Clinical Trials /

Testing the Drug Atezolizumab or Placebo With Usual Therapy in First-Line HER2-Positive Metastatic Breast Cancer

NCT03199885

Description:

This randomized phase III trial studies how well paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab works in treating patients with breast cancer that has spread to other parts of the body (metastatic). Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab is a form of "targeted therapy" because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Monoclonal antibodies, such as pertuzumab, may interfere with the ability of cancer cells to grow and spread. Immunotherapy with monoclonal antibodies, such as atezolizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab may kill more tumor cells.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Drug Atezolizumab or Placebo With Usual Therapy in First-Line HER2-Positive Metastatic Breast Cancer
  • Official Title: A Randomized, Double-Blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab With Atezolizumab or Placebo in First-Line HER2-Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01119
  • SECONDARY ID: NCI-2017-01119
  • SECONDARY ID: NRG-BR004
  • SECONDARY ID: NRG-BR004
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03199885

Conditions

  • Breast Adenocarcinoma
  • Metastatic Breast Adenocarcinoma
  • Recurrent Breast Carcinoma
  • Stage III Breast Cancer AJCC v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Stage IV Breast Cancer AJCC v6 and v7
  • Unresectable Breast Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm I (pertuzumab, trastuzumab, taxane therapy, atezolizumab)
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateArm I (pertuzumab, trastuzumab, taxane therapy, atezolizumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (pertuzumab, trastuzumab, taxane therapy, atezolizumab)
Pertuzumab2C4, 2C4 Antibody, HS627, MoAb 2C4, Monoclonal Antibody 2C4, Omnitarg, Perjeta, Pertuzumab Biosimilar HS627, rhuMAb2C4, RO4368451Arm I (pertuzumab, trastuzumab, taxane therapy, atezolizumab)
TrastuzumabABP 980, ALT02, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, Herzuma, Kanjinti, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, Ogivri, Ontruzant, PF-05280014, rhuMAb HER2, RO0452317, SB3, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar ALT02, trastuzumab biosimilar EG12014, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab Biosimilar SB3, Trastuzumab Biosimilar SIBP-01, Trastuzumab-anns, Trastuzumab-dkst, Trastuzumab-dttb, Trastuzumab-pkrb, Trastuzumab-qyyp, TrazimeraArm I (pertuzumab, trastuzumab, taxane therapy, atezolizumab)

Purpose

This randomized phase III trial studies how well paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab works in treating patients with breast cancer that has spread to other parts of the body (metastatic). Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab is a form of "targeted therapy" because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Monoclonal antibodies, such as pertuzumab, may interfere with the ability of cancer cells to grow and spread. Immunotherapy with monoclonal antibodies, such as atezolizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the
      progression-free survival (PFS), assessed by investigator using Response Evaluation Criteria
      in Solid Tumors (RECIST) 1.1 criteria, relative to the addition of a placebo to a regimen of
      pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) in patients with
      newly documented HER2-positive measurable metastatic breast cancer.

      SECONDARY OBJECTIVES:

      I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall
      survival (OS) relative to the addition of placebo to a regimen of pertuzumab and trastuzumab,
      combined with a taxane (paclitaxel or docetaxel).

      II. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall
      objective response (OR), assessed by investigator using RECIST 1.1 criteria, relative to the
      addition of placebo to a regimen of pertuzumab and trastuzumab combined with a taxane
      (paclitaxel or docetaxel).

      III. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve PFS, OR, and/or
      duration of objective response assessed by retrospective blinded central review using RECIST
      1.1 criteria, relative to the addition of placebo to a regimen of pertuzumab and trastuzumab
      combined with a taxane (paclitaxel or docetaxel).

      IV. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will decrease the incidence of
      subsequent brain metastases in patients without known brain metastases at study entry
      relative to the addition of placebo to a regimen of pertuzumab and trastuzumab combined with
      a taxane (paclitaxel or docetaxel).

