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A Study Evaluating Pertuzumab (Perjeta) Combined With Trastuzumab (Herceptin) and Standard Anthracycline-based Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Locally Advanced, Inflammatory, or Early-stage Breast Cancer

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ClinicalTrials.gov Identifier: NCT02132949
Recruitment Status : Active, not recruiting
First Posted : May 7, 2014
Results First Posted : April 13, 2017
Last Update Posted : October 24, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE May 6, 2014
First Posted Date  ICMJE May 7, 2014
Results First Submitted Date  ICMJE March 1, 2017
Results First Posted Date  ICMJE April 13, 2017
Last Update Posted Date October 24, 2019
Actual Study Start Date  ICMJE July 14, 2014
Actual Primary Completion Date March 3, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 1, 2017)
  • Percentage of Participants With New York Heart Association (NYHA) Class III and IV Heart Failure During the Neoadjuvant Treatment Period [ Time Frame: Baseline to 24 weeks ]
    Symptomatic left ventricular systolic dysfunction (LVSD) is defined as heart failure. NYHA classifies participants' heart failure condition based on the participant's symptoms. Class III: marked limitation of the physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. 95 percent (%) confidence intervals (CIs) are calculated with the use of the Clopper-Pearson method.
  • Percentage of Participants With Drop in Left Ventricular Ejection Fraction (LVEF) of at Least 10 Percentage Points From Baseline and to Below 50% During the Neoadjuvant Treatment Period [ Time Frame: Baseline to 24 weeks ]
    A confirmed event was defined as at least two consecutive readings of declines in LVEF. 95% CIs are calculated with the use of the Clopper-Pearson method.
Original Primary Outcome Measures  ICMJE
 (submitted: May 6, 2014)
  • Incidence of cardiac events as assessed by the investigator using National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) v. 4.0 [ Time Frame: Approximately 5 years ]
  • Changes in left ventricular ejection fraction assessed by ECHO or MUGA scan. [ Time Frame: Approximately 5 years ]
Change History Complete list of historical versions of study NCT02132949 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 1, 2017)
  • Percentage of Participants With NYHA Class III and IV Heart Failure During the Adjuvant Treatment Period at Primary Completion Date (03 March 2016) [ Time Frame: Cycle 9 to Cycle 21 (cycle length=3 weeks; up to approximately 8 months) up to clinical cut-off date, 03 March 2016 (Month 20) ]
    LVSD is defined as heart failure. NYHA classifies participants' heart failure condition based on the participant's symptoms. Class III: marked limitation of the physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. 95% CIs was calculated with the use of the Clopper-Pearson method.
  • Percentage of Participants With Drop in LVEF of at Least 10 Points From Baseline and to Below 50% During the Adjuvant Treatment Period at Primary Completion Date (03 March 2016) [ Time Frame: Cycle 9 to Cycle 21 (cycle length=3 weeks; up to approximately 8 months) up to clinical cut-off date, 03 March 2016 (Month 20) ]
    A confirmed event was defined as at least two consecutive readings of declines in LVEF. 95% CIs was calculated with the use of the Clopper-Pearson method.
  • Percentage of Participants With NYHA Class III and IV Heart Failure at the End of Study [ Time Frame: Baseline up to approximately 6.5 years ]
    LVSD is defined as heart failure. NYHA classifies participants' heart failure condition based on the participant's symptoms. Class III: marked limitation of the physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. 95% CIs will be calculated with the use of the Clopper-Pearson method.
  • Percentage of Participants With Drop in LVEF of at Least 10 Points From Baseline and to Below 50% at End of Study [ Time Frame: Baseline up to approximately 6.5 years ]
    A confirmed event was defined as at least two consecutive readings of declines in LVEF. 95% CIs will be calculated with the use of the Clopper-Pearson method.
  • Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Pertuzumab [ Time Frame: Screening then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 6.5 years) ]
  • Percentage of Participants With Total Pathological Complete Response (tpCR) Evaluated at the Time of Surgery Based on Local Pathologist's Assessment After Surgery [ Time Frame: 24 weeks after neoadjuvant therapy (Post 8 cycles of neo-adjuvant therapy [cycle length=2¬3 weeks]) ]
    tpCR is defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes.
  • Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period [ Time Frame: Baseline until disease progression or death due to any cause up to 24 weeks (assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks]) ]
    Clinical response was classified as either complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. SD: neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. PD: at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. 95% CIs are calculated with the use of the Clopper-Pearson method.
  • Event-Free Survival Determined by the Investigator According to RECIST v1.1 [ Time Frame: Baseline until disease progression or death due to any cause up to approximately 6.5 years (assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks] and every 3 months thereafter until study completion or early termination) ]
    EFS is defined as the time from enrollment to the first occurrence of progressive disease, relapse, or death from any cause. PD: at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions.
  • Invasive Disease Free Survival (iDFS) Determined by the Investigator According to RECIST v1.1 [ Time Frame: Baseline until disease progression or death due to any cause up to approximately 6.5 years (assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks] and every 3 months thereafter until study completion or early termination) ]
    iDFS is defined as the time from the first date of no disease (the date of surgery) to the first documentation of progressive invasive disease, relapse, or death. PD: at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions.
  • Overall Survival (OS) [ Time Frame: Baseline up to death (approximately 6.5 years) ]
    OS was defined as the time from enrollment to death from any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2014)
  • Incidence of adverse events [ Time Frame: Approximately 5 years ]
  • Incidence of anti-therapeutic antibodies to Perjeta [ Time Frame: Approximately 5 years ]
  • Total pathological complete response defined as the eradication of invasive disease according to pathologist assessment [ Time Frame: Approximately 5 years ]
  • Clinical response as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) v. 1.1 [ Time Frame: Approximately 5 years ]
  • Event-free survival defined as time from enrollment to first occurrence of progressive disease, relapse, or death from any cause. [ Time Frame: Approximately 5 years ]
  • Invasive disease-free survival defined as the time from the first date of no disease to the first documentation of progressive invasive disease, relapse, or death from any cause. [ Time Frame: Approximately 5 years ]
  • Overall survival, defined as the time from enrollment to death from any cause. [ Time Frame: Approximately 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Evaluating Pertuzumab (Perjeta) Combined With Trastuzumab (Herceptin) and Standard Anthracycline-based Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Locally Advanced, Inflammatory, or Early-stage Breast Cancer
Official Title  ICMJE A Multicenter, Multinational, Phase II Study to Evaluate Perjeta in Combination With Herceptin and Standard Neoadjuvant Anthracycline-Based Chemotherapy in Patients With HER2-Positive, Locally Advanced, Inflammatory, or Early-Stage Breast Cancer
Brief Summary This multicenter, non-randomized, open-label, phase 2 study is designed to evaluate the safety and efficacy of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and anthracycline-based chemotherapy as neoadjuvant treatment in participants with HER2-positive locally advanced, inflammatory, or early-stage breast cancer. Each investigator will choose a treatment regimen (A or B) for all of their participants to follow. Treatment regimen A (for Cohort A) will include dose-dense doxorubicin and cyclophosphamide (ddAC), followed by paclitaxel, with pertuzumab and trastuzumab given from the start of paclitaxel. Treatment regimen B (for Cohort B) will include 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by docetaxel, with pertuzumab and trastuzumab given from the start of docetaxel. Participants in both cohorts will subsequently undergo surgical treatment and then resume pertuzumab and trastuzumab treatment.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: 5-Fluorouracil
    Participants will receive 5-fluorouracil 500 mg/m^2 IV on Day 1 of each cycle q3w.
  • Drug: Cyclophosphamide
    Participants will receive cyclophosphamide 600 milligrams per square meter (mg/m^2) intravenous (IV) given on Day 1 of each cycle q2w.
  • Drug: Docetaxel
    Participants will receive docetaxel at a starting dose of 75 mg/m^2 IV for the first cycle and the dose may be escalated to 100 mg/m^2 for subsequent cycles q3w.
  • Drug: Doxorubicin
    Participants will receive doxorubicin 60 mg/m^2 IV on Day 1 of each cycle q2w.
  • Drug: Epirubicin
    Participants will receive epirubicin 100 mg/m^2 IV on Day 1 of each cycle q3w.
  • Drug: Paclitaxel
    Participants will receive paclitaxel 80 mg/m^2 IV given weekly.
