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Cancer, BreastPhase 2ALICENCT03164993

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

A Phase 2 study testing Atezolizumab, Pegylated liposomal doxorubicin and Cyclophosphamide in people with Cancer, Breast and Triple Negative Breast Cancer, run by Oslo University Hospital at 5 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Cancer, Breast, Triple Negative Breast Cancer
What is being tested?
Atezolizumab, Pegylated liposomal doxorubicin and Cyclophosphamide
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
68 participants
Where
5 sitesin 2 countries
Study dates
1 Jun 2017to 30 Sep 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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
  • 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 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
  • 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 in the protocol.

Who cannot join

  • 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 asymptomatic CNS metastases, provided all of the following criteria are met:
  • Measurable disease outside the CNS
  • No metastases to mesencephalon, pons, medulla oblongata, or spinal cord
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  • No ongoing requirement for dexamethasone as therapy for CNS disease
  • No radiation of brain lesions within 7 days prior to randomization
  • No leptomeningeal disease
  • 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
  • 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 14 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 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
  • 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:
  • Rash must cover less than 10% of body surface area.
  • Disease is well controlled at baseline and only requiring low potency topical steroids
  • 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
  • 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
  • Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
  • 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 1 week 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.

Trial locations and contacts

5 sites in 2 countries.

5 sites in 2 countries

Norway3 sites

  • Oslo University Hospital

    Oslo

  • Stavanger University Hospital

    Stavanger

  • St. Olavs Hospital

    Trondheim

Other trials in Norway

Denmark2 sites

  • Rigshospitalet

    Copenhagen, 2100

  • Vejle Sygehus

    Vejle, 7100

Other trials in Denmark

About this study

Official title: ALICE: A Randomized Placebo-controlled Phase II Study Evaluating 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).

Read the 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 limits.

Being tested
Atezolizumab, Pegylated liposomal doxorubicin, Cyclophosphamide, Placebo
Keywords
Neoplasms
Medical subject headings
Breast Neoplasms, Triple Negative Breast Neoplasms, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AtezolizumabDrug

    Also called Tecentriq

    Atezolizumab is a monoclonal antibody designed to target and bind to a protein called PD-L1 (programmed death ligand-1), which is expressed on tumour cells and tumour-infiltrating immune cells. PD-L1 interacts with PD-1 and B7.1, both found on the surface of T cells, causing inhibition of T cells. By blocking this interaction, Atezolizumab may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells.

  • Pegylated liposomal doxorubicinDrug

    Chemotherapy

  • CyclophosphamideDrug

    Chemotherapy

  • PlaceboOther

    Placebo

Study groups in NCT03164993
Study groupRoleWhat they receive
Arm Chemotherapy + PlaceboPlacebo comparatorChemo (pegylated liposomal doxorubicin + cyclophosphamide) + placebo
Receives: Drug: Pegylated liposomal doxorubicin; Drug: Cyclophosphamide; Other: Placebo
Arm Chemotherapy + AtezolizumabActive comparatorChemo (pegylated liposomal doxorubicin + cyclophosphamide) + Atezolizumab
Receives: Drug: Atezolizumab; Drug: Pegylated liposomal doxorubicin; Drug: Cyclophosphamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Assessment of toxicity of combined treatment with Atezolizumab, pegylated liposomal doxorubicin and cyclophosphamide

    Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0 and Adverse Event of Special Interest (AESIs) for Atezolizumab

    Measured: 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)

  2. Progression-free survival (PFS)

    Descriptive comparison of the PFS rates in the total per protocol (PP) population, and the PD-L1+ PP population

    Measured: 3 years

Secondary outcomes (10)

  1. Objective tumor response rate

    Assessment of clinical response

    Measured: 3 years

  2. Overall survival

    Assessment of clinical response

    Measured: 5 years

  3. Duration of response

    Assessment of clinical response

    Measured: 3 years

  4. Durable tumor response rate (DRR; >6 months)

    Assessment of clinical response

    Measured: 3 years

  5. Patient reported outcome Farigue

    Measured by the Chalder Fatigue Questionnaire (FQ)

    Measured: 3 years

  6. Patient reported outcome NRS

    11 point Numerical Rating Scale (NRS) for pain intensity

    Measured: 3 years

  7. Patient reported outcome QLQ-C15-PAL

    EORTC quality of life questionnaire (QLQ-C15-PAL)

    Measured: 3 years

  8. Assessment of changes in the immunological milieu in tumor and peripheral blood

    Considering each study arm separately, and by comparing arm A to arm B

    Measured: 3 years

  9. Clinical benefit rate

    Assessment of clinical response

    Measured: 3 years

  10. Assessment of PD-L1 expression, mutation load and immune gene expression

    Biomarkers for clinical response

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 May 2017
  2. Study start1 Jun 2017
  3. Primary completion25 Apr 2023
  4. Study completion30 Sep 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Randomized, double-blind, placebo-controlled
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
68 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03164993
Sponsor's protocol ID
ML39079_ALICE
Acronym
ALICE
Status last verified
Oct 2023
First submitted
12 May 2017
Last updated
15 Oct 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Rossevold AH, Andresen NK, Bjerre CA, Gilje B, Jakobsen EH, Raj SX, Falk RS, Russnes HG, Jahr T, Mathiesen RR, Lomo J, Garred O, Chauhan SK, Lereim RR, Dunn C, Naume B, Kyte JA. Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. Nat Med. 2022 Dec;28(12):2573-2583. doi: 10.1038/s41591-022-02126-1. Epub 2022 Dec 8.

    PubMed 36482103

  • Svalheim KG, Andresen NK, Bjerre C, Gilje B, Jakobsen EH, Falk RS, Naume B, Kaasa S, Kyte JA. Patient-reported outcomes from the randomized ALICE trial evaluating the addition of atezolizumab to anthracycline-based chemotherapy in metastatic triple-negative breast cancer. Breast. 2026 Apr;86:104704. doi: 10.1016/j.breast.2026.104704. Epub 2026 Jan 19.

    PubMed 41581361

  • Kyte JA, Rossevold A, Falk RS, Naume B. ALICE: a randomized placebo-controlled phase II study evaluating atezolizumab combined with immunogenic chemotherapy in patients with metastatic triple-negative breast cancer. J Transl Med. 2020 Jun 23;18(1):252. doi: 10.1186/s12967-020-02424-7.

    PubMed 32576225

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Atezolizumab, Pegylated liposomal doxorubicin and Cyclophosphamide in people with Cancer, Breast and Triple Negative Breast Cancer, run by Oslo University Hospital at 5 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Norway, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03164993, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2024.

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