Clinical Trials /

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

NCT03164993

Description:

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:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

  • ORG STUDY ID: ML39079_ALICE
  • NCT ID: NCT03164993

Conditions

  • Cancer, Breast
  • Triple Negative Breast Cancer

Interventions

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

Purpose

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
      limits.
    

Trial Arms

NameTypeDescriptionInterventions
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:

          -  Metastatic or incurable locally advanced, histologically documented TNBC (absence of
             human epidermal growth factor receptor (HER2), endocrine receptor (ER), and
             progesterone receptors (PR) expression). HER2 negativity is defined as either of the
             following by local laboratory assessment: In situ hybridization (ISH) non-amplified
             (ratio of HER2 to chromosome 17 centromere(CEP17) < 2.0 or single probe average HER2
             gene copy number < 4 signals/cell), or Immunohistochemistry (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 principal investigator 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 Immune-related Response Evaluation Criteria In Solid
             Tumors (irRECIST)

          -  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 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 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 5 months after the last dose of study therapy

        Exclusion Criteria:

          -  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)

          -  Known Breast Cancer gene (BRCA) mutation, unless the patient has already received
             carboplatin or for other reasons should not receive carboplatin treatment, according
             to own preferences or recommendations by the treating physician.

          -  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 central nervous system (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 upper normal limit (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 psoralen plus ultraviolet A radiation (PUVA), 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 Interleukin-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 3 weeks prior to
             study Cycle 1, Day 1. However the following are allowed:

             a. Palliative radiotherapy for bone metastases > 2 weeks prior to 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

          -  Received a live vaccine within 30 days of planned start of study therapy, or is
             expected to receive such a vaccine while on therapy a. 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.
      
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:
Measure:Overall survival
Time Frame:5 years
Safety Issue:
Description:
Measure:Duration of response
Time Frame:3 years
Safety Issue:
Description:
Measure:Durable tumor response rate (DRR; >6 months)
Time Frame:3 years
Safety Issue:
Description:
Measure:Patient reported outcome
Time Frame:3 years
Safety Issue:
Description:Measured by the Chalder Fatigue Questionnaire (FQ)
Measure:Patient reported outcome
Time Frame:3 years
Safety Issue:
Description:11 point Numerical Rating Scale (NRS) for pain intensity
Measure:Patient reported outcome
Time Frame:3 years
Safety Issue:
Description:EORTC quality of life questionnaire (QLQ-C15-PAL)

Details

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

Trial Keywords

  • Neoplasms

Last Updated

March 4, 2020