      V. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will contribute to increased
      patient-reported fatigue in comparison to the addition of placebo to a regimen of pertuzumab
      and trastuzumab combined with a taxane (paclitaxel or docetaxel).

      VI. To determine the utility of PD-L1 immunohistochemistry (IHC) staining as a predictive and
      prognostic biomarker associated with clinical response, as assessed by investigator using
      RECIST 1.1 criteria, to atezolizumab in combination with trastuzumab and pertuzumab combined
      with a taxane (paclitaxel or docetaxel).

      VII. To determine the immune-related toxicity profile of the two treatment regimens.

      VIII. To determine the cardiac safety profile of the two treatment regimens.

      EXPLORATORY OBJECTIVES:

      I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
      trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the
      progression-free survival and overall objective response, assessed by investigator using
      immune-modified RECIST (iRECIST) criteria, relative to the addition of a placebo to a regimen
      of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

      II. To identify potential biomarkers that can predict benefit from the addition of
      atezolizumab in patients with newly documented HER2-positive measurable metastatic breast
      cancer treated with a regimen of pertuzumab and trastuzumab combined with a taxane
      (paclitaxel or docetaxel).

      III. To explore the toxicity profile of the two treatment regimens using patient-reported
      symptomatic adverse events in addition to standard adverse event reports.

      IV. To determine the feasibility and added value of frequent assessment of toxicity using
      Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) with
      electronic(e)PRO reporting.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on days 1 and 22,
      trastuzumab IV over 30-90 minutes on days 1 and 22, and paclitaxel IV over 60 minutes on days
      1, 8, 15, 22, 29, and 36 or docetaxel IV over 60 minutes on days 1 and 22. Cycles repeat
      every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also
      receive atezolizumab IV over 30-60 minutes on day 1 of cycle 1 and days 1 and 22 of
      subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients receive pertuzumab, trastuzumab, and paclitaxel or docetaxel as in Arm I.
      Patients also receive placebo IV 30-60 minutes on day 1 of cycle 1 and days 1 and 22 of
      subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 3 years and
      then every 6 months for 4 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (pertuzumab, trastuzumab, taxane therapy, atezolizumab)ExperimentalPatients receive pertuzumab IV over 30-60 minutes on days 1 and 22, trastuzumab IV over 30-90 minutes on days 1 and 22, and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 or docetaxel IV over 60 minutes on days 1 and 22. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on day 1 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Docetaxel
  • Paclitaxel
  • Pertuzumab
  • Trastuzumab
Arm II (pertuzumab, trastuzumab, taxane therapy, placebo)Active ComparatorPatients receive pertuzumab, trastuzumab, and paclitaxel or docetaxel as in Arm I. Patients also receive placebo IV 30-60 minutes on day 1 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
  • Docetaxel
  • Paclitaxel
  • Pertuzumab
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  The patient must have signed and dated an Institutional Review Board (IRB)-approved
             consent form that conforms to federal and institutional guidelines

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             or 1

          -  Histologically confirmed adenocarcinoma of the breast with locally recurrent,
             unresectable disease or metastatic disease outside the central nervous system (CNS)
             confirmed as described below; eligible patients include those with either:

               -  De novo metastatic disease presenting without prior history of HER2-positive
                  breast cancer:

                    -  Diagnosis should have been made from a biopsy of a metastatic disease site,
                       but biopsy from the breast primary or involved regional lymph nodes is
                       acceptable if biopsy of the metastatic sites was thought to carry excessive
                       risk for the patient

               -  Locally recurrent or metastatic disease following prior therapy for early breast
                  cancer:

                    -  Diagnosis must have been made from the biopsy of the locally recurrent or
                       metastatic disease

                    -  There must be an interval of >= 6 months between completion of
                       neoadjuvant/adjuvant HER2-targeted therapy and documentation of locally
                       recurrent or metastatic HER2-positive disease by biopsy

          -  Patients must have measurable disease based on RECIST 1.1, as determined by the site,
             which has not been irradiated to be eligible

