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Journal of Clinical Oncology, Vol 25, No 3 (January 20), 2007: pp. 257-262
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.07.0888
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Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer

Johann Sebastian de Bono, Joaquim Bellmunt, Gerhardt Attard, Jean Pierre Droz, Kurt Miller, Aude Flechon, Cora Sternberg, Chris Parker, Gerhard Zugmaier, Veronica Hersberger-Gimenez, Louise Cockey, Malcolm Mason, John Graham

From the Drug Development Unit and Department of Academic Urology, Royal Marsden Hospital, Surrey; Department of Oncology, University of Wales College Hospital, Wales; Department of Oncology, Bristol Oncology Centre, Bristol, United Kingdom; University Hospital Vall de Hebron, Department of Medical Oncology, Barcelona, Spain; Centre Leon Berard Department of Oncology, Lyon, France; University Clinic Benjamin Franklin, Department of Urology, Urological Clinic, FU Berlin, Germany; F. Hoffmann-La Roche, Department of Oncology, Basel, Switzerland; and San Camillo and Forlanini Hospitals, Department of Medical Oncology, Rome, Italy

Address reprint requests to Johann S. de Bono, MB, ChB, FRCP, MSc, PhD, Centre for Cancer Therapeutics, Institute for Cancer Research, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: jdebono{at}icr.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
PURPOSE: To determine the prostate-specific antigen (PSA) 50% decline rate within 24 weeks of starting treatment with single-agent pertuzumab in castrate patients with hormone-refractory prostate cancer (HRPC).

PATIENTS AND METHODS: Two independent Simon's two-stage designs were used to evaluate two doses of pertuzumab administered intravenously once every 3 weeks. An interim analysis of the first 23 assessable patients in the first cohort treated at 420 mg (loading dose of 840 mg) allowed termination of additional enrollment if ≤ three patients had a ≥ 50% decline in PSA after all patients had completed at least three cycles of therapy or withdrew due to insufficient therapeutic response, death, or study-related toxicity before completing three cycles. A second cohort of patients treated at 1,050 mg could be enrolled with the same design, and if more than three patients had a ≥ 50% decline in PSA, 27 more patients would be treated at 1,050 mg.

RESULTS: Sixty-eight castrate, chemotherapy-naive men with HRPC were enrolled. A total of 35 patients were treated at 420 mg; no PSA declines ≥ 50% were observed at the interim analysis and recruitment was stopped. A total of 33 patients were then treated at 1,050 mg, and no PSA declines ≥ 50% were observed at the interim analysis. Pertuzumab was well tolerated.

CONCLUSION: Pertuzumab has no clinically significant single-agent activity in castrate patients with HRPC at either of the tested dose levels. This may reflect the continued presence of significant levels of intraprostatic androgen driving androgen receptor signaling.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Prostate cancer is the most commonly diagnosed cancer, the second leading cause of cancer-related deaths in men in the United Kingdom and North America, and the third leading cause of cancer-related deaths in men in Western Europe.1,2 More than 80% of patients who present with metastatic disease or relapse after attempted curative local therapies respond to androgen deprivation by medical or surgical castration, but most subsequently experience relapse with hormone-refractory prostate cancer (HRPC).3 With the earlier use of castration and the frequent use of prostate-specific antigen (PSA) for monitoring, patients often are asymptomatic when the development of HRPC is identified, thus providing a window of opportunity for the conduct of clinical trials of low toxicity.

The erbB family consists of four tyrosine kinase receptors: ErbB1 (epidermal growth factor receptor, human epidermal growth receptor 1[HER1]), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Receptor activation after ligand binding (to HER1, HER3, or HER4) induces dimerization and initiates a signaling cascade that results in phosphorylation and activation of downstream targets important for cell growth and survival.4 A number of studies have implicated cross-talk between activated erbB receptors and androgen receptor (AR) signaling in the development of androgen independence.5-7 In particular, ErbB2-erbB3 signaling has been implicated in enhancing AR signaling by modulating its transcriptional activity and degradation in the presence of low androgen levels. 8-10 Pertuzumab (2C4 or Omnitarg; Genentech Inc, South San Francisco, CA) represents the first in a new class of agents known as HER dimerization inhibitors. Pertuzumab is a fully humanized immunoglobulin G1(K) monoclonal antibody that binds to HER2 and sterically inhibits its ability to form dimers with other HER receptors.11-15 Pertuzumab has demonstrated inhibition of tumor growth in both high and low HER2-expressing androgen-dependent and androgen-independent prostate cancer models.5-7,11

