Clinical Trial Result Information
Protocol number
MO16982
Title of Study
A phase I/II study of a loading regimen (6mg/kg weekly for 3 weeks) followed by maintenance regimen (6mg/kg every 3 weeks), of Herceptin monotherapy in women with HER2 positive metastatic breast cancer.
Sponsor
Hoffmann-La Roche AG
Company division
Pharmaceutical
Product name
Herceptin
Generic name
trastuzumab
Therapeutic area
Breast Cancer
Clinical study summary
This was a single arm, open label study of a new loading schedule of Herceptin (trastuzumab) monotherapy in women with metastatic breast cancer.
Study center(s)
15 centers in Canada, Spain and United Kingdom.
Phase of development
IV
Objectives
Primary objectives: To investigate the pharmacokinetics of a new loading schedule (6mg/kg weekly x 3) of Herceptin, in women with metastatic breast cancer that overexpresses or amplifies HER2; to evaluate the safety and tolerability (including changes in LVEF, incidence of symptomatic heart failure and infusion-related symptoms) of this loading schedule followed by a 3-weekly maintenance regimen of 6mg/kg Herceptin, in this patient population.
Secondary objectives: To determine serum concentrations of trastuzumab at steady state following the proposed dosing regimen; to determine response rates and time to disease progression.
Methodology
Eligible female patients with metastatic breast cancer and confirmed HER2 overexpression (IHC2+ or 3+, FISH +ve) at screening received a 6mg/kg loading dose of Herceptin (trastuzumab) given i.v. over 90 min on days 1, 8 and 15 of cycle 1, followed by a maintenance dose of 6mg/kg given every 3 weeks thereafter, commencing on day 22.
Blood samples for the PK analysis of trastuzumab were taken at pre-dose, at the end of the infusion and 1.5 h after the end of the infusion for all doses in cycles 1-4, and in addition on days 8 and 15 in cycle 2 and on days 4, 8, 11 and 15 in cycle 4 and pre-cycle 5. Cardiac safety assessments included an ECG performed at screening, and thereafter as clinically indicated, and LVEF assessments performed using echocardiography or MUGA scans at baseline and then every 12 weeks. General safety assessments (AEs, laboratory test parameters) were performed throughout the study. Vital signs were assessed at screening, during cycle 1 and at the end of the study.
Antitumor efficacy was determined by the investigator using RECIST criteria for response and date of disease progression. Tumor assessments were to be repeated prior to cycle 4 and every 9 weeks (3 cycles) thereafter until disease progression or one year. After one year, the frequency of assessments could be according to the investigator’s routine practice until disease progression.
Number of patients (planned/analyzed)
72 enrolled and evaluated
Diagnosis and main criteria for inclusion
Women (≥18 years of age) with metastatic breast cancer and HER2 overexpression (IHC3+ or IHC2+ or FISH positive).
Test product, dose and mode of administration or test procedure
Herceptin (trastuzumab). Loading dose: 6mg/kg weekly x 3 / i.v. 90 min infusions. Maintenance dose: 6mg/kg q3 weekly / i.v. 30 min infusions.
Duration of treatment
Until disease progression
Reference therapy, dose and mode of administration or reference procedure
N/A
Criteria for evaluation (efficacy, safety)
Pharmacokinetics: AUCτ (primary PK parameter), time to steady state, Cl, t½, Cmax, time to Cmax, Cmin (secondary PK parameters).
Efficacy: Tumor response and progression as measured by: CT or MRI scans, X-ray, bone scan and clinical examination, according to RECIST criteria.
Safety: Adverse events, hematological and biochemical laboratory parameters, left ventricular ejection fraction (LVEF), patient symptoms and signs of toxicity.
Statistical methods
Descriptive statistics were performed for primary and secondary efficacy and PK variables. No formal statistical hypothesis testing was performed.
Summary (efficacy, safety, other results)
Pharmacokinetic: The dosing regimen under investigation provided plasma levels of trastuzumab in the range of those seen in previous studies but achieved higher than steady state serum concentrations during the first 3 weekly treatment cycle.
Efficacy: A total of 72 women with HER2-positive metastatic breast cancer were recruited, of whom 41 had measurable disease and satisfied the eligibility criteria for the per protocol analysis (i.e. were the evaluable patient population). The primary efficacy variable was overall tumor response during the treatment period, defined as a complete response (CR) or a partial response (PR) as determined by the investigator according to the definition of the RECIST criteria. The response rate (CR or PR) in the safety population during the course of the study was 15.3% and the median time to response was 2.0 months (ranges 1.8 to 3.8 months).
In the per protocol population the overall response rate (CR or PR) was 26.8%.
Over the duration of the study, 48 of the 72 patients (66.7%) experienced disease progression. The median time to progression was 7.7 months (range 0.3 to 25.5 months).
Safety: As expected, the majority of adverse events considered related to Herceptin treatment were infusion-related reactions such as chills, fatigue, headache and pyrexia. Most of the events occurred only after the first infusion of Herceptin.
A total of 15 patients (21%) reported at least one grade III (severe) adverse event. The most frequent of these adverse events were dyspnea (3 patients) and central line infection (2 patients). Two patients reported a Grade IV (life-threatening) adverse event (cerebral ischemia, increase in aspartate aminotransferase) although neither was considered related to Herceptin treatment. For both grade IV events, treatment with Herceptin was continued uninterrupted and the events resolved without sequelae. Fourteen percent (10/72) of patients reported at least one serious adverse event. The only serious adverse events reported by more than 1 patient each were dyspnea, central line infection, chills and pyrexia, all reported in 2 patients each. Three patients were prematurely withdrawn from the study as a result of at least one adverse event, namely left ventricular failure, amnesia and hypoxia. The left ventricular failure and hypoxia were considered related to Herceptin treatment by the investigator. The amnesia followed craniotomy and was not considered related to trial treatment. A total of 8 patients died during the study period (or within 28 days of the study), all as a result of disease progression.
A total of 5 patients (8.2%) exhibited cardiac dysfunction defined as at least one drop in LVEF of ≥15 EF points from baseline, and 1 patient experienced an LVEF decrease to an absolute value of <40%. No patients experienced a drop in LVEF of ≥15 EF points and to an absolute value of <40%.
There were no clinically relevant mean changes from baseline in any laboratory test parameters or vital signs during the study.
Conclusions
The 6mg/kg i.v. loading dose of Herceptin given weekly x3 followed by a maintenance dose of 6mg/kg given i.v. every 3 weeks has been shown to be safe and well tolerated in patients with metastatic breast cancer. This dosing regimen provided plasma levels of trastuzumab in the range of those seen in previous studies but achieved higher than steady state serum concentrations during the first 3 weekly treatment cycle. In addition, the response rate achieved in patients with measurable disease confirms the favourable efficacy of the intensive loading dose regimen.
Date of report
4/1/2008
Click here for the protocol registry listing of this trial.
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