          -  Patients with brain metastases are eligible if they meet ALL the following criteria:

               -  Four or fewer metastatic sites to CNS

               -  Largest unexcised tumor does not exceed 3 cm

               -  No metastases to brain stem, midbrain, pons, medulla or the optic nerves and
                  chiasm

               -  Must have measurable disease outside the CNS, based on RECIST 1.1, as determined
                  by the site, which has not been irradiated

               -  If patient presented with symptoms from CNS metastases, the symptoms must have
                  resolved with initiation of steroids and initial local therapy (surgery,
                  radiation therapy, or both)

               -  Must have been evaluated by Medical Oncologist and plan is to administer
                  trastuzumab, pertuzumab, and a taxane as first-line systemic therapy

               -  May have received administration of trastuzumab OR lapatinib concurrently with
                  radiation therapy for brain metastases. Toxicities related to lapatinib if
                  administered, should be

               -  =< grade 1 per the CTCAE v5.0, and the lapatinib must have been completed at
                  least 2 weeks prior to study entry

               -  No history of intracranial hemorrhage or spinal cord hemorrhage

               -  No neurosurgical resection or brain biopsy within 10 days prior to study entry

          -  After study entry and before randomization, send tissue for central HER2 confirmation;
             a tumor specimen obtained at the time of diagnosis of locally recurrent or metastatic
             disease must have been determined to be HER2-positive based on local testing according
             to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
             guidelines (Wolff 2018); HER2 status should initially be assessed using an Food and
             Drug Administration (FDA)-cleared IHC assay; positive is defined as IHC 3+ staining
             intensity; if HER2 IHC results are equivocal (2+), then HER2 status will be determined
             using a FDA-cleared HER2 in situ hybridization (ISH) test according to ASCO/CAP
             guidelines; Note: Once HER2-positive is confirmed on central testing, patients will be
             randomized to atezolizumab/placebo; randomization within 14 days from study entry will
             ensure that the Pharmaceutical Management Branch (PMB)-supplied agents will be
             received at the site for treatment on day 22 of cycle 1

          -  The tumor specimen obtained at the time of diagnosis used for HER2 testing must also
             have central testing for PD-L1 status; patients will be eligible irrespective of PD-L1
             testing result including PD-L1 indeterminant

          -  The tumor specimen obtained at the time of diagnosis used for HER2 and PD-L1 testing
             should also have central testing for estrogen receptor (ER) and progesterone receptor
             (PgR) according to current ASCO/CAP guideline recommendations for hormone receptor
             testing; patients with < 1% ER and PgR staining by IHC will be classified as negative;
             if enough material for central confirmation of ER and PgR is unavailable, local
             testing results for ER and PgR may be used for eligibility

          -  Localized palliative radiation therapy to sites of non-measurable disease is allowed
             for symptom management and may begin prior to study entry and continue following study
             entry while receiving study therapy

          -  Patients must have imaging of the chest/abdomen/pelvis, preferably with a computed
             tomography (CT) scan, and a bone scan within 5 weeks prior to study entry; (NOTE: if a
             patient is unable to receive CT contrast, a magnetic resonance imaging [MRI] of the
             abdomen/pelvis and non-contrast chest CT should be performed; positron emission
             tomography/computed tomography [PET/CT] is not an acceptable alternative)

          -  MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo
             MRI) must be obtained in patients with symptoms suggesting possible central nervous
             system (CNS) metastatic disease; neuroimaging is recommended but not required in
             asymptomatic patients

          -  Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 14 days prior to study
             entry)

          -  Platelet count must be >= 100,000/mm^3 (within 14 days prior to study entry)

          -  Hemoglobin must be >= 8 g/dL (within 14 days prior to study entry)

          -  Total bilirubin must be =< 1.5 x upper limit of normal (ULN) for the lab or direct
             bilirubin =< ULN for patients with bilirubin levels > 1.5 x ULN (within 14 days prior
             to study entry)

