ALICE

Atezolizumab Combined With Immunogenic Chemotherapy in Patients With Metastatic Triple-negative Breast Cancer. NBCG16, PI: Jon Amund Kyte.

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for study entry:

Metastatic or incurable locally advanced, histologically documented TNBC (negative for HER2, ER and PR ). HER2 negativity is defined as either of the following by local laboratory assessment: In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the PI to establish eligibility of the patient). ER and PR negativity are defined as < 1% and <10%, respectively, of cells expressing hormonal receptors via IHC analysis
Adequate newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. No anti-tumor treatment is allowed between the time point for biopsy and study entry. If a patient has undergone chemotherapy in the metastatic setting, a new biopsy must be obtained after this therapy
Measurable disease according to iRECIST
Signed Informed Consent Form
Women or men aged ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
In patients that have received (neo)adjuvant treatment with anthracyclines or cyclophosphamide, a minimum of 12 months from treatment with anthracyclines or cyclophosphamide until relapse of
A maximum of one previous line with chemotherapy in the metastatic setting
Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Female subjects of childbearing potential should agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, during the treatment period and for at least 5 months after the last dose of study therapy. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, proper use of hormonal contraceptives that inhibit ovulation and hormone-releasing intrauterine devices (IUDs). Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study therapy
Able to swallow orally administrated medication
Adequate organ function as defined in Table 1

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject has/is:

Malignancies other than breast cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer
Patients with known PD-L1 positive TNBC, as assessed by the Ventana SP142 assay (IC ≥1%), and no previous chemotherapy in the metastatic setting, should be offered standard therapy with nab-paclitaxel/atezolizumab outside of the trial, if they had a disease free interval of >12 months after previous (neo)adjuvant chemotherapy, unless the patient for other reasons should not receive nab-paclitaxel, according to own preferences, drug availability or recommendations by the treating physician. A history of progression on taxanes in the neoadjuvant setting, or severe side effects from taxane therapy, may represent sufficient reason to offer the patient inclusion into the the ALICE-trial, if the physician considers that the patient should receive antracyclines rather than taxanes as 1st line therapy for metastatic disease. If more than one TNBC biopsy has been evaluated for PD-L1 by the SP142 assay, and the results differ, the patient’s PD-L1 status determination will be based on best clinical judgment.
Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met:
1. Measurable disease outside the CNS
2. No metastases to mesencephalon, pons, medulla oblongata, or spinal cord
3. No evidence of progression after completion of CNS-directed therapy
4. No ongoing requirement for dexamethasone as therapy for CNS disease
5. No radiation of brain lesions within 14 days prior to randomization
6. No leptomeningeal disease
7. Patients with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may be eligible without the need for an additional brain scan prior to enrolment, if all other criteria are met
Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed
Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization
Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed
Pregnant or breastfeeding
Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
Severe infection within 21 days prior to randomization, requiring hospitalization
Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1. Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible
Major surgical procedure within 21 days prior to randomization or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis. Placement of central venous access catheter(s) is not considered a major surgical procedure and is therefore permitted
A history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
Known hypersensitivity to doxorubicin or cyclophosphamide or any of their excipients
A history of 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., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet all of the following conditions:
1. Rash must cover less than 10% of body surface area
2. Disease is well controlled at baseline and only requiring low potency topical steroids
3. No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
Undergone allogeneic stem cell or solid organ transplantation
A history of idiopathic pulmonary fibrosis (including pneumonitis) drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
A positive test for HIV
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
Active tuberculosis
Currently 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 treatment
Received treatment with immune checkpoint modulators, including anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibodies
Received treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
Received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study
2. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed
Received anti-cancer therapy (medical agents or radiation) within 2 weeks prior to study Cycle 1, Day 1
A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
Any reason why, in the opinion of the investigator, the patient should not participate. This includes a careful evulation of whether standard therapy is preferable to the study therapy, for the individual patient.
Received a live vaccine within 30 days of planned start of study therapy, or is expected to receive such a vaccine while on therapy or within 5 months after the last dose of atezolizumab
1. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Contact information: Jon Amund Kyte; Jon.Amund.Kyte@rr-research.no