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Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies

Authors' Affiliations: ¹ Georgetown University Medical Center, Washington, District of Columbia; ² University of California at Los Angeles School of Medicine, Los Angeles, California; ³ Duke University Medical Center, Durham, North Carolina; ⁴ Cancer Therapy and Research Center, San Antonio, Texas; ⁵ Abgenix, Inc., Fremont, California; and ⁶ Amgen, Inc., Thousand Oaks, California

Requests for reprints: Louis M. Weiner, Georgetown University Medical Center Research Building, Suite E501, 3970 Reservoir Road Northwest, Washington DC 20057-1465. Phone: 202-687-2110; Fax: 202-687-6402; E-mail: Weinerl{at}georgetown.edu.

	Abstract

Top Abstract Patients and Methods Results Discussion References

 
Purpose: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor receptor in patients with previously treated epidermal growth factor receptor–expressing advanced solid tumors.

Experimental Design: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored. Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn at preset intervals. Tumor response was assessed at week 8.

Results: Ninety-six patients received panitumumab. Median (range) age was 61 years (32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22% prostate, 16% renal, 15% non–small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal, and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively. The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was reached. No human anti-panitumumab antibodies were detected. No investigator-determined panitumumab infusion-related reactions were reported. Serum panitumumab concentrations were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response, and 9 of 39 patients (23%) with colorectal cancer had stable disease.

Conclusions: Panitumumab was well tolerated with comparable exposure and safety profiles for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin occurred more frequently in the dose cohorts receiving 2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.

The EGFR pathway has been linked to cancer through mutations or gene overexpression that may enhance EGFR signaling (4, 5). Overexpression of EGFR has been reported in many tumor types, including renal cell carcinomas (6, 7), pancreatic (8), non–small cell lung cancer (9), and colorectal cancer and has been shown to predict tumor progression (4, 10).

Targeted agents such as small-molecule kinase inhibitors and monoclonal antibodies directed against EGFR have shown promising clinical results (11). A number of anti-EGFR monoclonal antibodies (e.g., cetuximab, panitumumab, matuzumab) are currently indicated or under investigation in clinical trials for the treatment of various solid malignancies (12). Cetuximab is a chimeric anti-EGFR monoclonal antibody indicated in the United States in patients with colorectal cancer refractory or intolerant to irinotecan and in patients with squamous cell carcinoma of the head and neck (13). Preliminary data from studies of these antibodies administered with chemotherapy have suggested high response rates (12).

Panitumumab is a fully human IgG2 anti-EGFR monoclonal antibody that binds with high affinity (K_D = 5 x 10^–11 mol/L) to the EGFR (14). Clinical trials have shown antitumor activity of panitumumab in patients with chemorefractory metastatic colorectal cancer (15–17).

Pharmacokinetic and pharmacodynamic data from a phase 2 study in patients with renal cell carcinoma were used to calculate the optimal panitumumab dose of 2.5 mg/kg weekly (18). In this study, panitumumab exhibited nonlinear pharmacokinetics in a dose range of 1 to 2.5 mg/kg weekly. Clearance decreased with increasing dose, consistent with progressive saturation of the EGFR. The 2.5 mg/kg weekly dose resulted in a 100% incidence of skin rash, a known dose-dependent surrogate biomarker for EGFR blockade in skin, with no grade 4 adverse events or human anti-panitumumab antibodies.

Here, we report on a phase 1, open-label study evaluating panitumumab monotherapy in patients with advanced refractory EGFR-expressing tumors at various doses and schedules to assess safety, pharmacokinetics, and activity.

	Patients and Methods

Top Abstract Patients and Methods Results Discussion References

 
Patients. Eligible patients were 18 years old; had advanced, treatment-refractory renal, prostate, pancreatic, non–small cell lung, colorectal, or esophageal/gastroesophageal junction cancer (tumor must be evaluable by standard criteria for the specific tumor type); had EGFR staining tumor cells (must be the sum of 1+, 2+, and 3+ in 10% of evaluated tumor cells); had adequate hematologic, renal, and hepatic function; had an Eastern Cooperative Oncology Group score of 0 to 1; and had a Karnofsky performance score of 70%. Selected exclusion criteria included uncontrolled brain metastases, concomitant cancer therapy of any kind (concomitant steroid or hormone therapy was allowed), chemotherapy within 6 weeks of first panitumumab infusion, systemic anticancer therapy within 30 days of first panitumumab infusion, or prior anthracycline therapy.

The protocol was approved by institutional review boards at participating centers, and patients provided informed consent before any study-related procedures were done.

