Hoffmann-La Roche Ltd
E. Kolthof (Roche Nederland B.V.) A.E. van Leeuwen-Stok (BOOG Study Center)
Roche Nederland B.V.
Roche Nederland B.V.
This is a Phase III, prospective, two-cohort, non-randomized, multi-centre, multinational, open label study in approximately 2,500 patients with HER2-positive EBC whose tumour has been excised. Eligible patients will be allocated to Cohort A or B at the investigators’ discretion: Cohort A (approximately 1,800 patients): trastuzumab SC at a fixed dose of 600mg, assisted administration into the thigh over a period of up to 5 minutes, using conventional handheld syringes with hypodermic needles, for a total of 18 cycles (3-weekly); Cohort B (approximately 700 patients): trastuzumab SC at a fixed dose of 600mg, first assisted-, then self-administered (select patients) into the thigh over a period of up to 5 minutes, using the SID, for a total of 18 cycles (3-weekly). For enrolment into Cohort B, patients need to be willing to self-administer the study drug based on the instructions for use supplied with the SID and personal instructions provided by a health care professional (HCP) during the first assisted administration. After at least one assisted administration, patients assessed by the investigator as competent to self-administer the study drug using the SID will be allowed to self-administer the remaining trastuzumab SC doses under the direct supervision of a HCP. The SID Satisfaction Questionnaire will only be completed by a subset of Cohort B patients who have successfully completed a minimum of 2 self-administrations of the study drug. Patients not deemed competent to self-administer the study drug will have all their trastuzumab SC doses administered by a trained HCP (physician or nurse).
Primary objectives The primary objective of the study is to assess the overall safety and tolerability of trastuzumab SC in HER2-positive EBC patients with assisted administration using a conventional syringe and needle (vial formulation) or with assisted- and self-administration using a SID in selected patients. Secondary objectives Secondary objectives include the evaluation of the following parameters: Efficacy (both cohorts): Disease Free Survival (DFS) Overall Survival (OS) Patient satisfaction with trastuzumab SC administration using the SID (patients in Cohort B who went on to self-administration of the study drug).
Primary: Safety Endpoints
The analysis of the safety endpoints will be performed for the safety population defined as all enrolled patients who received at least one study medication. There will be the safety population for Cohort A (SP1) and safety population for Cohort B (SP2). The safety endpoints described below will be summarized for each cohort and overall.
The incidence of adverse events and SAEs will be summarized according to the primary system-organ class (SOC) and within each SOC, by MedDRA preferred term. The time to first onset of the first episode of cardiac AEs will be summarized using Kaplan-Meier approach. Laboratory parameters, hematology and biochemistry, will be presented in shift tables of NCI-CTC grade at baseline versus worst grade during trastuzumab SC treatment for each trastuzumab SC treatment period and overall. LVEF will be summarized over time by means of mean, median and range (mean and maximum) and will be presented graphically for each trastuzumab SC treatment period and overall. Immunogenicity assessments for cohort B only will also be summarized by means of percentage of patients who are anti-human antibodies (HAHAs) positive for both trastuzumab SC and rHuPH20.
Other safety variables will be analysed in a similar way.
Secondary: Efficacy Endpoints
The intent to treat (ITT) population will include all patients enrolled in the study. The per-protocol population (PP) will include all ITT patients who have received at least one dose of study medication and did not have major protocol violations (which will be defined in the statistical analysis plan).
EFS is defined as time from the date of first treatment to the date of local, regional or distant recurrence, contralateral breast cancer or death due to any cause. OS is defined as time from the date of first treatment until date of death, regardless of the cause of death.
Efficacy endpoint, EFS and OS, will be analyzed as a time-to-event variable for the ITT and PP populations and each Cohort. Estimates and corresponding 95% confidence intervals for the survivor function for the time-to-event variable will be obtained by using the KM approach. A frequency table will be also provided for the type of EFS event (e.g. local, regional or distant recurrence, contralateral or death).
Other Endpoints
“Patients’ satisfaction with handling of a trastuzumab SC administration using the SID (Cohort B only)”
Patients’ satisfaction with handling of a trastuzumab SC administration using the SID for cohort B only will be summarized by frequency tables and graphically presented by vertical bars.
Demographic profile and medical history will be summarized by means of median, mean, standard deviation, range (minimum and maximum) and 25th-75th quartiles for continuous variables, and number/percentage of patients in each category for categorical variables.
Main inclusion Criteria: Adult male or female patients, >/= 18 years of age Histologically confirmed early invasive HER2-positive carcinoma of the breast with no evidence of residual, locally recurrent or metastatic disease and defined as clinical stage I to IIIC that is eligible for adjuvant treatment with trastuzumab Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Screening left ventricular ejection fraction (LVEF) >/= 55% Main exclusion Criteria: Previous neoadjuvant or adjuvant breast cancer treatment with an approved or investigational anti-HER2 agent History of other malignancy, except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma and patients with other curatively treated malignancies who have been disease-free for at least 5 years Past history of ductal carcinoma in situ and/or lobular carcinoma that has been treated with any systemic therapy or with radiation therapy to the ipsilateral breast where the invasive cancer subsequently develops Metastatic disease Inadequate bone marrow, hepatic or renal function Serious cardiac or cardiovascular disease Uncontrolled hypertension, or history of hypertensive crisis or hypertensive encephalopathy History of severe allergic or immunological reactions, e.g. difficult to control asthma Pregnant or lactating women
