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Cancer Therapy: Clinical Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies Louis M. Weiner,1 Arie S. Belldegrun,2 Jeffrey Crawford,3 Anthony W. Tolcher,4 Pamela Lockbaum,5 Rosalin H. Arends,5 Lynn Navale,6 Rafael G. Amado,6 Gisela Schwab,5 and Robert A. Figlin2 Abstract 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 z2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer. The epidermal growth factor receptor (EGFR) is a member of 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 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 the erbB family of transmembrane tyrosine kinase receptors that includes family members erbB1/EGFR, erbB2/Her2, erbB3, and erbB4. Ligands including EGF, transforming growth factora, amphiregulin, betacellulin, heparin-binding EGF, epiregulin, and neuregulin (1, 2) bind with high specificity to the EGFR, resulting in autophosphorylation and internalization of the EGFR and activation of diverse signaling pathways that induce proliferation, angiogenesis, inhibition of apoptosis, and metastasis (3). Authors’ Affiliations: 1Georgetown University Medical Center, Washington, District of Columbia; 2University of California at Los Angeles School of Medicine, Los Angeles, California; 3Duke University Medical Center, Durham, North Carolina; 4 CancerTherapy and Research Center, San Antonio,Texas; 5Abgenix, Inc., Fremont, California; and 6Amgen, Inc.,Thousand Oaks, California Received 6/18/07; revised 9/5/07; accepted 10/22/07. 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. 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 @ georgetown.edu. F 2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1509 Clin Cancer Res 2008;14(2) January 15, 2008 502 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Dose and Schedule of Panitumumab for Advanced Cancers 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). Prostatespecific 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 V1 mg/kg and for 1 h at doses z1.5 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. 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 Patients. Eligible patients were z18 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 z10% 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 z70%. 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, doseescalating, 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 2 loading dose at week 1; patients receiving weekly doses of 0.75 to 1.0 mg/kg were evaluated either with or without a 2 loading dose (Fig. 1). Patients were enrolled sequentially into ascending dose cohorts after an interim safety review of the previous cohort. A dose-limiting toxicity (DLT) was defined as any grade 3 or 4 adverse event (considered related by the investigator) as defined in the National Cancer Institute Common Toxicity Criteria, version 2.0, or any severe or life-threatening abnormality not covered in National Cancer Institute Common Toxicity Criteria, version 2.0, or any toxicity deemed probably related or any skin toxicity as previously described that required discontinuation of panitumumab (18). Dosing of any higher dose cohort did not continue until 2 additional patients (3 patients for the 6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks dose cohorts) were dosed, and these 2 (or 3) new patients did not exhibit a DLT. If one (or more) of these patients exhibited a DLT, then the dose level below this dose was considered the maximum tolerated dose. Two to 4 patients were planned for each of the weekly cohorts, and 5 patients were planned for the every 2 weeks and every 3 weeks cohorts. Any cohort could be expanded up to 10 patients if deemed necessary by the investigator and sponsor. 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 www.aacrjournals.org Results 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. 503 Clin Cancer Res 2008;14(2) January 15, 2008 Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Cancer Therapy: Clinical Fig. 1. The mean observed serum panitumumab concentrations after 4 weekly i.v. infusions of panitumumab, represented as symbols with (o), (y), (5), (.), (5), (E), (w ), 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). Safety and adverse events. Panitumumab administration at all dose levels was generally well tolerated. Dose escalation to the 9.0 mg/kg every 3 weeks cohort was achieved without reaching the maximum tolerated dose. No infusion reactions were reported as adverse events by the investigators. 