Study design and methods. This was a multicenter, sequential, dose-escalating, phase 1 study of panitumumab monotherapy. Patients received four doses of panitumumab in one of the following dose schedules: weekly at 0.01, 0.03, 0.1, 0.3, 0.75, 1.0, 1.5, 2.0, 2.5, 3.5, or 5.0 mg/kg; every 2 weeks at 6.0 mg/kg; and every 3 weeks at 9.0 mg/kg. Patients receiving weekly doses of 0.01 to 0.3 mg/kg also received a 2x loading dose at week 1; patients receiving weekly doses of 0.75 to 1.0 mg/kg were evaluated either with or without a 2x loading dose (Fig. 1 ).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. The mean observed serum panitumumab concentrations after 4 weekly i.v. infusions of panitumumab, represented as symbols with (), (), (), (), (), (), (), for the 0.75, 1.0, 1.5, 2.0, 2.5, 3.5, 5.0 mg/kg/wk doses, respectively on linear scale (left) and on log scale (right).

The doses selected in this study were based on preclinical xenograft findings and a toxicology study in monkeys. A dose of 0.01 mg/kg weekly was selected as the starting dose in this study. Loading doses (twice the assigned dose at the first infusion only) were administered at doses ranging from 0.01 to 1.0 mg/kg weekly to achieve steady-state more rapidly. As the dose was increased from 0.75 to 2.5 mg/kg weekly, an increase in skin rash incidence was observed, reaching a rate of 100% at 2.5 mg/kg, suggesting a plateau in panitumumab pharmacologic activity. Higher weekly doses, including 3.5 and 5 mg/kg, further characterized panitumumab safety. Less frequent dosing schedules were tested, chosen based on pharmacokinetic modeling which predicted that 6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks would result in trough concentrations similar to those observed for the 2.5 mg/kg weekly cohort.

Patients with a tumor response or stable disease were allowed to continue treatment on a separate maintenance trial at their respective dose for an additional 6 months or until disease progression. Data from this maintenance trial are included in this report.

Study objectives. The primary objective was to assess the safety and tolerability of multidose administration of panitumumab in patients with advanced, treatment-refractory solid malignancies. Secondary objectives were to determine the pharmacokinetics, dose-response relationship, and clinical effect of panitumumab.

Assessments. Adverse events were assessed by the investigator at each patient visit using the National Cancer Institute Common Toxicity Criteria, version 2.0. Immunogenicity was assessed by evaluating the human anti-panitumumab antibody response by ELISA at baseline and at two time points following the last panitumumab administration. An interim safety review of adverse events, vital sign data, laboratory tests, and all serious adverse events, followed by a dose escalation, occurred when all weekly patients completed their last dosing visit and when every 2 weeks and every 3 weeks patients completed their second dosing visit.

Blood was obtained for serum panitumumab pharmacokinetic analyses within 15 min before administration of each dose and 30 min after completion of each infusion. Additional pharmacokinetic samples were taken for the weekly dosing cohorts 1, 4, 8, and 24 h and 4 days following the week 0 dose; for the every 2 weeks dosing cohorts, additional pharmacokinetic samples were taken 8 and 24 h and 4, 7, 10, and 12 days following the week 0 and week 4 doses; and for the every 3 weeks dosing cohorts, additional pharmacokinetic samples were taken 8 and 24 h and 4, 7, 14, and 17 days following the week 0 and week 6 doses. Serum panitumumab concentration profiles were described by a two-compartment model previously reported (18).

Objective tumor response for measurable disease was evaluated by investigator assessment using modified WHO criteria (19, 20). Prostate-specific antigen levels were assessed to evaluate response in patients with prostate cancer. Responses were confirmed at least 4 weeks after response criteria were initially met.

Drug administration. Panitumumab was administered i.v. for 2 h at doses 1 mg/kg and for 1 h at doses 1.5 mg/kg (infusion times were reduced after initial safety assessments). No premedication was required but could be administered at the discretion of the investigator. Patients were monitored for any reactions up to 8 h after the completion of the infusion.

Statistics. The primary efficacy and safety analyses included all enrolled patients who received any amount of panitumumab. Tumor response was summarized by tumor type, EGFR staining intensity, and incidence and severity of skin rash.

For pharmacokinetic analyses, panitumumab serum concentrations were not measurable at doses of 0.02 and 0.06 mg/kg after the first dose and were only available 24 h after dosing at the 10-fold higher 0.2 and 0.6 mg/kg doses, insufficient for characterizing the pharmacokinetic profile for weekly treatments at these low dose levels. Therefore, pharmacokinetic profiles for doses <0.75 mg/kg were not included in the mean profiles presented for the higher dose cohorts.

