This is an open label single-arm phase II study to evaluate the combination therapy of the
AKT inhibitor, ipatasertib, and the anti-PD-L1 antibody, atezolizumab, in patients with
triple negative breast cancer.
The research study procedures include screening for eligibility and study treatment including
laboratory evaluations, stool collection and follow up visits.
This research study involves the following investigational drugs:
Participants will receive study treatment for 24 weeks and will be followed for every 6
months for 3 years.
It is expected that about 40 people will take part in this research study.
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug or drug combination
works in treating a specific disease. "Investigational" means that the drug combination is
The U.S. Food and Drug Administration (FDA) has not approved atezolizumab (Tecentriq) for
residual triple negative breast cancer but it has been approved for advanced triple negative
breast cancer and other cancers. Atezolizumab is a protein that affects your immune system by
blocking the PD-L1 pathway. The PD-L1 pathway controls your body's natural immune response,
but for some types of cancer the immune system does not work as it should and is prevented
from attacking tumors. Atezolizumab works by blocking the PD-L1 pathway, which may help your
immune system identify and catch tumor cells.
The U.S. Food and Drug Administration (FDA) has not approved ipatasertib as a treatment for
Ipatasertib is a drug that inhibits (stops) an enzyme called Akt in cancer cells. It is
thought that inhibiting Akt may make cancer cells more sensitive to treatment, especially in
combination with a drug that activates the immune system, like atezolizumab.
- Pathologically confirmed residual invasive breast cancer, in the breast and/or lymph
node(s), following neoadjuvant chemotherapy. In the absence of residual invasive
disease in the breast, lymph node must contain at least 2mm of invasive disease.
- HER2 negative by local pathology assessed according to current ASCO/CAP guidelines:
- In situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe
average HER2 gene copy number < 4 signals/cell), OR
- Immunohistochemistry (IHC) 0 or IHC 1+.
- NOTE: If more than one test result is available and not all results meet the
inclusion criterion definition, all results should be discussed with the
Principal Investigator to establish eligibility
- ER and PR negative defined as < 1% of cells expressing hormonal receptors via IHC
analysis by local laboratory assessment.
- Patients must have received neoadjuvant chemotherapy prior to breast surgery.
Investigational agents as part of the neoadjuvant regimen are allowed, with the
exception of PI3K/Akt/mTor inhibitors and/or immune checkpoint inhibitors.
- Patients must be within 12 months of last therapy (definitive breast surgery,
radiation and/or all intended adjuvant therapy). Definitive breast surgery includes
lumpectomy or mastectomy with pathologically clear margins (i.e. no ink on tumor). For
patients undergoing lumpectomy, this must be followed by whole breast irradiation.
Definitive surgery also includes axillary surgery, either sentinel lymph node biopsy
or axillary lymph node dissection at the discretion of the attending surgeon.
- Evidence of circulating tumor cfDNA in blood sample collected after completion of all
local and systemic neoadjuvant and adjuvant therapy (preoperative and postoperative
chemotherapy, surgery and radiation), confirmed by central testing. Detection of any
tumor specific mutations (TSMs) within the sample will be considered positive for
purposes of study eligibility.
- Concurrent receipt of bone modifying agents (bisphosphonates or rank-ligand
- ECOG Performance Status of 0 or 1
- Men and women, age ≥ 18 years
- Adequate hematologic and organ function defined by the following:
- ANC ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support
- WBC count ≥ 2.5 × 109/L (2500/μL)
- Absolute Lymphocyte count ≥ 0.5 × 109/L (500/μL)
- Platelet count ≥ 100 × 109/L (100,000/μL)
- Hemoglobin ≥ 90 g/L (9.0 g/dL), with or without transfusion
- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 × institutional upper limit of
- Serum bilirubin ≤ 1.5 × institutional ULN with the following exception:
- Patients with known Gilbert syndrome: serum bilirubin level ≤ 3 ×
- Serum creatinine < 1.5 x institutional ULN
- Serum albumin ≥ 25 g/L (2.5 g/dL)
- Fasting glucose < 150 mg/dL and hemoglobin (HBA1c) < 7.5%
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 ×
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
- Women of childbearing potential (pre-menopausal) must have a negative serum or urine
pregnancy test within 7 days prior to start of therapy. A woman is defined as
premenopausal if she is less than 12 months from last menstrual period with no
identified cause other than menopause (medication induced amenorrhea is not
acceptable). Pregnancy test is not required in women who are surgically sterile via
bilateral salpingooophorectomy or hysterectomy.
