Pyrotinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer. (PHOEBE)

Study Overview
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Brief Summary
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Pyrotinib is an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2 receptors. This study is a randomized,open-label,multi-center,active-controlled, parallel design study of the combination of pyrotinib and capecitabine versus Lapatinib plus capecitabine in HER2+ MBC patients, who have prior received taxane and trastuzumab.Patients will be randomized in a 1:1 ratio to one of the following treatment arms.Arm A: pyrotinib (400 mg once daily) + capecitabine (1000 mg/m^2 twice daily),Arm B: Lapatinib (1250 mg once daily) + capecitabine (1000 mg/m^2 twice daily).Patients will receive either arm of therapy until disease progression, unacceptable toxicity, or withdrawalof consent.

Official Title
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A Randomised, Open-label, Parallel Controlled, Multicentre, Phase 3 Clinical Trial of Pyrotinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer:

Conditions
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HER2 Positive Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Pyrotinib Plus Capecitabine
* Drug: Lapatinib Plus Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 and ≤70 years. ECOG performance status of 0 to 1. Life expectancy of more than 12 weeks. According to RECIST 1.1, at least one measurable lesion exists Histologically or cytologic confirmed HER2 positive metastatic breast cancer. Prior treatment with trastuzumab (≥2 cycles in metastatic setting, or ≥3 months in adjuvant/neoadjuvant setting) and Taxane(≥2 cycles in any setting or untill unendurable AE or progression during treatment). Previously reveived ≤2 chemotherapy regimens in metastasis setting; Required laboratory values including following parameters: ANC: ≥ 1.5 x 10^9/L; Platelet count: ≥ 90 x 10^9/L; Hemoglobin: ≥ 90 g/L; Total bilirubin: ≤ 1.5 x upper limit of normal (ULN); ALT and AST: ≤ 2 x ULN(patients with liver metastases: ≤5 x ULN); BUN and Creatinine: ≤ 1x ULN;CCR≥50 mL/min;LVEF: ≥ 50%;QTcF: < 450 ms (male)，< 470 ms（female）; Signed informed consent. Exclusion Criteria: Received capecitabine in metastatic setting; Received HER2 targeted tyrosine kinase inhibitor (including Lapatinib, Neratinib and Pyrotinib); Cumulated dosage of Doxorubincin >400 mg/m^2 or Epirubicin >800 mg/m^2 or equal dosage of other anthracycline drugs in adjuvant/neoadjuvant/metastatic setting ); Received surgery，chemotherapy,radiotherapy or target therapy within 28 days prior to randomization. Received hormone therapy within 7 days prior to randomization; Participated in other clinical trial within 28 days prior to randomization. Known dihydro pyrimidine dehydrogenase（DPD）defect; CT or MRI confirmed brain metastases; Bone or skin lesion as unique target lesion; Second malignancies within 5 years, except for cured skin basal cell carcinoma,carcinoma in-situ of uterine cervix and squamous-cell carcinoma; Factors influencing the usage of oral administration (e.g. unable to swallow, chronic diarrhea and intestinal obstruction, etc.); Uncontrolled third space effusion (such as pleural fluid and ascites) by drainage or other clinical intervention; Receiving any other anti-tumour therapy after informed consent; Unprogressed after or during the last anti-tumour therapy,according to RECIST1.1; History of any kind of Heart disease,including 1)Angina pectoris; (2) Arrhythmia required medication or with clinical significance; (3) Myocardial infarction; (4) Heart failure; (5) Any other heart disease judged by researcher as not suitable for participating in this study, etc; History of Immunodeficiency, acquired or congenital immunodeficiency (HIV positive) ,history of organ transplantation; History of neurological or psychiatric disorders, including epilepsy or dementia; Concomitant disease judged by investigators that may bring serious harm to the safety of patients or the completion of this study; All female patients in breastfeeding period or in child-bearing period or with positive pregnancy test result or refusing to take a reliable method of birth control during the study; Any other situations judged by investigator as not suitable for participating in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyrotinib Plus Capecitabine<br> | Drug: Pyrotinib Plus Capecitabine<br>* pyrotinib(400 mg once daily) + capecitabine (2000 mg/m^2 daily, 1000 mg/ m^2 BID)<br>|
| Active Comparator: Lapatinib Plus Capecitabine<br> | Drug: Lapatinib Plus Capecitabine<br>* Lapatinib (1250 mg once daily)+ capecitabine (2000 mg/m^2 daily, 1000 mg/m^2 BID)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival(PFS) | From infromed consent to progression or death | Estimated 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: AE | AE | AE recorded from infromed consent to 28 days after treatment completion | 
| Overall Survival (OS) | From infromed consent to death | Estimated 30 months | 
| Objective Response Rate (ORR) | CR+PR | Estimated 10 months | 
| Time to Progression (TTP) | From infromed consent to progression | Estimated 10 months | 
| Duration of Response (DOR) | CR+PR+SD | Estimated 10 months | 
| Clinical Benefit rate (CBR) | CR+PR+SD≥24 weeks | Estimated 10 months |