In phase I studies, pertuzumab was well tolerated; the most common adverse events were fatigue, nausea, and vomiting.16 The maximum tolerated dose was not reached with dose escalation to 15 mg/kg. Pharmacokinetic studies indicated a terminal elimination half-life of 2 to 4 weeks supporting dosing once every 3 weeks. Pertuzumab infusions given every 3 weeks at doses ≥ 5.0 mg/kg maintained serum concentrations in excess of 20 µg/mL. Dose-response studies of pertuzumab in nonclinical models showed that more than 80% suppression of tumor growth is achieved at steady-state trough concentrations of approximately 5 to 25 µg/mL.17 The recommended regimen for phase II testing was therefore a fixed dose of 420 mg (equivalent to 6 mg/kg for a 70-kg patient) every 3 weeks. However, using this dosing regimen, steady-state concentrations are only attained after approximately 90 days. A loading dose of 840 mg was therefore recommended. Simulated trough concentrations for pertuzumab predicted that in patients treated with a fixed dose of 1,050 mg (equivalent to a dose of 15 mg/kg for a 70-kg patient; the highest dose studied in the phase I setting), 90% of patients would achieve steady-state trough concentrations ≥ 28.8 µg/mL. This higher dose could therefore confer a benefit to a subset of patients for whom 420 mg was suboptimal. Of the five patients with HRPC treated in a phase I study, an unconfirmed partial response was reported in one patient and stable disease of 2.6, 2.7, and 5.5 months duration was reported in three of the other patients, respectively.17 The robust biologic evidence for HER2 activation of AR signaling in androgen-depleted states and preliminary evidence of clinical anticancer activity led to the conduct of this phase II trial to evaluate the antitumor activity of two different dose levels of pertuzumab. This study also was designed to evaluate the tolerability, safety profile, and pharmacokinetics of pertuzumab.


   PATIENTS AND METHODS
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient Eligibility
Castrate patients with a histologic diagnosis of prostate adenocarcinoma and progressive disease as defined by the PSA Working Group (PSAWG)18 were eligible for this study. Patients with progression of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST)19 or progression of disease to bone also had to fit the criteria for PSA progression. A minimum of 6 months from therapy to the prostate had to have passed before patients started pertuzumab. All patients previously treated with an antiandrogen agent were required to undergo antiandrogen withdrawal of ≥ 4 weeks duration for flutamide and ≥ 6 weeks for bicalutamide or nilutamide. Patients were required to wait 28 days after the use of systemic corticosteroids or any other investigational therapy before study entry. Patients who had received chemotherapy previously; a radionuclide or immunotherapy for their prostate cancer; treatment with any agent that targeted the HER receptor family; or a cumulative doxorubicin dose of more than 360 mg/m2 or the equivalent were not allowed to participate in this study.

The institutional review boards at all participating sites approved the study protocol, and written informed consent was obtained before any study-related procedures. Patients were required to be free from opiate-requiring pain and have a Karnofsky performance status ≥ 80% with a life expectancy of at least 12 weeks. Other eligibility criteria included a serum calcium within normal limits and adequate bone marrow (absolute neutrophil count ≥ 1,500/µL, platelet count ≥ 75,000/µL, and hemoglobin ≥ 10 g/dL), renal (creatinine ≤ 1.5x upper limit of normal or creatinine clearance of ≥ 40 mL/min), hepatic (bilirubin ≤ 1.5x upper limit of normal and AST ≤ 2x the upper limit of normal), and cardiac (baseline left ventricular ejection fraction [LVEF] of ≥ 50%) function. Similarly, patients were excluded from the study if they had uncontrolled hypertension, known brain metastases or spinal cord compression, or any prior malignancy, cardiac condition, or serious medical illness that would affect their management according to the study protocol.