  • Drug: Pertuzumab
    Participants will receive pertuzumab at a loading dose of 840 milligrams (mg) IV loading dose, then 420 mg IV q3w.
    Other Name: Perjeta
  • Drug: Trastuzumab
    Participants will receive trastuzumab at a loading dose of 8 milligrams per kilogram (mg/kg) IV, then 6 mg/kg IV q3w.
    Other Name: Herceptin
Study Arms  ICMJE
  • Experimental: Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    ddAC: dose dense doxorubicin and cyclophosphamide. Participants will receive doxorubicin and cyclophosphamide every 2 weeks (q2w) for 4 cycles, followed by paclitaxel for 12 weeks, with pertuzumab and trastuzumab given every 3 weeks (q3w) (8 cycles of chemotherapy in total prior to surgery) from the start of paclitaxel. Following surgery, participants will receive further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: Paclitaxel
    • Drug: Pertuzumab
    • Drug: Trastuzumab
  • Experimental: Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    FEC: 5-fluorouracil, epirubicin and cyclophosphamide. Participants will receive 5-fluorouracil, epirubicin, and cyclophosphamide given q3w for 4 cycles, followed by docetaxel q3w for 4 cycles, with pertuzumab and trastuzumab given q3w (8 cycles of chemotherapy in total prior to surgery) from the start of docetaxel. Following surgery, participants will receive further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.
    Interventions:
    • Drug: 5-Fluorouracil
    • Drug: Cyclophosphamide
    • Drug: Docetaxel
    • Drug: Epirubicin
    • Drug: Pertuzumab
    • Drug: Trastuzumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 1, 2017)
401
Original Estimated Enrollment  ICMJE
 (submitted: May 6, 2014)
400
Estimated Study Completion Date  ICMJE August 26, 2020
Actual Primary Completion Date March 3, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and female participants with locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer. Participants with inflammatory breast cancer must be able to have a core needle biopsy
  • Primary tumor greater than (>) 2 centimeters (cm) in diameter, or > 5 millimeters (mm) in diameter and node-positive
  • HER2-positive breast cancer confirmed by a central laboratory
  • Availability of tumor tissue specimen
  • Baseline LVEF greater than or equal to (>/=) 55%
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (</=) 1
  • At least 4 weeks since major unrelated surgery, with full recovery
  • Women of childbearing potential and male participants with partners of childbearing potential must agree to use a "highly effective" non-hormonal form of contraception or two "effective" forms of non-hormonal contraception by the patient and/or partner. Contraception must continue for the duration of study treatment and for at least 7 months after the last dose of study treatment

Exclusion Criteria:

  • Metastatic disease (Stage IV) or bilateral breast cancer
  • Participants who have had an incisional biopsy of the primary tumor or the primary tumor excised
  • Prior breast or non-breast malignancy within 5 years prior to study entry, except for carcinoma in situ and basal cell and squamous cell carcinoma of the skin. Participants with malignancies occurring more than 5 years prior to study entry are permitted if curatively treated
  • Any previous systemic therapy (including chemotherapy, immunotherapy, HER2 targeted agents, and antitumor vaccines) for cancer, or radiation therapy for cancer
  • Participants with a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) are not allowed to enter the study if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast (they are allowed to enter the study if treated with surgery alone)
  • High-risk participants who have received chemopreventive drugs in the past are not allowed to enter the study
  • Inadequate bone marrow, renal, or liver function
  • History or evidence of cardiovascular condition
  • Dyspnea at rest or other diseases that require continuous oxygen therapy
  • Severe, uncontrolled systemic disease
  • Participants with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications
  • Pregnancy or breast-feeding women
  • Participants who received any investigational treatment within 4 weeks of study start
  • Participants with known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
  • Current chronic daily treatment with corticosteroids (dose >10 mg methylprednisolone or equivalent [excluding inhaled steroids])
  • Known hypersensitivity to any of the study drugs or excipients
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Denmark,   France,   Germany,   Italy,   Mexico,   Norway,   Poland,   Portugal,   Spain,   United Kingdom,   United States
Removed Location Countries Brazil,   Costa Rica,   Dominican Republic,   El Salvador,   Guatemala
 
Administrative Information
NCT Number  ICMJE NCT02132949
Other Study ID Numbers  ICMJE WO29217
2014-000156-28 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP