Clinical Trial Result Information

Protocol number
BO16934

Title of Study
Open label, phase II, multicenter, randomized study of efficacy and safety for two different doses of a recombinant humanized antibody to HER2 (rhuMAb 2C4) administered every 3 weeks to patients with metastatic breast cancer with low expression of HER2.

Sponsor
F. Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
pertuzumab

Therapeutic area
Breast Cancer

Clinical study summary
This was an open-label, multicenter, randomized, two-arm, efficacy and safety study of pertuzumab in patients with metastatic breast cancer. Simon’s two-stage design was implemented to allow for early termination if the criterion of at least 2 responses (CR and/or PR) in at least one of the dose arms was not met at the interim analysis, conducted when the first 23 evaluable patients had been recruited into each arm and each had completed at least 2 cycles of therapy.

Study center(s)
18 centers in Australia, Belgium, Finland, Germany, Italy, Netherlands, Spain and United Kingdom.

Phase of development
II

Objectives
To evaluate within the first 24 weeks of treatment, or 8 cycles of therapy, whichever is later, the objective response rate for each treatment regimen (420 and 1050 mg) of pertuzumab administered by intravenous (IV) infusion every 3 weeks to patients with metastatic breast cancer which has low expression of HER2.
To evaluate the safety of pertuzumab in each arm.
To characterize the pharmacokinetics of pertuzumab at the two dose levels tested.
To determine the utility of tumor markers detectable in paraffin-embedded tissue in predicting response to pertuzumab.

Methodology
Eligible patients with metastatic breast cancer were randomized to receive one of two dosage regimens of pertuzumab. Arm A received a loading dose of 840mg at the first infusion, followed by a maintenance dose of 420mg, and Arm B received 1050mg , with no loading dose. Pertuzumab was administered every 3 weeks. Patients were assessed for disease response or progression according to RECIST every 6 weeks for the first 8 cycles, and subsequently every 12 weeks.

Number of patients (planned/analyzed)
79

Diagnosis and main criteria for inclusion
Women with low expression of HER2 (FISH negative and IHC HER2 0, 1+, 2+) with metastatic breast cancer.

Test product, dose and mode of administration or test procedure
In Arm A, pertuzumab was given as a loading dose of 840 mg followed by single doses of 420 mg every three weeks until the end of the study.
In Arm B, pertuzumab was given at doses of 1050 mg (no loading dose) every three weeks as an iv infusion until the end of the study.

Duration of treatment
24 weeks/8 cycles to primary analysis. Pertuzumab was administered until a patient experienced unacceptable toxicity or disease progression.

Reference therapy, dose and mode of administration or reference procedure
N/A

Criteria for evaluation (efficacy, safety)
Efficacy: objective tumor response rate, time to and duration of response, time to disease progression.
Safety: adverse events, hematology, biochemistry, cardiac monitoring (LVEF).
Pharmacokinetic: C_max, C_min, t_max, t_1/2, AUC.

Statistical methods
The goal of the study was to evaluate separately the anti-tumor activity of two different doses of pertuzumab in patients with metastatic breast cancer. The null hypothesis was that the objective response rate was ≤5% versus the alternative that it was >5%, i.e.
Ho (Null Hypothesis): ORR ≤5%
Ha (Alternative Hypothesis): ORR >5%.

Summary (efficacy, safety, other results)
Efficacy: Among the 78 evaluable patients, 2 patients from the 420 mg dose group showed a partial response (4.9%) (as summarized in the table below). Of these, only one patient had shown a PR at the time of the interim analysis. Consequently, the decision was made to stop recruitment.

	Pertuzumab 420 mg (N = 41)	Pertuzumab 1050 mg (N = 37)
Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) Missing	0 2 (4.9%) 18 (43.9%) 21 (51.2%) 0	0 0 14 (37.8%) 22 (59.5%) 1 (2.7%)
Median (range) time to response (wks) N=2	12.1 (6.1, 18.0)	0
Median (range) duration of response (wks) N=2	24.6 (18.1,31.0)	0
Median (range) duration of clinical benefit (wks) N=4/2	36.5 (22.1,74.9)	33.6 (31.0, 36.3)
Median (range) time to PD (wks) N=38/36	6.1 (2.0, 37.0)	6.1 (2.7, 36.3)

Six patients had clinical benefit, defined as patients whose best response was PR or SD that lasted more than 8 cycles (approximately 6 months). No difference was observed between the two doses.

Pharmacokinetic: Based on preclinical studies, suppression of tumor growth was achieved when the steady-state trough concentrations of pertuzumab was ~5-20 µg/mL. In both dosing regimens, the expected steady-state trough concentrations were exceeded.

Safety: The most commonly reported adverse events (AE) were diarrhea, nausea, asthenia, and vomiting with mainly NCI-CTC grades 1 or 2. Six patients had a serious adverse event (sepsis, decreased LVEF (2 pts), cardiac failure, diarrhea grade 3 and a grade 2 urticaria), assessed as related to pertuzumab. During pertuzumab infusion, five out of 78 (6%) patients experienced infusion-associated reactions (dizziness, urticaria with formication, chills with pyrexia, dyspnoea, erythema)-all grade 1 with the exception of a grade 2 urticaria. Overall, there was no clear evidence of a dose relationship. Eight patients had drops in LVEF ≥10%-points to <50%. All were asymptomatic except for one occurrence of cardiac failure. Two patients died; one 1 year after receiving the last pertuzumab infusion due to an adverse event (suspected suicide) and one 6 months after the last pertuzumab infusion for unknown reasons.

Conclusions
There were 2 partial responses (2/41 patients in Arm A, 0/37 patients in Arm B for an overall objective response rate of 2/78 (2.6%)). Overall, 6 out of 78 patients responded or had SD for more than 8 cycles of therapy. However, at the interim analysis, the criterion to see at least 2 responses (CR and/or PR) in at least one of the two dose arms during 2 cycles was not met. Treatment with pertuzumab was generally well-tolerated, with the most frequently observed adverse events being diarrhea, asthenia, nausea and vomiting, mainly grade 1 or 2.
The pharmacokinetic data support a fixed dose of pertuzumab administered every 3 weeks in terms of steady state trough levels and time to reach steady state. Overall, there was no difference in efficacy or safety between the two doses of pertuzumab tested in this study.

Publications (references, if available)
Cortes et al. ASCO 2005 (Poster).

Date of report
11/1/2005

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