Study Design and Treatment
This was a single-arm, two-cohort, multi-institutional study at seven participating centers. Pertuzumab was administered as an intravenous infusion every 21 days to all patients. The first treatment was administered during 90 minutes (± 10 minutes) and patients were observed for a minimum of 6 hours for infusion-associated reactions. If the infusion was well tolerated, subsequent doses were administered during 30 minutes (± 10 minutes) and patients were observed for a period of 2 hours. Two dose levels were studied. Patients in cohort A received one loading dose of 840 mg at the first cycle followed by single doses of 420 mg every 21 days. Patients in cohort B received 1,050 mg of pertuzumab every 21 days (no loading dose). Pertuzumab was provided by F. Hoffmann-La Roche (Basel, Switzerland). Each 10-mL single-use vial contained 175 mg pertuzumab formulated in 10 mmol/L L-histidine (pH 6.0), 240 mmol/L sucrose, and 0.02% Tween-20.

Hematology and biochemistry were evaluated at the end of every cycle and results were available before administration of the next dose. Pharmacokinetic parameters were estimated from pertuzumab concentrations measured by a central laboratory using serum samples obtained immediately before and within 15 minutes after the end of every infusion, and on days 8 and 15 in cycles 1 and 2. Concentrations of pertuzumab were determined by a receptor-binding, enzyme-linked immunosorbent assay.16 PSA was measured at the end of each cycle. Bone scans were performed at the end of cycles 8 and 16. A serum sample for antibody to pertuzumab was taken at screening and at the end of cycle 8. Cardiac safety was monitored in all patients because of reports of cardiotoxicity associated with HER2 inhibition.20 Cardiac function was assessed by echocardiogram or multiple-gated acquisition scan in all patients at the end of cycles 2 and 4, and every four cycles thereafter. All adverse events were recorded and graded according to National Cancer Institute Common Toxicity Criteria version 2. Therapy was to be continued until treatment failure as a result of progressive disease by PSAWG criteria after a minimum of three cycles of therapy, progressive disease according to RECIST, unacceptable toxicity, patient request, or investigator discretion.

Response Assessment
The primary efficacy end point was a ≥ 50% PSA decline within the first 24 weeks of treatment confirmed by a second PSA value 4 weeks later (PSAWG). PSA progression was defined as a 25% increase over the baseline or nadir PSA value (whichever was lower) that was confirmed by a second measurement. Measurable disease was monitored using RECIST. Progression-free survival (PFS) time was defined as the time elapsed from the start of therapy until the onset of the earliest of the following events: disease progression according to PSAWG or RECIST, two or more new bone lesions on a repeat bone scan at least 6 months after the start of therapy, an event due to metastatic prostate cancer requiring intervention (eg, urinary obstruction), or death.

The primary analysis population for efficacy at the interim analysis included all patients who received at least three cycles of therapy, had at least one postbaseline efficacy evaluation after three cycles of therapy, and had no major protocol violations. The intent-to-treat population included all patients who had received any amount of study medication.

Statistical Considerations
The primary objective was to determine the rate of patients demonstrating a ≥ 50% decline in PSA after 24 weeks of treatment with single-agent pertuzumab. The targeted ≥ 50% PSA decline rate was 30%, with a rate of no interest of 15%. With 48 assessable patients within a cohort, this study had an 80% power to detect a ≥ 50% decline in PSA in 30% of patients, with a one-sided {alpha} level of 5%. A Simon's two-stage design was used to investigate the two doses. An interim analysis was planned after accrual of 23 assessable patients at the lower dose level. If a ≥ 50% decline in PSA was observed in more than three patients after three cycles of treatment, accrual of an additional 27 patients to a maximum of 50 patients (at least 48 assessable) would continue at the same dose. If among the first 23 patients treated, three or fewer patients demonstrated a ≥ 50% decline in PSA, the first cohort would be closed to additional recruitment and a second cohort opened, to accrue an additional 23 assessable patients at the higher dose level. If more than three patients demonstrated a ≥ 50% decline in PSA at this higher dose, an additional 27 patients would be enrolled to a maximum of 50 patients (at least 48 assessable). Otherwise, the study would be terminated.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
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Patient Characteristics
At the interim analyses the first 23 assessable patients of each cohort were assessable for efficacy. Recruitment was halted in each occasion but all patients who had already signed an informed consent were admitted to the trial, resulting in overenrollment in both cohorts. A total of 35 patients were enrolled into cohort A (420 mg) from September to December 2003. Thirty-three patients were enrolled subsequently to cohort B (1,050 mg) between February and July 2004. Two patients in cohort A and two patients in cohort B did not complete three cycles of treatment for reasons unrelated to study medication. Table 1 lists the demographic and clinical characteristics of the 68 patients treated on this study.


