Clinical Trials /

Paclitaxel, Trastuzumab, and Pertuzumab With or Without Atezolizumab in Treating Patients With 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. Drugs used in chemotherapy, 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. Immunotherapy with trastuzumab, pertuzumab, and 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 Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Paclitaxel, Trastuzumab, and Pertuzumab With or Without Pembrolizumab in Treating Patients With Metastatic Breast Cancer
  • Official Title: A Randomized Phase III Trial of Paclitaxel/Trastuzumab/Pertuzumab Compared to Paclitaxel/Trastuzumab/Pertuzumab/Pembrolizumab 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

  • HER2/Neu Positive
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (pertuzumab, trastuzumab, paclitaxel)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm II (pertuzumab, trastuzumab, paclitaxel, pembrolizumab)
Pertuzumab2C4, 2C4 Antibody, MoAb 2C4, Monoclonal Antibody 2C4, Perjeta, rhuMAb2C4, RO4368451Arm I (pertuzumab, trastuzumab, paclitaxel)
TrastuzumabABP 980, 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, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, PF-05280014, rhuMAb HER2, RO0452317, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar PF-05280014Arm I (pertuzumab, trastuzumab, paclitaxel)

Purpose

This randomized phase III trial studies how well paclitaxel, trastuzumab, and pertuzumab with or without pembrolizumab works in treating patients with breast cancer that has spread to other parts of the body. Drugs used in chemotherapy, 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. Monoclonal antibodies, such as trastuzumab, pertuzumab, and pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving paclitaxel, trastuzumab, and pertuzumab with pembrolizumab may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

      I. To determine whether the addition of pembrolizumab to a regimen of paclitaxel, pertuzumab,
      and trastuzumab will improve the overall survival (OS) relative to a regimen of paclitaxel,
      pertuzumab, and trastuzumab.

      II. To determine whether the addition of pembrolizumab to a regimen of paclitaxel,
      pertuzumab, and trastuzumab will improve the overall objective response, as assessed by
      RECIST 1.1 criteria, relative to a regimen of paclitaxel, pertuzumab, and trastuzumab.

      III. To determine whether the addition of pembrolizumab to a regimen of paclitaxel,
      pertuzumab, and trastuzumab will improve the duration of objective response, as assessed by
      RECIST 1.1 criteria, relative to a regimen of paclitaxel, pertuzumab, and trastuzumab.

      IV. To determine whether the addition of pembrolizumab to a regimen of paclitaxel,
      pertuzumab, and trastuzumab will decrease the incidence of subsequent brain metastases in
      patients without known brain metastases at study entry relative to a regimen of paclitaxel,
      pertuzumab, and trastuzumab.

      V. To determine whether the addition of pembrolizumab to a regimen of paclitaxel, pertuzumab,
      and trastuzumab will contribute to increased patient-reported fatigue in comparison to a
      regimen of paclitaxel, pertuzumab, and trastuzumab.

      VI. To determine whether the addition of pembrolizumab to a regimen of paclitaxel,
      pertuzumab, and trastuzumab will contribute to poorer patient-reported physical function in
      comparison to a regimen of paclitaxel, pertuzumab, and trastuzumab.

      VII. To determine the toxicity profile of the two treatment regimens using patient-reported
      symptom assessments in addition to standard adverse event reports.

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

      IX. To determine the cardiac safety profile of the two treatment regimens. X. To identify
      potential biomarkers that can predict benefit from the addition of pembrolizumab in patients
      with newly documented HER2-positive metastatic breast cancer treated with a regimen of
      paclitaxel, pertuzumab, and trastuzumab.

      TERTIARY OBJECTIVES:

      I. To determine whether the addition of pembrolizumab to a regimen of paclitaxel, pertuzumab,
      and trastuzumab will improve the progression-free survival and overall objective response, as
      assessed by immune-related response criteria immune-related response criteria (irRECIST),
      relative to a regimen of paclitaxel, pertuzumab, and trastuzumab.

      II. To determine the feasibility and added value of frequent assessment of toxicity using
      patient-reported outcomes version of the Common Terminology Criteria for Adverse Events
      (PRO-CTCAE) with electronic patient-reported outcomes (ePRO) reporting.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on day 1 and
      trastuzumab IV over 30-90 minutes on day 1. Patients also receive paclitaxel IV over 60
      minutes on days 1 and 8. Treatment with paclitaxel repeats every 3 weeks for up to 9 courses
      in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive pertuzumab, trastuzumab, and paclitaxel as in Arm I. Patients also
      receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to
      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 six months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (pertuzumab, trastuzumab, paclitaxel)Active ComparatorPatients receive pertuzumab IV over 30-60 minutes on day 1 and trastuzumab IV over 30-90 minutes on day 1. Patients also receive paclitaxel IV over 60 minutes on days 1 and 8. Treatment with paclitaxel repeats every 3 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.
  • Paclitaxel
Arm II (pertuzumab, trastuzumab, paclitaxel, pembrolizumab)ExperimentalPatients receive pertuzumab, trastuzumab, and paclitaxel as in Arm I. Patients also receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Paclitaxel

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 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 be made from the biopsy of a metastatic disease site
                       (preferred), but biopsy from the breast primary or involved regional lymph
                       nodes is acceptable if biopsy of the metastatic sites is thought to carry
                       excessive risk for the patient

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

                    -  Diagnosis must be 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 with measurable and non-measurable disease are eligible

