This is an open-label, single arm study of the SV-BR-1-GM regimen in combination with
INCMGA00012 and epacadostat in patients with metastatic or locally recurrent breast cancer
who have failed at least two lines of therapy.
Patients will receive the SV-BR-1-GM regimen with combination immunotherapy. There will be an
initial evaluation of the combination of the SV-BR-1-GM regimen with INCMGA00012 every 3
weeks. If this is found to be safe and well tolerated in a cohort of at least 6 patients
(dose-limiting toxicities (DLTs) in less than 30% of the patients evaluated), then a triple
combination of the SV-BR-1-GM regimen with INCMGA00012 and epacadostat will be evaluated in a
cohort of 6 patients. If the DLT rate remains below 30%, additional higher dose levels of
epacadostat will be explored. Once a dose of epacadostat has been determined that is safe and
reliably normalizes plasma kynurenine levels, the study will expand to treat an additional 36
patients. If DLTs are seen in 30% or more of patients, the dose of epacadostat will be
further reduced and an additional cohort of 6 patients evaluated in a stepwise fashion until
a safe dose level is determined. Once the recommended phase II dose is determined, the study
will expand to treat an additional 36 patients.
The SV-BR-1-GM regimen consists of:
1. Pre- SV-BR-1-GM cyclophosphamide 2-3 days prior to SV-BR-1-GM inoculation
2. SV-BR-1-GM inoculation
3. Interferon-alpha-2b - at the inoculation sites 2 (±1 day) post-SV-BR-1-GM
4. Interferon-alpha-2b - at the inoculation sites 4 (±1 day) post-SV-BR-1-GM
The SV-BR-1-GM regimen will be administered with the following combination immunotherapy
regimen:
1. Combination therapy with INCMGA00012 (anti-PD-1)
2. Combination therapy with epacadostat (IDO inhibitor)
The SV-BR-1-GM regimen with INCMGA00012 will be administered every 21 days (± 3 days), except
when approved by the Investigator in consultation with the medical monitor. Epacadostat will
be dosed twice daily and will continue through each cycle. Note that hormonal therapy (e.g.,
aromatase inhibitors) is permitted if ongoing, but may be added while the patient is on this
study only with the medical monitor's approval (e.g. for hormone receptor positive patients
who are deriving clinical benefit but have not achieved a CR after >6 cycles of therapy).
Inclusion Criteria:
1. Have histological confirmation of breast cancer with recurrent and/or metastatic
lesions, as per the investigational site, and have failed prior therapy.
2. Patients with persistent disease and local recurrence must not be amenable to local
treatment.
3. For patients with metastatic disease:
1. Human epidermal growth factor 2 (HER2) positive and estrogen receptor (ER) or
progesterone receptor (PR) positive tumors: must be refractory to hormonal
therapy (e.g., aromatase inhibitor, tamoxifen or fluvestrant) and previously
treated with at least 2 regimens including at least two anti-HER2 agents (e.g.,
trastuzumab and pertuzumab).
2. HER2 negative and either ER or PR positive tumors: must be refractory to hormonal
therapy (e.g. aromatase inhibitor, tamoxifen or fluvestrant) and previously
treated with at least 2 chemotherapy containing regimens.
3. HER2 positive and ER and PR negative tumors: must have failed at least 2 regimens
including at least two anti-HER2 agents (e.g., trastuzumab and pertuzumab).
4. Triple Negative tumors: Must have exhausted other available therapies including
prior treatment with a taxane and carboplatin.
Patients with new or progressive breast cancer metastatic to the brain will be
eligible provided:
1. The brain metastases must be clinically stable (without evidence of progressive
disease by imaging) for at least 4 weeks prior to first dose
2. Must have received prior radiation therapy for brain metastases or be ineligible
for radiation therapy
3. There is no need for steroids and patients have not had steroids for at least 2
weeks
4. No individual tumor size is >50 mm
5. Tumor is not impinging on Middle Cerebral Artery/speech-motor strip
6. If surgically debulked, must be healed from surgery and at least 3 weeks have
elapsed since general anesthesia
7. Patients consent to MRI studies at 3-4 week intervals until evidence of tumor
regression on at least 2 imaging studies. In no case, will the interval between
MRI studies be longer than 3 months. MRI studies may be introduced at any time
should the patients develop new or clearly worsening symptoms and/or introduction
of steroids
4. Be 18 years of age or older and female
5. Have expected survival of at least 4 months
6. Have adequate performance status (ECOG 0-1)
7. Have provided written informed consent
Exclusion Criteria:
1. Concurrent or recent chemotherapy, immunotherapy (except the SV-BR-1-GM regimen), or
general anesthesia/major surgery within 21 days. Patients must have recovered from all
known or expected toxicities from previous treatment and passed a treatment-free
"washout" period of 3 weeks before starting this program (8 weeks for patients
receiving nitrosourea or mitomycin). Prior immune related toxicity should not have
exceeded Grade 2 (with exception of endocrinopathy).
2. Radiotherapy within 14 days of first dose of study treatment with the following
caveats:
1. 28 days for pelvic radiotherapy.