- Women of childbearing potential and men must agree to use adequate contraception for
the duration of protocol treatment and for 28 days after last dose of ipatasertib and
5 months after stopping atezolizumab. Hormonal contraceptives are not acceptable (see
- Ability to understand and the willingness to sign a written informed consent document.
- Patients must be willing to provide archival tissue for research purposes.
- Clinical evidence of metastatic disease
- Residual DCIS or LCIS alone without invasive cancer OR pT0N0i and pT0N1mic residual
- Prior treatment with an immune checkpoint inhibitor is permitted in the neoadjuvant
setting and prohibited in the adjuvant setting.
- Concurrent enrollment on another investigational therapy trial
- Prior treatment-related toxicity must be resolved to ≤ Grade 1 with the exception of
alopecia and peripheral neuropathy, prior to study enrollment.
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.
- Intercurrent illness including, but not limited to: ongoing or active infection
requiring systemic therapy, active tuberculosis, serious liver disease such as
cirrhosis, active bleeding diathesis, uncontrolled Type I or Type II diabetes
mellitus, Grade ≥ 2 uncontrolled or untreated hypercholesterolemia,
Hypertriglyceridemia or hypercalcemia
- Cardiovascular disease including: congestive heart failure of New York Heart
Association Class III or IV, myocardial infarction (<6 months prior to enrollment)
unstable angina pectoris, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease, in the opinion of the investigator
- 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 scan. History of radiation
pneumonitis in the radiation field (fibrosis) is permitted.
- Active (acute or chronic) autoimmune disease of any type except hypothyroidism on a
thyroid-replacement hormone,or celiac disease, or well-controlled psoriasis, eczema,
lichen simplex chronicus or vitiligo.
- Impairment of gastrointestinal function or active gastrointestinal disease that may
significantly alter the absorption of the study agents (e.g., ulcerative disease,
uncontrolled nausea(> grade 2), vomiting (> grade 2), diarrhea (> grade 2),
malabsorption syndrome or small bowel resection).
- Congenital long QT syndrome or screening QT interval corrected through use of
Fridericia's formula >480 ms.
- Participants known to be positive for the human immunodeficiency virus (HIV),
Hepatitis B antigen (HepBsAg), or Hepatitis C virus (HCV) RNA are ineligible.
- History of prior invasive breast cancer in either breast.
- Participants with history of prior malignancy other than breast cancer are eligible if
they have been disease-free for at least 5 years prior to enrollment with the
exception of patients with thyroid cancer that has been definitively treated without
spread to regional lymph nodes.
- Treatment with strong CYP3A4 inducers within 4 weeks or 5 drug-elimination half-lives,
whichever is longer, prior to initiation of study drug.
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine while on protocol treatment
- Known allergy or hypersensitivity to any of the study drugs or any of their
excipients, including chimeric or humanized antibodies or fusion proteins and Chinese
hamster ovary cell products or recombinant human antibodies
- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti−tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study
treatment, or anticipation of need for systemic immunosuppressive medication during
the course of the study, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible. o Patients who received
mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic
obstructive pulmonary disease or asthma, or low-dose corticosteroids for
orthostatic hypotension or adrenal insufficiency are eligible for the study.
- Pregnant women are excluded from this study because the effects of ipatasertib and
atezolizumab on a developing fetus are unknown. Breastfeeding should be discontinued
prior to entry onto the study.