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. The most common adverse events across all dose groups were rash (61%), fatigue (39%), nausea (27%), diarrhea (23%), dry skin (19%), and constipation (18%; Table 3). The most common treatment-related adverse events were skin-related toxicities, including rash (60%) and dry skin (19%). Fatigue, diarrhea, and nausea were less frequently attributed to panitumumab treatment, with treatment-related incidences of any grade of 16%, 14%, and 13%, respectively. Skin-related toxicities were frequent in every cohort, ranging from 58% in the weekly cohorts (excluding the 2.5 mg/kg weekly cohort), to 94% in the 6.0 mg/kg every 2 weeks cohort, to 100% in both the 2.5 mg/kg weekly cohort and the 9.0 mg/kg every 3 weeks cohorts. However, most skin-related toxicities 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. Table 1. Demographics and baseline disease characteristics All patients (N = 96) Age, y Mean Median Range Sex, n (%) Men Women Race, n (%) White Black Hispanic Asian Other Baseline ECOG, n (%) 0 1 Primary diagnosis, n (%) Colorectal cancer* Prostate cancer Renal cancer Non – small cell lung cancer Pancreatic cancer Gastroesophageal cancer Esophageal cancer Anal cancer 60.4 61.0 32-79 72 (75) 24 (25) 84 8 2 1 1 (88) (8) (2) (1) (1) 40 (42) 56 (58) 39 21 15 14 3 2 1 1 (41) (22) (16) (15) (3) (2) (1) (1) Abbreviation: ECOG, Eastern Cooperative Oncology Group. *Refers to colon or rectum. Clin Cancer Res 2008;14(2) January 15, 2008 504 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Dose and Schedule of Panitumumab for Advanced Cancers Table 2. Grade 3 and 4 adverse events—all doses and most common doses All other doses* 2.5 mg/kg 6.0 mg/kg 9.0 mg/kg Total QW (n = 48) QW (n = 8) Q2W (n = 17) Q3W (n = 23) (N = 96) Patients with any adverse event, n (%)c Grade 3 Grade 4 Any serious Patients with any treatment-related adverse events, n (%) Grade 3 Grade 4 Any serious Deaths on study, n (%) 47 13 4 7 38 3 0 1 1 (98) (27) (8) (15) (79) (6) (0) (2) (2)b 8 (100) 2 (25) 1 (13) 1 (13) 8 (100) 1 (13) 0 (0) 0 (0) 0 (0) 16 (94) 6 (35) 0 (0) 4 (24) 16 (94) 1 (6) 0 (0) 0 (0) 0 (0) 23 (100) 10 (44) 2 (9) 6 (26) 23 (100) 4 (17) 1 (4) 1 (4) 0 (0) 94 31 7 18 85 9 1 2 1 (98) (32) (7) (19) (89) (9) (1) (2) (1) Abbreviations: QW, weekly; Q2W, every 2 wk; Q3W, every 3 wk. *Doses ranged from 0.01 to 5.0 mg/kg weekly, excluding the 2.5 mg/kg weekly dose. cAdverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0. bThis patient was in the 3.5 mg/kg weekly cohort; death was due to disease progression. 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 Ag/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 Ag/mL for the 2.5 mg/kg weekly dose (18). After the third dose cycle, mean (SE) C trough values were 47 Ag/mL (5) and 49 Ag/mL (10) for the 6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks cohorts, respectively (Fig. 2). A profound dose-response relationship was observed for the skin-related toxicity incidence (Fig. 3). This relationship was similar to the one that has been previously reported for panitumumab in patients with renal cell carcinoma (18). Using the were grade 1 (25% across all cohorts) or grade 2 (46% across all cohorts) with a low incidence of grade 3 (7% across all cohorts) and no grade 4 (0% across all cohorts) toxicities. The severity of skin-related toxicities increased with increasing dose of panitumumab: 2 of 56 (4%) patients in the weekly cohort, 1 of 17 (6%) patient in the every 2 weeks cohort, and 4 of 23 (17%) patients in the every 3 weeks cohort had a grade 3 skin-related toxicity. The 2 patients in the weekly cohort had received a loading dose of panitumumab. 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 antipanitumumab antibodies after receiving panitumumab. Table 3. Adverse events occurring in at least 10% of subjects—all doses and most common doses All doses (N = 96) Adverse event, n (%) Rash Fatigue Nausea Diarrhea Dry skin Constipation Pyrexia Abdominal pain Vomiting Anorexia Stomatitis Arthralgia Dyspnea Headache Anxiety Back pain Dizziness 59 37 26 22 18 17 16 14 14 12 12 11 11 11 10 10 10 (61) (39) (27) (23) (19) (18) (17) (15) (15) (13) (13) (11) (11) (11) (10) (10) (10) 2.5 mg/kg QW (n = 8) 8 (100) 2 (25) 0 (0) 1 (13) 2 (25) 1 (13) 2 (25) 1 (13) 0 (0) 1 (13) 3 (18) 1 (13) 2 (25) 1 (13) 0 (0) 0 (0) 1 (13) 6.0 mg/kg Q2W (n = 17) 14 5 6 5 4 0 4 4 3 3 3 0 2 1 4 1 2 (82) (29) (35) (29) (24) (0) (24) (24) (18) (18) (18) (0) (12) (6) (24) (6) (12) 9.0 mg/kg Q3W (n = 23) 18 (78) 3 (13) 1 (4) 4 (17) 