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  		Table 1. Baseline Patient Characteristics

 
Response to Treatment
At the interim analysis no patients in the assessable population of either cohort demonstrated a ≥ 50% decline in PSA, and trial accrual was therefore discontinued. Of the 35 patients included in cohort A, 12 patients (34%) had a best response of nonprogression, with the median PFS time of 88 days for those patients. The median PFS time for all patients in cohort A using the Kaplan-Meier method was 43 days (95% CI, 23 to 81 days; Fig 1). One patient had an initial 75% decrease in PSA but this was not sustained at 4 weeks. There were also no ≥ 50% declines in PSA among the 33 patients enrolled onto cohort B. Ten patients (30%) had a best response of nonprogression, with a median PFS time of 83 days. The median PFS for all patients by the Kaplan-Meier method for patients in cohort B was also 43 days (95% CI, 25 to 63 days; Fig 1).


Figure 1
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  		Fig 1. Progression-free survival. (–· –· –) pertuzumab, 420 mg; (——) pertuzumab, 1,050 mg.

 
Serum Pharmacokinetics
Complete pharmacokinetic sampling was done on all patients. Pertuzumab appeared to be cleared at the same rate at either a dose of 840 mg (mean, 270 mL/d; range, 79 to 411 mL/d) or a dose of 1,050 mg (mean, 253 mL/d; range, 48 to 482 mL/d). The mean serum concentration half-life was higher for patients treated at 1,050 mg (19.3 days; range, 9.4 to 66.3 days) than for patients treated at 840 mg (13.7 days; range, 6.8 to 27.4 days), although the large ranges may be a function of the noncompartmental analyses, which can overestimate the terminal half-life. The mean volume of distribution at steady-state and the mean area under the curve were both higher in patients treated at 1,050 mg than at 840 mg (5,227 v 4,452 mL; 5,097 v 3,488 µg · d/mL, respectively). However, the area under the curve (at infinity) is extrapolated and may also be overestimated, which in turn influences the clearance in the same way. The maximum serum concentration was comparable for the two doses: 255 µg/mL (range, 148 to 411 µg/mL) at 840 mg and 294 µg/mL (range, 151 to 436 µg/mL) at 1,050 mg. The interpatient variability was in the ranges 22% to 42% for the 840-mg dose and 24% to 77% for the 1,050-mg dose. However, patients in both cohorts achieved mean serum concentrations of pertuzumab in excess of the level at which anticancer activity was reported in preclinical models (5 to 25 µg/mL). Summary pharmacokinetic parameters are presented in Table 2.


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  		Table 2. Pharmacokinetic Parameters

 
Toxicity
All 68 patients enrolled received at least one dose of pertuzumab and were assessable for toxicity. The total number of cycles administered was 153 in cohort A and 131 in cohort B. A median of three cycles were completed per patient for both cohorts (range for cohort A, two to 11 cycles; range for cohort B, one to 12 cycles). In this study pertuzumab was well tolerated. The most common adverse event assessed as related to pertuzumab was grade 1 to 2 diarrhea (37% in cohort A and 48% in cohort B; in addition, one patient in cohort A suffered grade 3 diarrhea), followed by fatigue (34% in cohort A and 9% in cohort B). One patient experienced hemolytic uremic syndrome and subsequently died. Hemolytic uremic syndrome was believed to be associated with the tumor but a contribution of pertuzumab could not be excluded.

Table 3 lists the drug-related adverse events that occurred in more than 10% of patients or were of grade 3 or 4 severity. Six patients presented with LVEF decreases of greater than 10% to an LVEF below 50% (five patients in cohort A and one patient in cohort B) with subsequent full and uncomplicated recovery in four patients. For two patients, no follow-up LVEF assessments were available. For two of the six patients, serious cardiac adverse events were reported. One patient was incidentally found to be in tachycardic atrial fibrillation and the second patient experienced T-wave inversion. Both patients had full recovery of LVEF. No antibodies to pertuzumab were detected in any of the patients.


