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A Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Participants With HER2-Positive Early Breast Cancer

NCT03493854

Description:

This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and trastuzumab for subcutaneous (SC) administration in combination with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the neoadjuvant/adjuvant setting.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Participants With HER2-Positive Early Breast Cancer
  • Official Title: A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Patients With HER2-Positive Early Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: WO40324
  • SECONDARY ID: 2017-004897-32
  • NCT ID: NCT03493854

Conditions

  • Early Breast Cancer

Interventions

DrugSynonymsArms
CyclophosphamideArm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
DoxorubicinArm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
DocetaxelArm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
PaclitaxelArm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
Pertuzumab IVPerjeta, RO4368451Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
FDC of Pertuzumab and Trastuzumab SCRO7198574Arm B: FDC of Pertuzumab and Trastuzumab SC + Chemotherapy
Trastuzumab IVHerceptin, RO0452317Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
Trastuzumab SCHerceptin, RO0452317Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
Hormone TherapyArm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy

Purpose

This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and trastuzumab for subcutaneous (SC) administration in combination with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the neoadjuvant/adjuvant setting.

Trial Arms

NameTypeDescriptionInterventions
Arm A: Pertuzumab IV + Trastuzumab IV + ChemotherapyActive ComparatorParticipants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor [G-CSF] support as needed according to local guidelines) followed by paclitaxel Q1W for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab will be given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles.
  • Cyclophosphamide
  • Doxorubicin
  • Docetaxel
  • Paclitaxel
  • Pertuzumab IV
  • Trastuzumab IV
  • Trastuzumab SC
  • Hormone Therapy
Arm B: FDC of Pertuzumab and Trastuzumab SC + ChemotherapyExperimentalParticipants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab will be given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.
  • Cyclophosphamide
  • Doxorubicin
  • Docetaxel
  • Paclitaxel
  • FDC of Pertuzumab and Trastuzumab SC
  • Hormone Therapy

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to comply with the study protocol, in the investigator's judgment

          -  Female and male patients with Stage II - IIIC (T2-T4, N0-N3, M0), locally advanced,
             inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast
             cancer

          -  Primary tumor >2 cm in diameter, or node-positive

          -  HER2-positive breast cancer confirmed by a central laboratory prior to study
             enrollment. HER2-positive status will be determined based on pretreatment breast
             biopsy material.

          -  Hormone receptor status of the primary tumor, centrally confirmed

          -  Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant
             therapy

          -  Availability of formalin-fixed, paraffin-embedded tumor tissue block for central
             confirmation of HER2 and hormone receptor status and additional biomarker research

          -  Baseline left ventricular ejection fraction (LVEF) greater than or equal to (>/=) 55%
             measured by echocardiogram or multiple-gated acquisition scan

          -  For women of childbearing potential (WOCBP) who are sexually active: agreement to
             remain abstinent or use one highly effective non-hormonal contraceptive method with a
             failure rate of < 1% per year, or two effective non-hormonal contraceptive methods
             during the treatment period and for 7 months after the last dose of HER2-targeted
             therapy

          -  For men: men must remain abstinent or use a condom with a spermicidal product during
             the treatment period and for 7 months after the last dose of HER2-targeted therapy to
             avoid exposing the embryo. Men must refrain from donating sperm during this same
             period.

          -  A negative serum pregnancy test must be available prior to randomization for WOCBP,
             unless they have undergone surgical sterilization

          -  No major surgical procedure unrelated to breast cancer within 28 days prior to
             randomization or anticipation of the need for major surgery during the course of study
             treatment

        Exclusion Criteria:

          -  Stage IV (metastatic) breast cancer

          -  Patients with a history of invasive breast cancer

          -  Patients with a history of concurrent or previously treated non-breast malignancies
             except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ
             carcinomas, including cervix, colon, and skin

          -  Patients who have received any previous systemic therapy for treatment or prevention
             of breast cancer, or radiation therapy for treatment of cancer

          -  Patients who have a past history of ductal carcinoma in situ or lobular carcinoma in
             situ if they have received any systemic therapy for its treatment or radiation therapy
             to the ipsilateral breast

          -  Patients with high-risk for breast cancer who have received chemo-preventative drugs
             in the past are not allowed to enter the study

          -  Patients with multicentric breast cancer, unless all tumors are HER2-positive

          -  Patients with bilateral breast cancer

          -  Patients who have undergone an excisional biopsy of primary tumor and/or axillary
             lymph nodes

          -  Axillary lymph node dissection prior to initiation of neoadjuvant therapy

          -  Sentinel lymph node biopsy prior to neoadjuvant therapy

          -  Treatment with any investigational drug within 28 days prior to randomization

          -  Serious cardiac illness or medical conditions

          -  Inadequate bone marrow function, renal function or impaired liver function

          -  Current severe, uncontrolled systemic disease that may interfere with planned
             treatment

          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within
             7 months after the last dose of HER2-targeted therapy

          -  Any serious medical condition or abnormality in clinical laboratory tests that, in the
             investigator's judgment, precludes the patient's safe participation in and completion
             of the study

          -  Known active liver disease, for example, active viral hepatitis infection, autoimmune
             hepatic disorders, or sclerosing cholangitis

          -  Concurrent, serious, uncontrolled infections, or known infection with HIV

          -  Known hypersensitivity to study drugs, excipients, and/or murine proteins

          -  Current chronic daily treatment with corticosteroids

          -  History of other malignancy within 5 years prior to screening, except for
             appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or
             Stage I uterine cancer

          -  History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such
             as structural heart disease, coronary heart disease, clinically significant
             electrolyte abnormalities, or family history of sudden unexplained death or long QT
             syndrome
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Trough Serum Concentration (Ctrough) of Pertuzumab During Cycle 7
Time Frame:Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Ctrough of Trastuzumab During Cycle 7
Time Frame:Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
Safety Issue:
Description:
Measure:Percentage of Participants with Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment
Time Frame:Following completion of surgery (up to 33 weeks)
Safety Issue:
Description:tpCR is defined as eradication of invasive disease in the breast and axilla (i.e., ypT0/isypN0)
Measure:Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria
Time Frame:Up to 5.5 years
Safety Issue:
Description:iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.
Measure:Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria
Time Frame:Up to 5.5 years
Safety Issue:
Description:iDFS including SPNBC is defined in the same way as iDFS but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site)
Measure:Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria
Time Frame:Up to 5.5 years
Safety Issue:
Description:EFS (excluding SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.
Measure:Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria
Time Frame:Up to 5.5 years
Safety Issue:
Description:EFS including SPNBC is defined in the same way as EFS, but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site)
Measure:Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria
Time Frame:Up to 5.5 years
Safety Issue:
Description:DRFI is defined as the time between randomization and the date of distant breast cancer recurrence
Measure:Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival
Time Frame:Up to 5.5 years
Safety Issue:
Description:Overall survival is defined as the time from randomization to death from any cause
Measure:Percentage of Participants With Adverse Events (Including Serious Adverse Events), Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4)
Time Frame:Up to 5.5 years
Safety Issue:
Description:
Measure:Percentage of Participants With a Primary Cardiac Event
Time Frame:From Baseline up to 5.5 years
Safety Issue:
Description:A primary cardiac event is defined as the occurrence of either of the following events: Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in Left Ventricular Ejection Fraction (LVEF) of at least 10-percentage points from baseline and to below 50%. or Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).
Measure:Percentage of Participants With a Secondary Cardiac Event
Time Frame:From Baseline up to 5.5 years
Safety Issue:
Description:A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as an LVEF decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

May 3, 2018