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A 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 Chinese Participants With HER2-Positive Early Breast Cancer

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ClinicalTrials.gov Identifier: NCT04024462
Recruitment Status : Not yet recruiting
First Posted : July 18, 2019
Last Update Posted : August 12, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This study will evaluate the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and trastuzumab for subcutaneous (SC) administration as compared with those of the pertuzumab intravenous (IV) and trastuzumab IV formulations in Chinese participants with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.

Condition or disease Intervention/treatment Phase
HER2-positive Early Breast Cancer Drug: Pertuzumab IV Drug: Trastuzumab IV Drug: FDC of Pertuzumab and Trastuzumab SC Drug: Doxorubicin Drug: Cyclophosphamide Drug: Docetaxel Procedure: Surgery Radiation: Post-Operative Radiotherapy Drug: Hormone Therapy Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Chinese Patients With HER2-Positive Early Breast Cancer
Estimated Study Start Date : September 25, 2019
Estimated Primary Completion Date : June 23, 2021
Estimated Study Completion Date : February 19, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
Participants will receive 8 cycles of neoadjuvant chemotherapy: 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.
Drug: Pertuzumab IV
Pertuzumab will be administered as a fixed non-weight-based loading dose of 840-milligrams (mg) IV and then a 420-mg IV maintenance dose Q3W.
Other Names:
  • Perjeta
  • RO4368451

Drug: Trastuzumab IV
Trastuzumab will be administered as an 8-milligram per kilogram of body weight (mg/kg) IV loading dose and then 6 mg/kg IV maintenance dose Q3W.
Other Names:
  • Herceptin
  • RO0452317

Drug: Doxorubicin
Doxorubicin 60 milligrams per meter squared of body surface area (mg/m^2) will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.

Drug: Cyclophosphamide
Cyclophosphamide 600 mg/m^2 will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.

Drug: Docetaxel
Docetaxel 75 mg/m^2 will be administered IV on Day 1 of Cycle 5. At the investigator's discretion the dose may be escalated to 100 mg/m^2 IV for Cycles 6-8 (Q3W) provided no dose-limiting toxicity occurs.

Procedure: Surgery
Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.

Radiation: Post-Operative Radiotherapy
If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).

Drug: Hormone Therapy
For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.

Experimental: Arm B: FDC of Pertuzumab and Trastuzumab SC + Chemotherapy
Participants will receive 8 cycles of neoadjuvant chemotherapy: 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.
Drug: FDC of Pertuzumab and Trastuzumab SC
The FDC of pertuzumab and trastuzumab will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.
Other Names:
  • RG6264
  • RO7198574

Drug: Doxorubicin
Doxorubicin 60 milligrams per meter squared of body surface area (mg/m^2) will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.

Drug: Cyclophosphamide
Cyclophosphamide 600 mg/m^2 will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.

Drug: Docetaxel
Docetaxel 75 mg/m^2 will be administered IV on Day 1 of Cycle 5. At the investigator's discretion the dose may be escalated to 100 mg/m^2 IV for Cycles 6-8 (Q3W) provided no dose-limiting toxicity occurs.

Procedure: Surgery
Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.

Radiation: Post-Operative Radiotherapy
If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).

Drug: Hormone Therapy
For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.




Primary Outcome Measures :
  1. Serum Trough Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8) [ Time Frame: Pre-dose at Cycle 8 (one cycle is 21 days) ]
  2. Serum Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8) [ Time Frame: Pre-dose at Cycle 8 (one cycle is 21 days) ]

Secondary Outcome Measures :
  1. Percentage of Participants with Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment [ Time Frame: Following completion of surgery (up to 33 weeks) ]
    tpCR is defined as eradication of invasive disease in the breast and axilla (i.e., ypT0/isypN0)

  2. 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: From date of surgery to iDFS (excluding SPNBC) event (up to 5 years) ]
    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.

  3. Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria [ Time Frame: From date of surgery to iDFS (including SPNBC) event (up to 5 years) ]
    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).

  4. Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria [ Time Frame: From baseline to EFS (excluding SPNBC) event (up to 5.5 years) ]
    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.

  5. Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria [ Time Frame: From baseline to EFS (including SPNBC) event (up to 5.5 years) ]
    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).

  6. Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria [ Time Frame: From baseline to DFRI event (up to 5.5 years) ]
    DRFI is defined as the time between randomization and the date of distant breast cancer recurrence.

  7. Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival [ Time Frame: From baseline to death from any cause (up to 5.5 years) ]
  8. Number of Participants with At Least One Adverse Event by Severity, Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4) [ Time Frame: From baseline until study completion (up to 5.5 years) ]
  9. Number of Participants with a Symptomatic Ejection Fraction Decrease (Heart Failure) of 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% [ Time Frame: From baseline until study completion (up to 5.5 years) ]
    New York Heart Association (NYHA) Class III is defined as: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. NYHA Class IV is defined as: Inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

  10. Number of Participants Who Died from a Definite or Probable Cardiac Death [ Time Frame: From baseline until study completion (up to 5.5 years) ]
    Definite cardiac death is defined as death due to heart failure, myocardial infarction, or documented primary arrhythmia. Probable cardiac death is defined as 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.

