Clinical Trials /

Atezolizumab Combined With Immunogenic Chemotherapy in Patients With Metastatic Triple-negative Breast Cancer



This is a randomized, double-blind, placebo-controlled phase II study evaluating the safety and efficacy of Atezolizumab when combined with immunogenic chemotherapy in subjects with metastatic triple-negative breast cancer. Atezolizumab, pegylated liposomal doxorubicin and cyclophosphamide are the Investigational Medicinal Products (IMPs).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Atezolizumab Combined With Immunogenic Chemotherapy in Patients With Metastatic Triple-negative Breast Cancer
  • Official Title: ALICE: A Randomized Placebo-controlled Phase II Study Evaluating Atezolizumab Combined With Immunogenic Chemotherapy in Patients With Metastatic Triple-negative Breast Cancer

Clinical Trial IDs

  • NCT ID: NCT03164993


  • Cancer, Breast
  • Triple Negative Breast Cancer


AtezolizumabTecentriqArm Chemotherapy + Atezolizumab
Pegylated liposomal doxorubicinArm Chemotherapy + Atezolizumab
CyclophosphamideArm Chemotherapy + Atezolizumab


This is a randomized, double-blind, placebo-controlled phase II study evaluating the safety and efficacy of Atezolizumab when combined with immunogenic chemotherapy in subjects with metastatic triple-negative breast cancer. Atezolizumab, pegylated liposomal doxorubicin and cyclophosphamide are the Investigational Medicinal Products (IMPs).

Detailed Description

      Breast cancer is rarely curable after metastasis, and the therapeutic options for metastatic
      triple negative breast cancer (TNBC) are limited. The host immune response is strongly
      predictive for the effect of chemotherapy in patients with TNBC. In the present trial, we
      combine Atezolizumab, an inhibitory antibody against Programmed Death Ligand-1 (PD-L1), with
      chemotherapy. Thereby, we aim to release the brake on the chemo-induced immune response. The
      chemotherapeutic regime is a combination of anthracycline and cyclophosphamide, applied in a
      semi-metronomic fashion (pegylated liposomal doxorubicin every 2nd week and daily
      cyclophosphamide for 2/4 weeks). The investigators hypothesize that the semi-metronomic
      regime will induce immunological cell death and counter T regulatory cells, while maintaining
      the leukocyte counts and the ability of the effector immune cells to respond. The use of
      pegylated liposomal doxorubicin (Caelyx) minimizes the adverse effects of anthracyclines on
      the heart and allows for continued treatment beyond the otherwise mandatory anthracycline

Trial Arms

Arm Chemotherapy + PlaceboPlacebo ComparatorChemo (pegylated liposomal doxorubicin + cyclophosphamide) + placebo
  • Pegylated liposomal doxorubicin
  • Cyclophosphamide
Arm Chemotherapy + AtezolizumabActive ComparatorChemo (pegylated liposomal doxorubicin + cyclophosphamide) + Atezolizumab
  • Atezolizumab
  • Pegylated liposomal doxorubicin
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          1. 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

          2. 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

          3. Measurable disease according to iRECIST

          4. Signed Informed Consent Form

          5. Women or men aged ≥ 18 years

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          7. 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 disease is required

          8. A maximum of one previous line with chemotherapy in the metastatic setting

          9. Female subject of childbearing potential should have a negative urine or serum
             pregnancy test 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

         10. 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

         11. 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

         12. Able to swallow orally administrated medication.

         13. Adequate organ function as defined in Table 1 in the protocol.

        Exclusion Criteria:

          1. 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)

          2. 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

          3. 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

          4. Known CNS disease, except for 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 ongoing requirement for dexamethasone as therapy for CNS disease

               4. No radiation of brain lesions within 7 days prior to randomization

               5. No leptomeningeal disease

               6. Patients with symptomatic CNS metastases must receive radiation therapy and/or
                  surgery for CNS metastases. Following treatment, these patients may be eligible,
                  if all other criteria are met

          5. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with
             indwelling catheters (e.g., PleurX®) are allowed

          6. 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

          7. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed

          8. Pregnant or breastfeeding

          9. 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

         10. 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

         11. Severe infection within 14 days prior to randomization, requiring hospitalization

         12. 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

         13. Major surgical procedure within 14 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

         14. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the atezolizumab formulation

         16. Known hypersensitivity to doxorubicin or cyclophosphamide or any of their excipients

         17. 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

               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)

         18. Undergone allogeneic stem cell or solid organ transplantation

         19. 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

         20. A positive test for HIV

         21. 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

         22. Active tuberculosis

         23. 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

         24. Received treatment with immune checkpoint modulators, including anti-CTLA-4,
             anti-PD-1, or anti-PD-L1 therapeutic antibodies

         25. 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

         26. 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

         27. Received anti-cancer therapy (medical agents or radiation) within 1 week prior to
             study Cycle 1, Day 1.

         28. 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

         29. Known psychiatric or substance abuse disorders that would interfere with cooperation
             and the requirements of the trial

         30. 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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assessment of toxicity of combined treatment with Atezolizumab, pegylated liposomal doxorubicin and cyclophosphamide
Time Frame:From inclusion until last follow-up visit (12 weeks after end of treatment if progressive disease; 12 months after end of treatment if no disease progression)
Safety Issue:
Description:Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0 and Adverse Event of Special Interest (AESIs) for Atezolizumab

Secondary Outcome Measures

Measure:Objective tumor response rate
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response
Measure:Overall survival
Time Frame:5 years
Safety Issue:
Description:Assessment of clinical response
Measure:Duration of response
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response
Measure:Durable tumor response rate (DRR; >6 months)
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response
Measure:Patient reported outcome Farigue
Time Frame:3 years
Safety Issue:
Description:Measured by the Chalder Fatigue Questionnaire (FQ)
Measure:Patient reported outcome NRS
Time Frame:3 years
Safety Issue:
Description:11 point Numerical Rating Scale (NRS) for pain intensity
Measure:Patient reported outcome QLQ-C15-PAL
Time Frame:3 years
Safety Issue:
Description:EORTC quality of life questionnaire (QLQ-C15-PAL)
Measure:Assessment of changes in the immunological milieu in tumor and peripheral blood
Time Frame:3 years
Safety Issue:
Description:Considering each study arm separately, and by comparing arm A to arm B
Measure:Clinical benefit rate
Time Frame:3 years
Safety Issue:
Description:Assessment of clinical response
Measure:Assessment of PD-L1 expression, mutation load and immune gene expression
Time Frame:3 years
Safety Issue:
Description:Biomarkers for clinical response


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oslo University Hospital

Trial Keywords

  • Neoplasms

Last Updated

April 26, 2021