11 (48) 0 (0) 0 (0) 2 (9) 3 (13) 1 (4) 3 (13) 0 (0) 5 (22) 5 (22) 2 (9) 1 (4) 0 (0) NOTE: Adverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0. www.aacrjournals.org 505 Clin Cancer Res 2008;14(2) January 15, 2008 Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Cancer Therapy: Clinical 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 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 investigatordetermined 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 antiEGFR 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 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 (.), (o), 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. same analytic method as that for the renal cell carcinoma data (18), we observed mean (95% CI) estimates for the two variables that describe this relationship of 2.1 mg/kg (1.22.9 mg/kg) for the ED90, which is the panitumumab dose that yields a 90% incidence of skin toxicity and of 4.1 (1.4-6.8) for the exponent c, which is the constant that describes the sigmoidicity or steepness of the curve. Objective tumor response. Across all dosing schedules, five patients had a best objective response of partial response (5%). The five confirmed responders included 1 patient in the 2.5 mg/kg weekly cohort, 2 patients in the 6.0 mg/kg every 2 weeks cohort, and 2 patients in the 9.0 mg/kg every 3 weeks cohort (Table 4). None received a loading dose of panitumumab. All five responders had colorectal cancer, prior surgery, and prior chemotherapy (fluorouracil, irinotecan, and oxaliplatin); 1 of these 5 patients had also received prior radiotherapy. These 5 patients had grade 2 or 3 skin toxicity, most commonly rash. Responders also had slightly greater EGFR tumor membrane staining (percentage of cells with positive staining: 94% for the responders and 72% for the nonresponders). Nineteen (20%) patients had stable disease and included 9 patients in the weekly cohort (excluding the 2.5 mg/kg weekly cohort), 5 patients in the 6.0 mg/kg every 2 weeks cohort, and 5 patients in the 9.0 mg/kg every 3 weeks cohort. Eight patients had colorectal cancer, 5 had non – small cell lung cancer, 3 had prostate cancer, 2 had renal cancer, and 1 had gastroesophageal cancer. 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, Clin Cancer Res 2008;14(2) January 15, 2008 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 E max model. This model predicted that 90% of patients would develop skin toxicity at 2.1mg/kg weekly (95% CI, 1.2-2.9 mg/kg weekly). 506 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Dose and Schedule of Panitumumab for Advanced Cancers Table 4. Objective response with panitumumab Best response Disease Partial response All, n (%) Colon, n Stable disease Progressive disease Patients with response All, n (%) Colon, n Rectal, n Prostate, n Renal, n Non – small cell lung, n Gastroesophageal, n All, n (%) Colon, n Rectal, n Prostate, n Renal, n Non – small cell lung, n Pancreatic, n Gastroesophageal, n Anal, n 5/96 (6) 1 2 2 19/96 (20) 7 1 3 2 5 1 70/96 (73) 23 2 18 13 9 3 1 1 Panitumumab dose 2.5 mg/kg QW 6.0 mg/kg Q2W 9.0 mg/kg Q3W QW dose; 6.0 mg/kg 9.0 mg/kg Q3W QW dose; 9.0 mg/kg QW dose; 6.0 mg/kg QW dose; 6.0 mg/kg QW dose Q2W;9.0 mg/kg Q3W; Q3W Q2W Q2W All doses 6.0 mg/kg Q2W All doses QW doses 2.5 mg/kg QW, QW doses QW doses QW dose 6.0 mg/kg Q2W NOTE: Tumor response was determined by investigator assessment using modified WHO criteria. Responses confirmed >4 wk after the initial assessment of response. ‘‘QW dose’’ represents all other QW doses than 2.5 mg/kg weekly. reached after f6 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 www.aacrjournals.org 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. 507 Clin Cancer Res 2008;14(2) January 15, 2008 Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Cancer Therapy: Clinical References 1. Klapper LN, Kirschbaum MH, Sela M, et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000;77:25 ^ 79. 2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2: 127 ^ 37. 3. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61: 203 ^ 12. 4. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19:183 ^ 232. 5. Voldborg BR, Damstrup L, Spang-Thomsen M, et al. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997;8:1197 ^ 206. 6. Sargent ER, Gomella LG, Belldegrun A, et al. Epidermal growth factor receptor gene expression in normal human kidney and renal cell carcinoma. J Urol 1989; 142:1364 ^ 8. 