Clinical Trial Result Information

Protocol number
WO16229

Title of Study
A multicenter, open-label, single arm phase II study of safety and efficacy of a three-weekly regimen of Herceptin monotherapy in patients with HER2-overexpressing/amplification in 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 open-label, multicenter single arm study evaluated the efficacy and safety of a three weekly regimen of Herceptin monotherapy in women with metastatic breast cancer with over-expressed or amplified HER2. Herceptin was administered as a loading dose of 8 mg/kg IV, followed by 6 mg/kg every three weeks.

Study center(s)
35 centers in Australia, Canada, China (Hong Kong), Germany, Italy, Mexico, New Zealand, Taiwan, Spain, Sweden and UK.

Phase of development
II

Objectives
Primary: To determine the response rate to three-weekly monotherapy Herceptin in women with metastatic breast cancer with overexpressed or amplified HER2.

Secondary: To determine median time to progression (TTP); to determine ‘clinical benefit rate’ (CR+PR+SD ≥6 months); to determine the rate of symptomatic heart failure; to determine the rate of severe infusion related symptoms; to determine detailed pharmacokinetic assessment of selected patients, and all-patient assessment of shed ECD; to compare the expression of cancer-related markers and different techniques of HER2 diagnosis with locally determined HER2 positivity and to compare response rates according to the patient’s HER2 overexpression/amplification.

Methodology
Baseline assessments included:physical examination, conformation of metastatic disease by radiography, CT, MRI etc, measurement of baseline LVEF by echocardiography or MUGA scan, haematology and biochemistry, and shed ECD measurement from a blood sample. The HER2 status was measured on an archive pathology block; it was not necessary to take new tumor samples.

Trough blood samples were collected from all patients on Day 1 of each cycle.Up to 6 additional samples could be collected from patients who discontinued Herceptin, during the 6 month period following discontinuation. A sub-set of 20 patients participated in a full pharmacokinetic assessment. On Day 1 of cycle 6 blood samples, for analysis of Herceptin, were collected immediately prior to dosing, and at 1.5(end of infusion), 2,3,4,6,8,24 (day 2), 96 (day 5), 168 (day 8) and 336 (day 15) hours post-dose.

Number of patients (planned/analyzed)
105 enrolled

Diagnosis and main criteria for inclusion
Women ≥ 18 years with metastatic breast cancer with HER2 overexpression/amplification (IHC3+ and/or FISH-positive confirmed by a central laboratory)

Test product, dose and mode of administration or test procedure
Herceptin 8mg iv loading dose, followed by 6mg iv every 3 weeks

Duration of treatment
Treatment with Herceptin was scheduled until disease progression.

Reference therapy, dose and mode of administration or reference procedure
None

Criteria for evaluation (efficacy, safety)
Efficacy:  Primary endpoint: Overall (complete and partial) response rate. Secondary endpoints: Clinical benefit rate (CR + PR + SD ≥ 6 months); Time and duration of response. Time to progression. Overall survival. Progression-free survival
Pharmacokinetics: Measurements of trough levels (Cmin) were made in all patients. Selected sites participated in more detailed PK analysis.
Safety: Safety parameters included: Grading of adverse events. Vital signs. Physical examinations (with particular attention to cardiovascular system). Laboratory assessments.

Statistical methods
Rates of response, clinical benefit rates, other response variables and corresponding 95% confidence limits were calculated for the full analysis set, the per protocol set and all subgroups according to the Pearson-Clopper method. If a response could not be documented then the overall response was assumed to be non-response.
For time to event endpoints, Kaplan-Meier curves were calculated and displayed. Medians and corresponding 95% confidence limits were given if they were obtained.

Summary (efficacy, safety, other results)
Efficacy: Herceptin in a three-weekly regimen proved to be efficacious in patients with HER2 overexpressing metastatic breast cancer.