2. 8 weeks for brain metastases
3. 6 months for thoracic region radiotherapy that is > 30 Gy in 2 Gy fractions.
3. Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline (with the
exception of any grade of alopecia and anemia not requiring transfusion support).
Endocrinopathy, if well-managed, is not exclusionary and should be discussed with
medical monitor.
4. Participant has not recovered adequately from toxicities and/or complications from
surgical intervention before starting study drug.
5. History of clinical hypersensitivity to the designated combination immunotherapy,
GM-CSF, Interferon-alpha-2b (Merck), yeast, beef, or to any components used in the
preparation of SV-BR-1-GM.
6. History of clinical hypersensitivity to any of the immunotherapies proposed for
combination treatment or their excipients.
7. Known hypersensitivity to another monoclonal antibody that cannot be controlled with
standard measures (e.g., antihistamines and corticosteroids) or known allergy or
hypersensitivity to any component of INCMGA00012 or formulation components.
8. Serum creatinine OR Measured or calculated Creatinine Clearance (CrCl) (GFR can also
be used in place of creatinine or CrCl) >1.5 × ULN OR <30 mL/min for participants with
creatinine levels >1.5 × institutional ULN.
9. Absolute granulocyte count <1500; platelets <100,000; hemoglobin ≤ 9 g/L.
10. Bilirubin ≥ 1.5 × ULN unless conjugated bilirubin ≤ ULN; alkaline phosphatase >5x
upper limit of normal (ULN); ALT/AST >2x ULN. For patients with hepatic metastases,
ALT/AST >5x ULN is exclusionary.
11. INR or PT or aPTT > 1.5 × ULN, unless the participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants. Note: See the restricted medications list in protocol section 5.9. If
an alternative cannot be found, the participant cannot be enrolled.
12. Receiving any medication listed in the prohibited medication (section 5.10 of the
protocol).
13. Participants may not have a history of serotonin syndrome after receiving 1 or more
serotonergic drugs.
14. Proteinuria >1+ on urinalysis or >1 gm/24hr.
15. Have a history or presence of an abnormal electrocardiogram (ECG) that, in the
investigator's opinion, is clinically meaningful. Screening corrected QT interval
(QTc) interval >480 milliseconds is excluded (corrected by Fridericia or Bazett
formula). In the event that a single QTc is >480 milliseconds, the participant may
enroll if the average QTc for the 3 ECGs is <480 milliseconds.
16. Left ventricular ejection fraction (LVEF as determined by cardiac echo or MUGA scan)
below the normal limits of the institutions' specific testing range. This assessment
may be repeated once at the discretion of the Investigator with the approval of the
Sponsor.
17. New York Heart Association stage 3 or 4 cardiac disease.
18. A pericardial effusion of moderate severity or worse.
19. Symptomatic pleural effusion or ascites. A participant who is clinically stable
following treatment for these conditions (including therapeutic thoraco- or
paracentesis) is eligible.
20. Any woman of childbearing potential (i.e., has had a menstrual cycle within the past
year and has not been surgically sterilized), unless she: agrees to take appropriate
precautions to avoid becoming pregnant during the study (with at least 99% certainty,
see Appendix A for permitted methods) and has a negative serum pregnancy test within 7
days prior to starting treatment.
21. Women who are pregnant or nursing.
22. Known additional malignancy that is progressing or requires active treatment, or
history of other malignancy within 3 years of study entry with the exception of cured
basal cell or squamous cell carcinoma of the skin, superficial bladder cancer,
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other
noninvasive or indolent malignancy, or cancers from which the participant has been
disease-free for > 1 year, after treatment with curative intent.
23. Patients who are HIV positive (by self-report) or have clinical or laboratory features
indicative of AIDS.
24. Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(doses exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study treatment.
a. Beta-blocker therapy, while not exclusionary, is discouraged and alternatives
should be sought if possible. The beta-blocker might compromise use of epinephrine for
the rare possibility of anaphylaxis.
25. Has had an allogeneic tissue/solid organ transplant.
26. Have an active autoimmune disease that has required systemic treatment in 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 allowed.
27. Patients with a history of colitis.
28. Has a history of (non-infectious) pneumonitis that required systemic steroids or
current pneumonitis/interstitial lung disease.
29. Known active HBA, HBV, or HCV infection, as defined by elevated transaminases with the
following serology: positivity for HAV IgM antibody, anti-HCV, anti-HBc IgG or IgM, or
HBsAg (in the absence of prior immunization).
30. Active infections requiring systemic therapy.
a. All antibiotic therapy within 28 days of initiating treatment must be recorded
31. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
32. Patients with severe psychiatric (e.g., schizophrenia, bipolar, or borderline
personality disorder) or other clinically progressive major medical problems, unless
approved by the Investigator in consultation with the medical monitor.
33. Has received a live vaccine within 28 days of the planned start of study drug. Note:
examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, chicken pox/zoster, yellow fever, rabies, BCG, and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live-attenuated
vaccines and are not allowed.
34. Male breast cancer patients.
35. Patients may not be on a concurrent clinical trial, unless approved by the
Investigator.
36. Has a history of a gastrointestinal condition or procedure that in the opinion of the
Investigator may affect oral drug absorption.