7. Yoshida K,Tosaka A. Epidermal growth factor binding by membranes of human renal cell carcinomas: establishment of an epidermal growth factor receptor assay for clinical use. Int J Urol 1994;1:319 ^ 23. 8. Yamanaka Y. The immunohistochemical expressions of epidermal growth factors, epidermal growth factor receptors and c-erbB-2 oncoprotein in human pancreatic cancer. Nippon Ika Daigaku Zasshi 1992;59: 51 ^ 61. 9. Franklin WA, Veve R, Hirsch FR, et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol 2002;29:3 ^ 14. 10. Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000;21:105 ^ 15. 11. Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 2003;4:397 ^ 406. 12. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445 ^ 59. 13. ErbituxTM. Prescribing information. Branchburg (NJ): Imclone Systems, Inc.; 2006. 14. Yang XD, Jia XC, Corvalan JR, et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999;59: 1236 ^ 43. 15. Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007;110:980 ^ 7. 16. Van Cutsem E, Peeters M, Siena S, et al. An openlabel, randomized, phase 3 clinical trial of panitumumab plus best supportive care versus best supportive care in patients with chemotherapy-refractory metastatic colorectal cancer. JClin Oncol 2007;25:1658 ^ 64. 17. Hecht JR, Mitchell E, Baranda J, et al. Panitumumab activity in metastatic colorectal cancer (mCRC) patients (pts) with low or negative tumor epidermal growth factor receptor (EGFr) levels: an updated analysis. J Clin Oncol 2007;24:Abstract #3547. 18. Rowinsky EK, Schwartz GH, Gollob JA, et al. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004;22:3003 ^ 15. 19.WHO handbook for reporting results of cancer treatment. World Health Organization offset publication no. 48; Geneva (Switzerland): WHO; 1979. 20. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47: 207 ^ 14. 21. Thomas M. Cetuximab: adverse event profile and recommendations for toxicity management. Clin J Oncol Nurs 2005;9:332 ^ 8. 22. Saltz LB, Meropol NJ, Loehrer PJ, Sr., et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201 ^ 8. 23. Saltz LB, Kies M, Abbruzzese JL, et al.The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003;22: abstr 817. 24. Cunningham D, HumbletY, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinote- Clin Cancer Res 2008;14(2) January 15, 2008 508 can-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337 ^ 45. 25. Baselga J, Mendelsohn J. Receptor blockade with monoclonal antibodies as anti-cancer therapy. Pharmacol Ther 1994;64:127 ^ 54. 26. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66: 3992 ^ 5. 27. Boedigheimer M, Freeman D, Fitzpatrick D, et al. Gene expression profiles can predict panitumumab monotherapy responsiveness in xenograft modelsIa ‘balanced’ approach. Proc Am Assoc Cancer Res 2005;46:Abstract #1. 28. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005;6:279 ^ 86. 29. Hecht JR, Chidlac T, Mitchell E, et al. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (bev) for metastatic colorectal cancer (mCRC). Presented at the 9thWorld Congress of Gastrointestinal Cancer, June 27 ^ 30, 2007, Barcelona, Spain. Abstract no. O-0033. 30. Crawford J, Swanson P, Prager D, et al. Panitumumab, a fully human antibody, combined with paclitaxel and carboplatin versus paclitaxel and carboplatin alone for first line advanced non-small cell lung cancer (NSCLC): a primary analysis. Proc ECCO 2005: Abstract 1123. 31. Crawford J, Burris H, Stein M, et al. Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and gemcitabine/cisplatin (GC) for the treatment of advanced solid malignancies. ASCO Annual Meeting Proceedings part I 2006. J Clin Oncol 2006; 24(18S):abstract 13005. 32. Blumenschein G, SandlerA, O’RourkeT, et al. Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and carboplatin/paclitaxel (CP) for the treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC). ASCO Annual Meeting Proceedings Part I 2006. J Clin Oncol 2006;24(18S): abstract 7119. www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on August 11, 2017. © 2008 American Association for Cancer Research. Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies Louis M. Weiner, Arie S. Belldegrun, Jeffrey Crawford, et al. Clin Cancer Res 2008;14:502-508. Updated version Cited articles Citing articles E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/14/2/502 This article cites 25 articles, 6 of which you can access for free at: http://clincancerres.aacrjournals.org/content/14/2/502.full#ref-list-1 This article has been cited by 10 HighWire-hosted articles. 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