Clinical Trial Result Information

Protocol number
BO17004

Title of Study
An open-label, phase II, multicenter study to evaluate the efficacy and safety of a recombinant humanized antibody to HER2 (pertuzumab) administered every 3 weeks to patients with hormone-refractory prostate cancer who have not been treated with chemotherapy.

Sponsor
F. Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
pertuzumab

Therapeutic area
Prostate Cancer

Clinical study summary
This was an open-label, multicenter, phase II, single arm, efficacy and safety study of pertuzumab in patients with prostate cancer. Simon’s two-stage design was implemented to allow for early termination due to lack of efficacy. An interim analysis was carried out after the 23^rd evaluable patient had undergone 3 cycles of treatment.

Study center(s)
9 centers in France, Germany, Italy, Spain and United Kingdom.

Phase of development
II

Objectives
To evaluate within the first 24 weeks of treatment the PSA (prostate specific antigen) response rate for the single agent pertuzumab; to evaluate the tolerability and safety profile of pertuzumab in patients with HRPC; to evaluate overall objective response by RECIST criteria (CR or PR) for patients with measurable disease; to estimate duration of PSA and measurable tumor response, time to prostate cancer pain progression, time to disease progression, changes in biochemical bone markers, overall survival; to evaluate pharmacokinetics of pertuzumab.

Methodology
Eligible patients with prostate cancer were enrolled into cohort A to receive a loading dose of 840mg pertuzumab at the first infusion, followed by a maintenance dose of 420mg. If the criterion to go into Stage II was not met (more than 3 responders out of 23 evaluable patients receiving at least 2 cycles of therapy) a 2^nd cohort (B) was opened to enrolment to receive 1050mg pertuzumab, with no loading dose. Pertuzumab was administered every 3 weeks. Patients were assessed for PSA response by PSAWG criteria, and disease response or progression according to RECIST, at intervals throughout the study.

Number of patients (planned/analyzed)
68

Diagnosis and main criteria for inclusion
Male patients with hormone-refractory prostate cancer (HRPC) with no previous chemotherapy.

Test product, dose and mode of administration or test procedure
Cohort A: Pertuzumab was given as a loading dose of 840 mg followed by single doses of 420 mg as an IV infusion every 3 weeks.
Cohort B: Patients did not receive a loading dose of pertuzumab but received a dose of 1050 mg as an IV infusion every 3 weeks.

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

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

Criteria for evaluation (efficacy, safety)
Efficacy: PSAWG (Prostate Specific Antigen Working Group) criteria were used for PSA evaluation. RECIST criteria were also used for patients with measurable disease. Tumor progression was measured by PSA levels, CT or MRI scans, bone scans and clinical examination.
Safety: adverse events, hematology, biochemistry, cardiac monitoring (ECG, MUGA, Troponin T).
Pharmacokinetics: Measurement of peak and trough pertuzumab levels made in all patients.

Statistical methods
The goal of this study was to demonstrate the anti-tumor activity of pertuzumab in patients with HRPC. The null hypothesis was that the PSA response rate (RR) was <=15% versus the alternative that it was >15%.

Summary (efficacy, safety, other results)
Efficacy: Among the 68 evaluable patients (35 in Cohort A and 33 in Cohort B), none showed a PSA response. Forty-five patients had progressive disease, as summarized in the table below. Consequently, the study was terminated.

	Pertuzumab 420 mg (N = 35)	Pertuzumab 1050 mg (N = 33)
PSA response Non-response Progressive disease Missing	0 12 (34.3%) 23 (65.7%) 0	0 10 (30.3%) 22 (66.7%) 1 (3%)
Kaplan-Meier median time to progressive disease (weeks)	6.14 (3.29, 11.57)	6.14 (3.57, 9.00)

Pharmacokinetic: Based on preclinical studies, suppression of tumor growth was achieved when the steady-state trough concentrations of pertuzumab were in the range of ~5-20 µg/mL. In both dosing regimens, serum trough concentrations of 20 µg/mL were exceeded in most patients. Steady-state concentrations were achieved by the second treatment cycle for the 420 mg dose cohort (following an 840 mg loading dose) and in approximately 100 days for the 1050 mg dose cohort.

Safety: The most commonly reported AEs were diarrhea, fatigue and nausea with mainly NCI-CTC grade 1 or 2. Five patients had a serious adverse event (fatal haemolytic uraemic syndrome, atrial fibrillation, ECG T-wave inversion, hypoglycemia, abdominal pain), assessed as related to pertuzumab. The patient with HUS died several days after the discontinuation of the treatment. Six patients had asymptomatic drops from baseline in LVEF ≥ 10%-points and absolute value <50% by the last ECHO. Two patients had no follow-up LVEF assessments and 4 others had their LVEF increased to >50% by the last ECHO. No cases of symptomatic cardiac failure were observed. During pertuzumab infusion, 4 patients out of 68 experienced adverse events (peripheral oedema, central line infection, vasovagal syncope, rhinorrhea). Two of these patients had adverse events attributed to pertuzumab and compatible with infusion-associated symptoms (vasovagal syncope, rhinorrhea). Overall, there was no clear evidence of a dose relationship.

Conclusions
None of the patients (0/35 patients in Cohort A and 0/33 patients in Cohort B) had shown a PSA response at the time of the interim analyses. Therefore, at the 2nd interim analysis, the study was terminated. Treatment with pertuzumab was generally well-tolerated, with the most frequently observed adverse events being diarrhea, fatigue and nausea. The pharmacokinetic data support administration of pertuzumab every 3 weeks. In both dose cohorts, serum trough concentrations of 20µg/mL were exceeded in most patients. Steady-state concentrations were achieved by the 2^nd treatment cycle for the 420 mg dose cohort (following an 840 mg loading dose), and in approximately 100 days for the 1050 mg dose cohort. Overall, there was no difference in efficacy or safety between the two doses of pertuzumab tested in this study.

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

Date of report
1/1/2006

Click here for the protocol registry listing of this trial.