	Results

Top Abstract Patients and Methods Results Discussion References

 
Patients. Of 97 patients enrolled, 96 patients received at least one dose of panitumumab. Fifty-six patients were enrolled in the weekly group, 17 patients in the 6.0 mg/kg every 2 weeks group, and 23 patients in the 9.0 mg/kg every 3 weeks group. Baseline demographics included 75% men; mean age was 60.4 years. The most common tumor types included colorectal (41% of patients), prostate (22% of patients), renal (16% of patients), and lung (15% of patients; Table 1 ) cancers.

Two patients in the 1.0 mg/kg weekly cohort had a DLT of severe maculo-papular rash. The dose was deescalated to 0.75 mg/kg weekly; no further DLTs were observed, and dose escalation was resumed in the 1.0 mg/kg weekly cohort. One patient in the 2.5 mg/kg weekly cohort had a DLT of severe asthenia, angina pectoris, and dyspnea. No other DLTs were observed, and dose escalation continued into all planned cohorts.

Adverse events of all grades were evenly balanced across all groups (Table 2 ), with an overall incidence of 32% grade 3 and 7% grade 4 events. Serious adverse events were reported in 18 (19%) patients and were not considered related to panitumumab in 17 patients. One patient in the 9.0 mg/kg every 3 weeks cohort experienced a grade 4 treatment-related serious adverse event of hypomagnesemia, which resolved without sequelae after the patient received i.v. and oral magnesium replacement.

Median time to first skin toxicity of any grade was 7 days [95% confidence interval (95% CI), 7-10 days] with a median time to resolution of 71 days (95% CI, 59-109 days). Median time to most severe skin toxicity of any grade was 14 days (95% CI, 12-20 days) with a median time to resolution of 39 days (95% CI, 29-46 days).

Human anti-panitumumab antibodies. Eighty patients (83%) had a baseline and post-dose sample available for antibody analysis. No patients tested positive for human anti-panitumumab antibodies after receiving panitumumab.

Pharmacokinetics. Serum panitumumab concentrations increased with weekly doses of 0.75 to 5 mg/kg (Fig. 1). In the terminal phase of the weekly dose concentration profile, there was a rapid decline in levels for doses 0.75 to 1.5 mg/kg weekly, whereas at higher doses this nonlinear decline was less apparent. Using preliminary pharmacokinetic data from all weekly dose groups, panitumumab pharmacokinetics were fitted to a model that accurately predicted a steady-state level of 50 µg/mL for the 6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks dosages. This target concentration was based on the observed steady-state level of 50 µg/mL for the 2.5 mg/kg weekly dose (18). After the third dose cycle, mean (SE) C_trough values were 47 µg/mL (5) and 49 µg/mL (10) for the 6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks cohorts, respectively (Fig. 2 ).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Observed concentration-time course for 6 mg/kg every 2 wk and 9 mg/kg every 3 wk compared with the observed and fitted concentration-time course for 2.5 mg/kg weekly. The observed panitumumab concentrations are represented with (), (), and () for the 2.5 mg/kg weekly, 6 mg/kg every 2 wk and 9.0 mg/kg every 3 wk doses, respectively. Points, mean; bars, SE. The model fit for the 2.5 mg/kg weekly dose is represented by the dashed line and predicts the levels beyond the 4 wk of treatment.

View larger version (7K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Scatter graph of the incidence of skin rash at different weekly panitumumab doses (), with the dashed line representing the predicted percentage of skin rash using a sigmoidal Emax model. This model predicted that 90% of patients would develop skin toxicity at 2.1 mg/kg weekly (95% CI, 1.2-2.9 mg/kg weekly).

Duration of treatment and duration of response. The study was designed for patients to receive four total doses of panitumumab. For patients who had at least stable disease and tolerated panitumumab, they could continue treatment on an extension study. Duration of treatment in the extension study ranged from 1 to 15.9 months. Median duration of skin toxicity was longer in the 6 mg/kg every 2 weeks and 9 mg/kg every 3 weeks dose cohorts (range of medians for all doses, 31-118 days); however, the duration of exposure was longer on the every 2 weeks and every 3 weeks schedules (8 and 12 weeks, respectively) than on the weekly schedule (4 weeks). Median duration of response for the five responders was 32 weeks (95% CI, 28-32 weeks).

	Discussion

Top Abstract Patients and Methods Results Discussion References

 
Targeted cancer therapies have the potential to be highly effective with less toxicity than chemotherapy and radiotherapy. Here, we describe the initial clinical experience with panitumumab, the first fully human monoclonal antibody directed against the EGFR for the treatment of advanced solid malignancies.