          -  Aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) must be =< 2.5 x
             ULN for the lab or =< 5 x ULN for patients with liver metastases (within 14 days prior
             to study entry)

          -  Serum creatinine =< 1.5 x ULN or measured or calculated creatinine clearance >= 50
             mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x
             ULN for the lab (within 14 days prior to study entry)

          -  Patients not receiving anti-coagulant therapy must have prothrombin time (PT) and
             international normalized ratio (INR) =< 1.5 x ULN within 14 days prior to study entry;
             for laboratories that do not report an ULN for the INR assay, use =< 1.5 as the value
             for the ULN; patients receiving anti-coagulants should have a baseline INR assessed,
             but the value does not affect eligibility

          -  A serum thyroid-stimulating hormone (TSH) and AM (preferably in morning) cortisol must
             be obtained within 14 days prior to study entry to obtain a baseline value; patients
             with abnormal TSH or AM cortisol baseline levels should be further evaluated and
             managed per institutional standards; asymptomatic patients who require initiation or
             adjustment of medication or are followed without initiating treatment based on
             endocrinologist's recommendations are eligible

          -  Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks
             prior to study entry; (LVEF assessment performed by echocardiogram is preferred;
             however, multigated acquisition scan (MUGA) scan may be substituted based on
             institutional preferences); the LVEF must be >= 50% regardless of the cardiac imaging
             facility's lower limit of normal

          -  Administration of atezolizumab may have an adverse effect on pregnancy and poses a
             risk to the human fetus, including embryo-lethality; women of child-bearing potential
             and men must agree to use adequate contraception (non-hormonal or barrier method of
             birth control; abstinence) prior to study entry, for the duration of study
             participation, and for 5 months (150 days) after the last dose of atezolizumab/placebo
             and 7 months after the last dose of trastuzumab and pertuzumab; should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months of study entry are eligible for
             this trial

        Exclusion Criteria:

          -  Patients with brain metastases are excluded if they meet ANY of the following
             criteria:

               -  Symptoms from brain metastases have not resolved prior to study entry

               -  Five or more clearly identified foci of metastases to the brain

               -  Largest unexcised tumor exceeds 3 cm

               -  Spinal cord metastases

               -  Medical Oncologist plans to employ HER2-directed tyrosine kinase inhibitor as
                  component of systemic therapy

               -  Metastatic disease limited to CNS

          -  Leptomeningeal carcinomatosis

          -  History of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for
             metastatic breast cancer (MBC) except as described in inclusion criteria

          -  History of exposure to cumulative doses of doxorubicin greater than 360 mg per square
             meter of body-surface area or its equivalent

          -  Prior treatment with mTOR inhibitors or CDK 4/6 inhibitors in combination with
             endocrine therapy for treatment of metastatic disease

          -  Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including
             anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

          -  History of non-breast malignancies (except for in situ cancers treated only by local
             excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
             to study entry

          -  Uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150 mmHg
             or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if
             initiation or adjustment of BP medication lowers pressure to meet entry criteria)

          -  History of asymptomatic LVEF decline to < 40% during or after prior HER2-targeted
             therapy even if the current LVEF is >= 50%

          -  Cardiac disease (history of and/or active disease) that would preclude the use of the
             drugs included in the treatment regimens; this includes but is not confined to:

               -  Active cardiac disease

                    -  Angina pectoris that requires the current use of anti-anginal medication;

                    -  Ventricular arrhythmias except for benign premature ventricular
                       contractions;

                    -  Supraventricular and nodal arrhythmias requiring a pacemaker or not
                       controlled with medication;

                    -  Conduction abnormality requiring a pacemaker;

                    -  Valvular disease with documented compromise in cardiac function; or

                    -  Symptomatic pericarditis

               -  History of cardiac disease

                    -  Prior myocardial infarction documented by elevated cardiac enzymes or
                       persistent regional wall abnormalities on assessment of left ventricular
                       (LV) function;

