A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE)

Study Overview
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Brief Summary
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This 2-arm, randomized, open-label study will evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Eligible patients will be randomized to receive either trastuzumab emtansine 3.6 mg/kg or trastuzumab 6 mg/kg intravenously every 3 weeks for 14 cycles. Radiotherapy and/or hormone therapy will be given in addition if indicated.

Official Title
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A Randomized, Multicenter, Open-Label Phase III Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy for Patients With HER2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically in the Breast or Axillary Lymph Nodes Following Preoperative Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: trastuzumab
* Drug: trastuzumab emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient, >/= 18 years of age HER2-positive breast cancer Histologically confirmed invasive breast carcinoma Clinical stage T1-4/N0-3/M0 at presentation (patients with T1a/bN0 tumors will not be eligible) Completion of preoperative systemic chemotherapy and HER2-directed treatment consisting of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based therapy Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as specified in protocol Pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy An interval of no more than 12 weeks between the date of surgery and the date of randomization Known hormone-receptor status Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate hematologic, renal and liver function Screening Left ventricular ejection fraction (LVEF) >/= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >/= 55% after completion of neoadjuvant chemotherapy. For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study drug Documentation of hepatitis B virus and hepatitis C virus serology is required Exclusion Criteria: Stage IV (metastatic) breast cancer History of any prior (ipsi- or contralateral breast cancer except lobular carcinoma in situ Evidence of clinically evident gross residual or recurrent disease following preoperative therapy and surgery Progressive disease during preoperative systemic therapy Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other non-breast malignancies with a similar outcome to those mentioned above Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons Current NCI CTCAE (Version 4.0) Grade >/= 2 peripheral neuropathy History of exposure to the following cumulative doses of anthracyclines: Doxorubicin > 240 mg/m2; Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®) > 480 mg/m2; For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m2 Cardiopulmonary dysfunction as defined by protocol Prior treatment with trastuzumab emtansine Current severe, uncontrolled systemic disease Pregnant or lactating women Any known active liver disease, e.g. due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis Concurrent serious uncontrolled infections requiring treatment or known infection with HIV History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Trastuzumab<br> | Drug: trastuzumab<br>* 6 mg/kg intravenously every 3 weeks, 14 cycles<br>|
| Experimental: Trastuzumab emtansine<br> | Drug: trastuzumab emtansine<br>* 3.6 mg/kg intravenously every 3 weeks, 14 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-free Survival (IDFS) | IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization. | From randomization to data cut-off date of 25 July 2018 (approximately up to 64 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-free Survival Including Second Primary Non-breast Cancer | IDFS including second primary non-breast cancer was defined the same way as IDFS for the primary endpoint but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ (CIS) of any site). 3-year IDFS including second primary non-breast cancer event-free rates per treatment arm in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization. | From baseline up to 12 years | 
| Disease-free Survival | Disease-free survival was defined as the time between randomization and the date of the first occurrence of an invasive disease-free survival event including second primary non-breast cancer event or contralateral or ipsilateral DCIS. 3-year DFS event-free rates per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization. | From baseline up to 12 years | 
| Overall Survival (OS) | Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. 5 years OS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 5 years after treatment. | Baseline up to 12 years | 
| Distant Recurrence-Free Interval (DRFI) | DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 3 years DRFI event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment. | Baseline up to 12 years | 
| Percentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs). | From Day 1 to 30 days after last dose of study drug, up to the clinical cutoff date (approximately 64 months) | 
| Percentage of Participants With Cardiac Dysfunction | Cardiac events were reported based on the NCI-CTCAE, v4.0. | From baseline up to 12 years | 
| Change From Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) | The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1). | Baseline, Cycle 5, 11, Follow-up (FU) Month 6, Follow-up Month 12 | 
| Change From Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23) | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated deterioration in quality of life (QOL) and negative change from baseline indicated an improvement in QOL. For symptom scales, positive change from baseline indicated an improvement in quality of life (QOL) and negative change from baseline indicated a deterioration in QOL. | Baseline, Cycle 5, 11, Follow-up Month 6, Follow-up Month 12 | 
| Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine (Including Total Trastuzumab and DM1) | Blood and serum samples for measurement of trastuzumab emtansine, total trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab emtansine arm. | Cycle (C) 1, Day (D) 1 and C4D1 of pre-infusion, C1D1 and C4D1 post-infusion, C2D1 and C5D1 pre-infusion and study treatment termination | 
| Serum Concentrations (AUC) of Trastuzumab | Serum blood samples were collected for trastuzumab measurement prior to dosing and 15-30 minutes post infusion for Cycle 1 and Cycle 4. Additional serum samples were collected at study treatment termination. | C1D1 and C4D1 of post-infusion and study treatment termination | 
| Plasma Concentrations of DM1 |  | Day 1 on Cycles 1 and 4. Each cycle is 21 days. | 
| Trastuzumab Emtansine Exposure |  | Day 1 on Cycles 1, 2, 4 and 5, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days. | 
| Anti-trastuzumab Emtansine Antibody (ATA) |  | Day 1 on Cycles 1, and 4, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days. | 
| Anti-trastuzumab Antibody (ATA) |  | Day 1 on Cycles 1, and 4, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days. |