapy with an anti- PD-1, anti- PD-L1, anti-PD-L2, anti-CD137 antibody, or
anti-CTLA- 4 antibody compound, T-VEC or any other oncolytic immunotherapy.
5. Prior therapy with tumor vaccine.
6. Currently receiving treatment in another investigational device or study drug, or less
than 28 days since ending treatment on another investigational device or study drug.
7. History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis,
vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or
syndrome that has required systemic treatment in the past 2 years (ie, with use of
disease modifying agents, corticosteroids or immunosuppressive drugs). with the
following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on thyroid
replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
Rash must cover 10% of body surface. Disease is well controlled at baseline and
requires only low-potency topical corticosteroids.
No occurrence of acute exacerbations of the underlying condition requiring psoralen
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12
months.
8. Active herpetic skin lesions or prior complications of herpetic infection (e.g.
herpetic keratitis or encephalitis) and must not require intermittent or chronic
treatment with an antiherpetic drug (e.g. acyclovir), other than intermittent topical
use.
9. Received live vaccine within 28 days prior to enrollment or within 5 months after the
last dose of atezolizumab.
10. Evidence of clinically significant immunosuppression such as the following:
- diagnosis of immunodeficiency
- concurrent opportunistic infection
- receiving systemic immunosuppressive therapy (> 2 weeks) or within 7 days prior
to the first dose of study treatment, including oral steroid doses > 10 mg/day of
prednisone or equivalent. Subjects that require intermittent use of
bronchodilators or local steroid injection will not be excluded from the study.
11. Cardiopulmonary dysfunction as defined by:
- Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic > 100 mm Hg)
despite optimal medical management.
- Inadequately controlled angina or serious cardiac arrhythmia not controlled by
adequate medication.
- History of symptomatic congestive heart failure (CHF): Grade = 3 per NCI CTCAE
version 4.0 or Class = II New York Health Association (NYHA criteria).
- Myocardial infarction within 6 months prior to enrollment.
- Current dyspnea at rest due to complications of advanced malignancy, or other
disease requiring continuous oxygen therapy
12. Current severe, uncontrolled systemic disease (e.g. clinically significant
cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone
fractures).
13. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX) are allowed.
14. Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12
mg/dL or corrected serum calcium ULN)
15. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan. History of
radiation pneumonitis in the radiation field (fibrosis) is permitted.
16. Major surgical procedure or significant traumatic injury within approximately 28 days
prior to enrollment or anticipation of the need for major surgery during the course of
study treatment.
17. Concurrent, serious, uncontrolled infections or current known infection with HIV or
active hepatitis B and/or hepatitis C.
18. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment with exception of prophylactic antibiotics
19. Has a known history of active Bacillus tuberculosis
20. Female subject is pregnant or breast-feeding, or planning to become pregnant during
study treatment and through 3 months after the last dose of talimogene laherparepvec
or 5 months after the last dose of atezolizumab, whichever is later
21. Female subject of childbearing potential who is unwilling to use acceptable method(s)
of effective contraception during study treatment and through 3 months after the last
dose of talimogene laherparepvec or 5 months after the last dose of atezolizumab,
whichever is later. Note: Women not of childbearing potential are defined as:
- postmenopausal (defined as at least 12 months with no menses without an
alternative medical cause; in women < 45 years of age a high follicle stimulating
hormone (FSH) level in the postmenopausal range may be used to confirm a
post-menopausal state in women not using hormonal contraception or hormonal
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH
measurement is insufficient.) OR
- have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR
- has a congenital or acquired condition that prevents childbearing.
Note: Acceptable methods of effective contraception are defined in the informed
consent form and Appendix A.
22. Subject has known sensitivity to any of the products or components to be administered
during dosing
23. Assessment by the investigator to be unable or unwilling to comply with the
requirements of the protocol.
24. History of other malignancy within 5 years prior to screening, except for
appropriately treated basal or squamous cell carcinoma, carcinoma in situ of the
cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.
25. History of significant co-morbidities that, in the judgment of the investigator, may
interfere with the conduction of the study, the evaluation of response, or with
informed consent.
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