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  		Table 3. All Related Adverse Events of Grade 1 or 2 With an Incidence of ≥ 10% and/or of Grade 3 or 4

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Increased expression of membrane-bound HER2 has been reported in up to 50% of hormone-sensitive prostate cancers, and has been linked to an inferior patient prognosis and to the development of hormone resistance, making it a valid therapeutic target.21-28 Unlike breast and ovarian cancers, the mechanism underlying increased HER2 expression is not HER2 gene amplification and remains unclear.23-26 Although the evidence for increased HER2 expression in androgen-independent tumors is conflicting and its relevance is controversial,13,22-31 preclinical models have proposed mechanisms for how HER2 can modulate androgen receptor transcriptional activity in the absence of androgenic steroid ligands, promoting prostate cancer cell proliferation and survival.5,8-10,13 These data support the investigation of therapeutic strategies that inhibit HER2 tyrosine kinase phosphorylation in castrate patients with HRPC. However, the positive outcomes reported with targeting HER2 in breast cancer32 and epidermal growth factor receptor in colorectal cancer33 have not been reproduced in HRPC.34,35 Previous studies with trastuzumab and gefitinib have reported minimal antitumor activity in this disease.34,35 Preclinical evidence has implicated heregulin and HER2-HER3 heterodimer signaling in HRPC cells that may not be targeted by trastuzumab or gefitinib.8,11-13 In this study, we sought to investigate the potential role of a HER2-targeting antibody that can block heregulin-driven HER2-HER3 signaling.

In this phase II study, the pharmacokinetic profile confirmed that the mean serum concentrations of pertuzumab achieved with administration once every 3 weeks were in excess of the levels at which anticancer activity was reported in preclinical, androgen-depleted, in vivo models. In other studies, pertuzumab (administered at the dose of 420 mg once every 3 weeks with a loading dose of 840 mg) has demonstrated clinically significant single-agent activity in refractory or recurrent ovarian cancer.36 This suggests that the schedules tested in this trial should have been able to modulate HER2-HER3 signaling. However, no clinically significant antitumor activity was observed. Tumor histology acquired at diagnosis and circulating HER2 extracellular domain blood levels were collected for HER2 testing but in view of the absence of antitumor activity, these studies have not been completed. Assuming an incidence of HER2 overexpression of 20% to 50% in our study population, failure to select patients using HER2 status is unlikely to explain the absence of any ≥ 50% declines in PSA in the 68 patients treated. Moreover, preclinical studies did not report a correlation between the level of HER2 expression and pertuzumab antitumor activity.37

The negative results of our study may indicate that the antitumor activity of pertuzumab is abrogated by activation of other functional erbB receptor dimers (eg, HER1-HER1, HER1-HER3, and so on),38-40 or that the residual levels of intraprostatic androgens in castrate patients can prevent pertuzumab from mediating its antitumor effects.41-43 If future studies of ErbB inhibitors in HRPC are to be pursued, agents that can also target these alternative erbB pathways should be evaluated in the presence of optimal blockade of androgen synthesis. However, in view of the negative results reported in this clinical trial, the therapeutic relevance of ErbB heterodimer receptor signaling in HRPC is uncertain.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Gerhard Zugmaier, Hoffmann-La Roche Co; Veronica Hersberger-Gimenez, Hoffmann-La Roche Co; Louise Cockey, Hoffmann-La Roche Co Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Gerhard Zugmaier, Veronica Hersberger-Gimenez, Louise Cockey

Administrative support: Louise Cockey

Provision of study materials or patients: Johann Sebastian de Bono, Joaquim Bellmunt, Gerhardt Attard, Jean Pierre Droz, Kurt Miller, Aude Flechon, Cora Sternberg, Chris Parker, Malcolm Mason, John Graham

Collection and assembly of data: Johann Sebastian de Bono, Joaquim Bellmunt, Gerhardt Attard, Jean Pierre Droz, Kurt Miller, Aude Flechon, Cora Sternberg, Chris Parker, Gerhard Zugmaier, Veronica Hersberger-Gimenez, Louise Cockey, Malcolm Mason, John Graham

Data analysis and interpretation: Johann Sebastian de Bono, Gerhard Zugmaier, Veronica Hersberger-Gimenez, Louise Cockey

Manuscript writing: Johann Sebastian de Bono

Final approval of manuscript: Johann Sebastian de Bono, Joaquim Bellmunt, Gerhardt Attard, Jean Pierre Droz, Kurt Miller, Aude Flechon, Cora Sternberg, Chris Parker, Gerhard Zugmaier, Veronica Hersberger-Gimenez, Louise Cockey, Malcolm Mason, John Graham


   NOTES
 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
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Submitted April 28, 2006; accepted September 11, 2006.


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