          -  The tumor specimen obtained at the time of diagnosis at the time of locally recurrent
             or metastatic disease must have been determined to be HER2-positive based on standard
             methods used to determine HER2 status of locally recurrent or metastatic disease;
             HER2-positive is defined as HER2/chromosome enumeration probe 17 (CEP17) ratio >= 2.0
             or >= 6 average HER2 copy number per cell by fluorescence in situ hybridization (FISH)
             or immunohistochemistry (IHC) 3+ by current American Society of Clinical
             Oncology/College of American Pathologists (ASCO/CAP) guidelines

          -  The tumor specimen obtained at the time of diagnosis used for HER2 testing must also
             have estrogen receptor (ER) analysis performed on it according to current ASCO/CAP
             Guideline Recommendations for hormone receptor testing; if negative for ER, assessment
             of progesterone receptor (PgR) must also be performed 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

          -  Patients may have received one endocrine therapy regimen for locally recurrent or
             metastatic breast cancer with or without co-administration of trastuzumab before
             randomization

          -  Localized palliative radiation therapy is allowed for symptom management if completed
             >= 2 weeks prior to randomization

          -  Patients must have imaging of the chest/abdomen/pelvis, preferably with a computed
             tomography (CT) scan, and a bone scan within 4 weeks prior to randomization; (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

          -  Patients with brain metastases documented concurrently with initial non-CNS metastases
             will be eligible after completing therapy for their brain metastases and are
             tolerating steroid tapering; patients who received treatment with trastuzumab or
             lapatinib concurrently with radiation therapy for brain metastases are eligible

          -  Absolute neutrophil count (ANC) must be >= 1200/mm^3

          -  Platelet count must be >= 100,000/mm^3

          -  Hemoglobin must be >= 9 g/dL (without packed red blood cell transfusion within 4 weeks
             prior to randomization or not erythropoietin dependent)

          -  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

          -  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.

          -  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

          -  A serum thyroid-stimulating hormone (TSH) must be obtained within 10 days prior to
             randomization to obtain a baseline value

          -  Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks
             prior to randomization; (LVEF assessment performed by echocardiogram is preferred;
             however, multigated acquisition scan (MUGA) scan may be substituted based on
             institutional preferences); the LVEF must be >= 55% regardless of the cardiac imaging
             facility's lower limit of normal

        Exclusion Criteria:

          -  Central nervous system metastases that are untreated or require chronic corticosteroid
             therapy

          -  Leptomeningeal carcinomatosis

          -  Patients with metastatic disease limited to the CNS

          -  History of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for MBC
             with exceptions of:

               -  One prior hormonal regimen for metastatic breast cancer (MBC) with or without
                  co-administration of trastuzumab; and/or

               -  Administration of trastuzumab or lapatinib concurrently with radiation therapy
                  for brain metastases

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

          -  Prior or current treatment with PD-1 or PD-L1 inhibitors or other immune-based therapy

          -  Prior treatment with CDK 4/6 inhibitors for treatment of metastatic disease

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to
             randomization or who has not recovered (i.e., =< grade 1 or at baseline) from adverse
             events due to agents administered more than 4 weeks earlier

          -  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 randomization

          -  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

          -  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 Common Terminology Criteria for Adverse Events
             (CTCAE) version (v) 4.0

          -  Has received transfusion of blood products (including platelets or red blood cells) or
             administration of colony stimulating factors (including granulocyte colony-stimulating
             factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or
             recombinant erythropoietin) within 4 weeks prior to randomization

          -  Active autoimmune disease that has required systemic treatment in past 2 years (i.e.,
             with use of disease modifying agents, corticosteroids, or immunosuppressive drugs);
             replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 2 weeks prior to randomization; 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 known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus (HCV) ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Patients known to be human immunodeficiency virus (HIV) positive are eligible if they
             meet the following criteria within 4 weeks prior to randomization:

               -  Stable and adequate CD4 counts (>= 350/mm^3); and

               -  Serum HIV viral load of < 25,000 IU/mL; and

               -  Must be on a stable anti-retroviral regimen

          -  Has an active infection requiring systemic therapy

          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis
             or history of interstitial lung disease

          -  Has received a live-virus vaccination within 28 days of randomization; seasonal flu
             vaccines that do not contain live virus are permitted

          -  Known hypersensitivity to any of the study drugs or excipients, (e.g., Cremophor EL)

          -  Other non-malignant systemic disease that would preclude the patient from receiving
             study treatment or would prevent required follow-up

          -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
             investigator, would preclude the patient from meeting the study requirements or
             interfere with interpretation of study results

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 7 months
             after the last dose of study treatment; (NOTE: pregnancy testing according to
             institutional standards for women of childbearing potential must be performed within
             72 hours prior to randomization)

          -  Use of any investigational product within 4 weeks prior to randomization
      
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 5 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 prior trastuzumab; prior trastuzumab and no pertuzumab; prior trastuzumab and pertuzumab), estrogen receptor status (positive; negative), and disease sites (any visceral without brain metastasis; non-visceral only without brain me

Secondary Outcome Measures

Measure:Cumulative incidence of brain metastases
Time Frame:The time from randomization to documentation of brain metastases, assessed up to 5 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:Duration of 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 5 years
Safety Issue:
Description:Tumor responses will be based on the current Response Evaluation Criteria in Solid Tumors 1.1 criteria.
Measure:Frequency of adverse events, including late immune-related toxicities
Time Frame:Up to 5 years
Safety Issue:
Description:Will be categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
Measure:Objective response, defined as complete response or partial response
Time Frame:Up to 5 years
Safety Issue:
Description:Will be determined using Response Evaluation Criteria in Solid Tumors 1.1 criteria.
Measure:Overall survival
Time Frame:The time from randomization to death from any cause, assessed up to 5 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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 16, 2017