                    -  History of documented congestive heart failure (CHF) defined as symptomatic
                       heart failure with an LVEF < 40%; or

                    -  Documented cardiomyopathy

          -  Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
             sensory neuropathy) >= grade 2, per the CTCAE v 5.0

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             pertuzumab or trastuzumab or to any of its excipients, as well as any chimeric or
             humanized antibodies or fusion proteins

          -  Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
             or other recombinant antibodies

          -  Known allergy or hypersensitivity to the components of the atezolizumab formulation or
             to any of the study drugs or excipients, (e.g., Cremophor EL, polysorbate 80)

          -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis

               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone may be eligible

               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
                  be eligible

               -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

                    -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
                       ocular manifestations

                    -  Rash must cover less than 10% of body surface area (BSA)

                    -  Disease is well controlled at baseline and only requiring low-potency
                       topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
                       flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

                    -  No acute exacerbations of underlying conditions 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)

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer,
             prior to study entry

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis [anti-TNF] factor agents) within 14 days prior to study entry or anticipation
             of need for systemic immunosuppressive medications during the study; Note: Intranasal
             and inhaled corticosteroids or systemic corticosteroids at doses that do not exceed 10
             mg/day of prednisone or an equivalent corticosteroid are allowed

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 2 weeks prior to study entry

          -  Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B
             surface antigen (HBsAg) test at screening; patients with a past or resolved HBV
             infection, defined as having a negative HBsAg test and a positive total hepatitis B
             core antibody (HBcAb) test at screening, are eligible for the study if active HBV
             infection is ruled out on the basis of HBV deoxyribonucleic acid (DNA) viral load per
             local guidelines

          -  Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
             test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV
             ribonucleic acid (RNA)

          -  Patients with clinically active tuberculosis

          -  Severe infection within 4 weeks prior to study entry, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Symptomatic peripheral ischemia

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis or >= grade 1 pulmonary fibrosis, per the CTCAE v5.0, on screening chest
             CT scan

          -  Administration of a live, attenuated vaccine within 4 weeks prior to study entry or
             anticipati
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival
Time Frame:The time from randomization to the first documented progressive disease assessed up to 7 years
Safety Issue:
Description:Will be determined using the current Response Evaluation Criteria in Solid Tumors 1.1 criteria. Analysis will be based on the intent to treat population. The stratified log-rank test will be used to compare the progression free survival between the two treatment arms with the following stratification factors: prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), estrogen receptor status (positive; negative), disease sites (any visceral without brain metastasis; non-visceral only without brain metastasis; brain metastasis), and choice of taxane (paclitaxel; docetaxel). The Kaplan-Meier estimates will be calculated by treatment arms. Stratified Cox proportional hazards models to estimate the hazard ratio.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:The time from randomization to death from any cause, assessed up to 7 years
Safety Issue:
Description:Analysis will be based on the intent to treat population. The Kaplan-Meier estimates will be calculated by treatment arms. Stratified Cox proportional hazards models to estimate the hazard ratio.
Measure:Overall objective response
Time Frame:Up to 7 years
Safety Issue:
Description:Defined as complete response or partial response. Will be determined using Response Evaluation Criteria in Solid Tumors 1.1 criteria.
Measure:Duration of objective response
Time Frame:From the date of initial confirmed partial response or complete response until the date of progressive disease or death from any cause assessed up to 7 years
Safety Issue:
Description:Tumor responses will be based on the current Response Evaluation Criteria in Solid Tumors 1.1 criteria.
Measure:Cumulative incidence of brain metastases
Time Frame:The time from randomization to documentation of brain metastases, assessed up to 7 years
Safety Issue:
Description:Analysis will be based on the intent to treat population. The Kaplan-Meier estimates will be calculated by treatment arms. Stratified Cox proportional hazards models to estimate the hazard ratio.
Measure:Frequency of adverse events, including late immune-related toxicities
Time Frame:Up to 7 years
Safety Issue:
Description:Will be categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

August 27, 2021