In this dose-finding study, panitumumab was generally well tolerated. Dose escalation to 9.0 mg/kg every 3 weeks was achieved and no maximum tolerated dose was reached. Premedication before panitumumab administration was not required, short infusion times were safe, and no investigator-determined infusion-related reactions were reported. The incidence of adverse events was comparable with the safety profiles of other anti-EGFR agents, and the most prevalent treatment- and dose-related adverse events were dry skin and rash (21). Similar to studies of other anti-EGFR agents, rash was associated with response (22–24). Further analysis of skin toxicity as a pharmacodynamic response marker is needed in future studies.

No de novo anti-panitumumab antibodies were detected. This finding contrasts with a phase 1 study of the chimeric anti-EGFR monoclonal antibody cetuximab that reported that 4% of patients generated human anti-chimeric antibodies (25).

In this study, panitumumab exhibited predictable pharmacokinetics, with low intrapatient and interpatient variability. The minimal serum panitumumab concentrations (C_trough) were similar among the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks doses, with steady-state reached after 6 weeks for all schedules. Although the maximum tolerated dose was not reached, it is unlikely that increasing the dose beyond these doses would result in increased panitumumab activity because EGFR seems to be saturated at these dose levels, and no additional anti-EGFR activity would be predicted at increased doses.

In our study, five patients experienced partial responses, and 19 patients showed stable disease. All five responders had colorectal cancer and received panitumumab 2.5 mg/kg weekly or at higher doses given less frequently, resulting in a 13% response rate in patients with colorectal cancer. In addition, 23% of patients with colorectal cancer had stable disease. One colorectal cancer patient improved to partial response during the extended maintenance period after achieving stable disease during the study trial period, indicating that long-term administration of panitumumab is beneficial for some patients. Additionally, no cumulative toxicities were observed with long-term administration of panitumumab in this study; skin-related toxicities were not dose-limiting in the five partial responders who received panitumumab for a mean of 235 days.

At the time of the design and execution of this study, EGFR tumor membrane expression level was presumed to be important. The restriction of patient eligibility to patients with at least 10% of tumor cells expressing EGFR may have excluded individuals who may have benefited from therapy. Other studies have shown that EGFR levels detected by immunohistochemistry do not correlate with response to anti-EGFR treatment (15, 17, 22, 24).

Although some colorectal cancer patients experienced dramatic responses to therapy, most patients did not respond. Identification of patients likely to benefit from therapy remains an urgent priority for treatment with EGFR inhibitors. EGFR gene amplification, EGFR polymorphisms, KRAS mutations, and gene signatures have recently been reported as possible predictive markers of response to EGFR inhibitors, but the role of these biomarkers remains unclear (26–28). Ongoing studies examining the role of EGFR ligands and downstream and parallel signaling pathways may help identify predictive markers of benefit with panitumumab therapy, alone or with chemotherapy.

From our pharmacokinetic findings, panitumumab may be flexibly dosed from weekly to every 3 weeks schedule, which allows for panitumumab administration with common every 2 weeks or every 3 weeks chemotherapy regimens. Panitumumab dosing on the same day of chemotherapy may result in greater compliance and increased quality of life. While a study combining panitumumab with bevacizumab and chemotherapy showed increased toxicity and no efficacy benefit (29), other studies suggested that panitumumab can be safely administered with irinotecan-containing regimens (FOLFIRI) in patients with metastatic colorectal cancer, and with other chemotherapy or targeted agents in patients with solid tumors (30–32). Further evaluations of combination regimens with panitumumab are ongoing.

In summary, panitumumab monotherapy is well tolerated at various doses and dosing intervals. Panitumumab administration does not require premedication or a loading dose. Panitumumab monotherapy has antitumor activity with durable objective responses in patients with colorectal cancer, and is under further clinical investigated in numerous tumor types.

	Acknowledgments

 
We thank the patients and their families who participated in this study; the clinical study staff at all of the institutions; and the following individuals: Eric Rowinsky, M.D., for study participation; Sophie Visonneau, Ph.D., for study management; Michiel Hagendoorn, B.S.; for programming support; Tab Hoda, M.S., for data management; Bing-Bing Yang, Ph.D., and Peggy Lum, B.S., for pharmacokinetics analyses; and James Ziobro, B.A., and Mee Rhan Kim, Ph.D., for assistance with the writing and preparation of the manuscript.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for R.A. Figlin: City of Hope, Los Angeles, CA.

Received 6/18/07; revised 9/ 5/07; accepted 10/22/07.

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Top Abstract Patients and Methods Results Discussion References

 

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