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)
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| ClinicalTrials.gov Identifier: NCT01772472 |
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Recruitment Status :
Active, not recruiting
First Posted : January 21, 2013
Results First Posted : October 1, 2019
Last Update Posted : February 6, 2024
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Sponsor:
Hoffmann-La Roche
Collaborators:
NSABP Foundation Inc
German Breast Group
Information provided by (Responsible Party):
Hoffmann-La Roche
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Breast Cancer | Drug: trastuzumab Drug: trastuzumab emtansine | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 1487 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | April 3, 2013 |
| Actual Primary Completion Date : | July 25, 2018 |
| Estimated Study Completion Date : | April 3, 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Breast cancer
MedlinePlus related topics:
Breast Cancer
| Arm | Intervention/treatment |
|---|---|
| Active Comparator: Trastuzumab |
Drug: trastuzumab
6 mg/kg intravenously every 3 weeks, 14 cycles |
| Experimental: Trastuzumab emtansine |
Drug: trastuzumab emtansine
3.6 mg/kg intravenously every 3 weeks, 14 cycles |
Primary Outcome Measures :
- Invasive Disease-free Survival (IDFS) [ Time Frame: From randomization to data cut-off date of 25 July 2018 (approximately up to 64 months) ]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.
Secondary Outcome Measures :
- Invasive Disease-free Survival Including Second Primary Non-breast Cancer [ Time Frame: From baseline up to 12 years ]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.
- Disease-free Survival [ Time Frame: From baseline up to 12 years ]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.
- Overall Survival (OS) [ Time Frame: Baseline up to 12 years ]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.
- Distant Recurrence-Free Interval (DRFI) [ Time Frame: Baseline up to 12 years ]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.
- Percentage of Participants With Adverse Events [ Time Frame: From Day 1 to 30 days after last dose of study drug, up to the clinical cutoff date (approximately 64 months) ]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).
- Percentage of Participants With Cardiac Dysfunction [ Time Frame: From baseline up to 12 years ]Cardiac events were reported based on the NCI-CTCAE, v4.0.
- 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) [ Time Frame: Baseline, Cycle 5, 11, Follow-up (FU) Month 6, Follow-up Month 12 ]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).
- 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) [ Time Frame: Baseline, Cycle 5, 11, Follow-up Month 6, Follow-up Month 12 ]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.
- Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine (Including Total Trastuzumab and DM1) [ Time Frame: 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 ]Blood and serum samples for measurement of trastuzumab emtansine, total trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab emtansine arm.
- Serum Concentrations (AUC) of Trastuzumab [ Time Frame: C1D1 and C4D1 of post-infusion and study treatment termination ]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.
- Plasma Concentrations of DM1 [ Time Frame: Day 1 on Cycles 1 and 4. Each cycle is 21 days. ]
- Trastuzumab Emtansine Exposure [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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. ]
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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:
- 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
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): NCT01772472
Locations
Show 276 study locations
Sponsors and Collaborators
Hoffmann-La Roche
NSABP Foundation Inc
German Breast Group
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Study Documents (Full-Text)
Documents provided by Hoffmann-La Roche:
Documents provided by Hoffmann-La Roche:
Study Protocol [PDF] October 13, 2015
Statistical Analysis Plan [PDF] November 5, 2012
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT01772472 |
| Other Study ID Numbers: |
BO27938 2012-002018-37 ( EudraCT Number ) |
| First Posted: | January 21, 2013 Key Record Dates |
| Results First Posted: | October 1, 2019 |
| Last Update Posted: | February 6, 2024 |
| Last Verified: | February 2024 |
Additional relevant MeSH terms:
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Breast Neoplasms Neoplasm, Residual Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Neoplastic Processes Pathologic Processes Trastuzumab Ado-Trastuzumab Emtansine Maytansine |
Antineoplastic Agents, Immunological Antineoplastic Agents Antineoplastic Agents, Phytogenic Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Immunotoxins Immunoconjugates Immunologic Factors Physiological Effects of Drugs |