[1] FAS = Full analysis set, where not indicated otherwise;
[2] ORR = complete (CR) + partial response (PR)
[3] PPS = Per protocol set;   
[4] CBR = CR + PR + SD ³ 6 months

Pharmacokinetics: Time to reach steady state was approximately 14 weeks which is similar to the weekly regimen. As expected, mean serum peak concentrations (at cycle 6) were higher (approximately 2-fold) than for the weekly regimen, and trough levels (all cycles) were slightly lower (~ 90% of a weekly regimen although the errors around the means overlapped to a great extent). Therefore, exposure across the study period is expected to be similar between the 3-weekly regimen tested in this study and the standard weekly regimen. (4 mg/kg followed by 2 mg/kg at weekly intervals). A large inter-patient variability in Herceptin trough concentrations was observed (e.g. CV = 30 - 60% at pre-dose cycle 6).

Safety: A total of 94/105 patients experienced one or more adverse event (AE). About one quarter of the patients had an event considered to be severe. Approximately one in five patients experienced one or more serious AE – two were cardiac related and led to withdrawal. One patient died due to an AE other than progressive disease (PD) (cerebral vascular accident).

Overview of Adverse Event Incidence

Common adverse events were those often associated with infusions, the most frequent being headache, nausea, pyrexia and rigors. Other common complaints included complications in the GI tract (diarrhea and vomiting), respiratory, thoracic and mediastinal disorders (dyspnea, cough), musculoskeletal and connective tissue disorders (back pain, arthralgia). Most of the events were mild or moderate in intensity.
Deaths other than PD: There were no deaths associated with Herceptin treatment. One Herceptin non-related death occurred due to a cerebral vascular accident.
Serious adverse events: 18% of patients experienced a total of 29 serious adverse events. The most frequently reported SAEs were respiratory, thoracic and mediastinal disorders, GI disorders, general disorders and infections. Six of these were considered by the investigator related to Herceptin treatment. Two out of these 6 were cardiac related (see below “Cardiovascular disorders/LVEF”), the remaining 4 were: diarrhea, moderate pain, dyspnea caused by pleural effusion and hypoxia. All these events resolved after treatment.
Withdrawals for safety reasons: Three patients withdrew from the study due to cardiac-related adverse events [two cardiac-related serious adverse events and one asymptomatic decrease in LVEF (see section “Cardiovascular disorders/LVEF”)].
Cardiovascular disorders/LVEF: There were a total of 14 adverse events in 12 patients judged by the investigator as possibly cardiac-associated. Out of these, five events were considered by the investigator related to Herceptin treatment. Four of these 5 events were mild to moderate in severity. One event was a cardiac failure which led to withdrawal of the patient from the study. This event resolved after discontinuation of Herceptin. One severe case of cardiac tamponade during the follow-up period was considered not related to Herceptin treatment.
A total of 16 patients had a drop in LVEF of ≥15% and/or a value < 50% some time during the study. Most were able to continue Herceptin treatment without worsening dysfunction or development of symptoms. Two of these 16 patients (one cardiac failure and one patient with a decreased LVEF < 50% after cycle 12) withdrew due to a drop in LVEF which was considered related to Herceptin treatment.
Infusion-related AEs: All except 3 infusion-related AEs were reported mild or moderate in intensity. Two of the serious infusion-related AEs (one case of moderate pain and one case of severe hypoxia) resolved and treatment was continued. One severe case of hypoxia resulted in withdrawal of the patient from the study.

Conclusions
Herceptin (8 mg/kg starting dose, 6 mg/kg thereafter) administered once every three weeks at three times the standard weekly dose to patients with HER2-positive metastatic breast cancer had similar anti-tumor efficacy to the standard weekly regimen: 2% of patients had a complete and 17% of patients had a partial tumor response. The overall response rate in the per protocol subset (patients with measurable and centrally confirmed HER2 positive disease) was 23%.
Herceptin given to patients once every three weeks at three times the standard weekly dose was well tolerated and had a similar safety profile to the once weekly regimen. The incidence and severity of cardiac toxicity was similar to the standard weekly schedule. Although the incidence of infusion reactions appeared to be higher, this observation was very likely due to differences in reporting conventions and definitions.
The pharmacokinetics of the three-weekly dosing regimen for Herceptin were not significantly different from those of the marketed weekly dosing regimen. In particular, time to reach steady state and exposure were very similar.

Date of report
1/1/2004

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