  11. Number of Participants with an Asymptomatic or Mildly Symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II [ Time Frame: From baseline until study completion (up to 5.5 years) ]
    An LVSD ("Ejection fraction decreased") of NYHA Class II is defined as an LVEF decrease of ≥10-percentage points below the baseline measurement to an absolute LVEF value of <50%, confirmed by a second assessment within approximately 3 weeks confirming a decrease of ≥10-percentage points below the baseline measurement and to an absolute LVEF value of <50%.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to comply with the study protocol, in the investigator's judgment
  • Eastern Cooperative Oncology Group (ECOG) Performance Status greater or equal to (≤)1
  • Stage II−IIIC (T2−T4 plus any N, or any T plus N1−3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer
  • Primary tumor greater than (>)2 centimeters (cm) in diameter, or node-positive disease (clinically or on imaging, and node positivity confirmed with cytology and/or histopathology)
  • Human Epidermal Growth Factor Receptor 2 (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 and defined as 3+ by immunohistochemistry (IHC) and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies
  • 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 (FFPE) tumor tissue for central confirmation of HER2, hormone receptor status, and PIK3CA mutational analyses
  • Baseline left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
  • For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent (refrain from heterosexual intercourse) or use one highly effective non-hormonal contraceptive method with a failure rate of less than (<)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, and agreement to refrain from donating eggs during this same period
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom in combination with a spermicidal foam, gel, film, cream, or suppository, and agreement to refrain from donating sperm, as specified in the protocol
  • A negative serum pregnancy test must be available prior to randomization for WOCBP (premenopausal women and women <12 months after the onset of menopause), unless they have undergone surgical sterilization (removal of ovaries and/or uterus)
  • 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
  • History of invasive breast cancer
  • 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
  • Have received any previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted agents, endocrine therapy [selective estrogen receptor modulators, aromatase inhibitors], and antitumor vaccines) for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer
  • Have a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast
  • High-risk for breast cancer and have received chemopreventative drugs in the past
  • Multicentric (multiple tumors involving more than one quadrant) breast cancer, unless all tumors are HER2-positive
  • Bilateral breast cancer
  • Have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes
  • Axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy
  • Sentinel lymph node biopsy (SLNB) 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
  • Impaired liver function
  • Inadequate renal function with serum creatinine >1.5X upper limit of normal (ULN)
  • Current severe, uncontrolled systemic disease that may interfere with planned treatment (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders)
  • 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 (i.e., hepatitis B or hepatitis C), 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 (dose >10 milligrams [mg] methylprednisolone or equivalent excluding inhaled steroids)
  • History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma
  • History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04024462


Contacts
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Contact: Reference Study ID Number: YO41137 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. Only) global-roche-genentech-trials@gene.com

Locations
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China
The First Hospital of Jilin University Not yet recruiting
Changchun City, China, 130021
Jilin Cancer Hospital Not yet recruiting
Changchun, China, 130012
West China Hospital, Sichuan University Not yet recruiting
Chengdu, China, 610041
Fujian Medical University Union Hospital Not yet recruiting
Fujian, China, 350001
Fuzhou General Hospital, PLA Nanjing Military Area Command Not yet recruiting
Fuzhou, China, 110016
Sun Yet-sen University Cancer Center Not yet recruiting
Guangzhou, China, 510060
Zhejiang Cancer Hospital; Breast Surgery Not yet recruiting
Hangzhou City, China, 310022
The Second Affiliated Hospital, Zhejiang University Not yet recruiting
Hangzhou, China, 310009
Harbin Medical University Cancer Hospital Not yet recruiting
Harbin, China, 150081
Shandong Cancer Hospital Not yet recruiting
Jinan, China, 250117
Jiangsu Province Hospital Not yet recruiting
Nanjing, China, 210036
The Affiliated Hospital of Medical College Qingdao University Not yet recruiting
Qingdao, China, 266003
Ruijin Hospital, Shanghai Jiaotong University School of Medicine Not yet recruiting
Shanghai City, China, 200025
Fudan University Shanghai Cancer Center Not yet recruiting
Shanghai, China, 200032
Union Hospital Tongji Medical College Huazhong University of Science and Technology Not yet recruiting
Wuhan City, China, 430023
Hubei Cancer Hospital Not yet recruiting
Wuhan, China, 430079
The First Affiliated Hospital of Xian Jiao Tong University Not yet recruiting
Xi'an City, China, 710061
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04024462     History of Changes
Other Study ID Numbers: YO41137
First Posted: July 18, 2019    Key Record Dates
Last Update Posted: August 12, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Docetaxel
Doxorubicin
Liposomal doxorubicin
Trastuzumab
Pertuzumab
Hormones
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Hormones, Hormone Substitutes, and Hormone Antagonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological