| Eligibility |
Inclusion Criteria:
- Nineteen years of age or older on the day of signing informed consent.
- Willing and able to provide written informed consent for voluntary participation in
the trial.
- Has previously untreated, clinical stage II/III triple negative breast cancer (TNBC)
or low estrogen receptor (ER) tumor where ER is expressed in =10% tumor cells) .
- Willing to provide biopsies from the primary tumor or lymph nodes at screening to the
central laboratory and agrees to have a core needle biopsy or incisional or excisional
tumor biopsy after 14 days and 28 days of olaparib treatment (before and after
durvalumab treatment) if tumor biopsy is feasible as judged by the investigator.
- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Female subjects must either be of non-reproductive potential (ie, post-menopausal by
history: =60 years old and no menses for >1 year without an alternative medical cause;
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
and agree to use contraception if they or their partner are of reproductive potential.
- Has adequate organ function.
- Hemoglobin = 10.0 g/dL
- Absolute neutrophil count (ANC) = 1.5 x 109/L (> 1500 per mm3)
- Platelet count = 100 x 109/L (>100,000 per mm3)
- Serum bilirubin = 1.5 x institutional upper limit of normal (ULN)
- AST (SGOT)/ALT (SGPT) = 2.5 x institutional ULN unless due to Gilbert's syndrome
- INR/PT/APTT each = 1.5 x ULN
- TSH within normal limits
- Serum creatinine < 1.5 x ULN or serum creatinine CL > 51 mL/min by the
Cockcroft-Gault formula (Cockroft and Gault 1976) or by 24-hour urine collection
for determination of creatinine clearance
- Subject 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
up.
Exclusion Criteria:
- Underweighted populations - =30kg
- Has evidence of metastatic breast cancer, inflammatory breast cancer, or concurrent
bilateral invasive breast cancer where ER is expressed in >10% tumor cells.
(Note) Patients with bilateral invasive breast cancers can be enrolled if both tumors are
TNBCs, including low estrogen receptor (ER) tumor where ER is expressed in =10% tumor
cells.
• Has another malignancy within the last 3 years. Exceptions include basal cell carcinoma
of the skin, squamous cell carcinoma of the skin, and thyroid cancer that has undergone
potentially curative surgery, or in situ cervical cancer.
(Note) These patients should be consulted to the principal investigator for a case-by-case
decision before enrollment.
- Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy
that targets immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell
receptors within the past 12 months.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
- Is currently participating and receiving study therapy, or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of study drug.
- Has received a live vaccine within 30 days of the first dose of durvalumab. Note:
Patients, if enrolled, should not receive live vaccine up to 30 days after the last
dose of IP.
- Has an active autoimmune disease or inflammatory disorders (including inflammatory
bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of
diverticulosis], celiac disease, irritable bowel disease, or other serious
gastrointestinal chronic conditions associated with diarrhea, systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.])
that has required systemic treatment in past 2 years. The followings are exceptions to
this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement or psoriasis not requiring systemic treatment.
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 3 years may be included but only
after consultation with the principal investigator.
- Patients with celiac disease controlled by diet alone may be included but only
after consultation with the principal investigator.
- Has a diagnosis of immunodeficiency
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection)
- Systemic corticosteroid at physiologic dose not to exceed 10 mg/day of prednisone
or its equivalent
- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)
- Has a known history of Human Immunodeficiency Virus (HIV).
- Active infection, including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B, hepatitis C, or human immunodeficiency virus
(HIV, positive HIV 1 or 2 antibodies). Active hepatitis B virus (HBV) infection is
defined by a positive HBV surface antigen (HBsAg) and positive titer for HBV
DNA.result. Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core IgG antibody and the absence of HBsAg, deoxyribonucleic acid [DNA]
negative) are eligible. Patients positive for hepatitis C virus (HCV) antibody are
eligible only if polymerase chain reaction is negative for HCV ribonucleic acid
(RNA)..
- Has evidence of active, non-infectious pneumonitis.
- Has history of pneumonitis requiring treatment with steroids or history of
interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has significant cardiovascular disease, such as: History of myocardial infarction,
acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the
last 6 months; Congestive heart failure (CHF) New York Heart Association (NYHA) Class
II-IV or history of CHF NYHA class III or IV
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the study.
- Is pregnant or breastfeeding, or expecting to conceive children within the projected
duration of the study, starting with the screening visit through 120 days after the
last dose of study drug.
- Has a known hypersensitivity to the components of the study drug or its analogs.
- Concurrent use of any medications or substances that are strong inhibitors of
cytochrome P450 (CYP) 3A (CYP3A), such as ketoconazole, itraconazole, ritonavir,
indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir, or strong
inducers of CYP3A4. Dihydropyridine calcium-channel blockers are permitted for
management of hypertension.
- Previous allogenic bone marrow transplant or (single) umbilical cord blood
transplantation
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, as long as not received within
28 days of start of treatment.
- Mean QT interval corrected for heart rate (QTc) =470 ms calculated from 3
electrocardiograms (ECGs) using Frediricia's Correction within 14 days of treatment
- 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
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
- History of leptomeningeal carcinomatosis
|
