Updated results from a dose and schedule study of Panitumumab (ABX-EGF) monotherapy, in patients with advanced solid malignancies

Weiner, Louis M.; Belldegrun, Arie S.; Rowinsky, Eric K.; Crawford, J.; Lockbaum, Pamela; Huang, Shiang-Fu; Arends, Rosalin; Schwab, G.; Figlin, Robert A.

doi:10.1200/jco.2005.23.16_suppl.3059

Cited by 36 publications

(33 citation statements)

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“…Five patients responded, all with colorectal cancer (n 5 39; 13%), and an additional 7 (18%) patients with colorectal cancer had stable disease. 16,17 The QW dose for phase 2 testing was selected based on expected target trough concentrations consistent with receptor saturation. We therefore conducted a phase 2 trial of panitumumab in colorectal cancer patients whose tumors had progressed on chemotherapy.…”

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confidence: 99%

Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer

Hecht

Patnaik²,

Berlin

et al. 2007

Cancer

193

111

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BACKGROUND. The safety and efficacy of the fully human antibody panitumumab was evaluated in patients with metastatic colorectal cancer refractory to available therapies. METHODS. This phase 2 open‐label, multicenter study of panitumumab enrolled patients with metastatic colorectal cancer who had progressed on chemotherapy that included a fluoropyrimidine and irinotecan or oxaliplatin, or both. All patients had tumors with ≥10% 1+ epidermal growth factor receptor (EGFr) staining by immunohistochemistry. Patients were stratified into 2 strata (high or low staining intensity) and received intravenous panitumumab 2.5 mg/kg weekly 8 of every 9 weeks until disease progression or unacceptable toxicity. RESULTS. In all, 148 patients received panitumumab, 105 in the high EGFr stratum, 43 in the low EGFr stratum. Overall response by central review was 9% (95% confidence interval [CI], 5%–15%) and was similar between strata. An additional 29% of patients had stable disease. Median progression‐free survival was 14 weeks (95% CI, 8–16) and median overall survival was 9 months (95% CI, 6–10). Toxicities were manageable, with skin toxicity reported in 95% of patients (5% grade 3 or 4). Four patients discontinued therapy because of toxicity. No antipanitumumab antibodies were detected. One patient had an infusion reaction but was able to continue therapy. CONCLUSIONS. Panitumumab given weekly was well tolerated and had single‐agent activity in previously treated patients with colorectal cancer. Dermatologic toxicity was common but rarely severe. Ongoing studies will determine panitumumab activity earlier in the course of treatment for colorectal cancer and in combination with other antineoplastic agents. Cancer 2007. © 2007 American Cancer Society.

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confidence: 99%

Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer

Hecht

Patnaik²,

Berlin

et al. 2007

Cancer

193

111

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“…Thus, the phase I studies with the agent recommended a dose of 2.5 mg/kg based on saturation of elimination, frequency and severity of rash, and achievement of plasma levels above the levels needed for activity in preclinical models (5). Subsequent studies showed that a dose of 6 and 9 mg/kg resulted in equivalent exposure and that a loading dose was not needed to achieve the desired plasma levels (6). As discussed below, the dose of 6 mg/kg was selected for phase III studies.…”

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confidence: 99%

Panitumumab, a Monoclonal Anti–Epidermal Growth Factor Receptor Antibody in Colorectal Cancer: Another One or the One?

Messersmith

Hidalgo

2007

Clinical Cancer Research

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Panitumumab (Vectibix, Amgen, Inc.) is a fully human IgG2 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Panitumumab, formerly called ABX-EGF, was initially developed by Abgenix using the XenoMouse transgenic technology. This methodology is based on inactivating the mouse immunoglobulin genes that are replaced by a megabase gene containing the human heavy and n chains. The result is the generation of fully human antibodies that do not contain murine portions of the IgG molecule as chimeric antibodies do. This property avoids the formation of human antimouse antibodies, which may result in more frequent hypersensitivity reactions and shorter half-life (1).Panitumumab binds specifically and selectively to the EGFR, preventing binding of activating ligands, such as the EGF and transforming growth factor-a. In preclinical studies, this action reduces EGFR signaling and causes cell cycle arrest. The panitumumab-coated receptor is rapidly internalized resulting in receptor down-regulation although is not clear if the receptor is next degraded or recycled to the plasma membrane. In selected studies, panitumumab reduces angiogenesis as well. The preclinical activity of the agent is more pronounced in cells expressing the EGFR at levels of z15,000 per cell and inactive in EGFR-negative tumors. As with most of the EGFR-targeting agents, preclinical studies do show synergistic effects when combined with chemotherapy and radiation therapy (2, 3).The initial clinical development of panitumumab aimed to define the most effective and safe dose and schedule for patient treatment. Based on previous experiences with cetuximab, a chimeric anti-EGFR antibody, it was unlikely that an approach based solely on toxicity was appropriate to that end. Two important factors were considered in the design of these studies. First, it was expected that clearance of the antibody would be dose dependent, reflecting full saturation of EGFR binding sites because the principal mechanism of elimination of the agent is by degradation of antibody-occupied receptors (4). Second, it was already apparent that patients who developed skin rash after treatment with EGFR inhibitors had better treatment outcome. Thus, the phase I studies with the agent recommended a dose of 2.5 mg/kg based on saturation of elimination, frequency and severity of rash, and achievement of plasma levels above the levels needed for activity in preclinical models (5). Subsequent studies showed that a dose of 6 and 9 mg/kg resulted in equivalent exposure and that a loading dose was not needed to achieve the desired plasma levels (6). As discussed below, the dose of 6 mg/kg was selected for phase III studies.It should be noted, however, that there are some limitations in the criteria used for dose selection. Although the hypothesis of the EGFR sink is appealing and pharmacokinetically intuitive, the notion that receptor saturation is the only and principal factor accounting for the observed saturation in clearance has not been shown experimentally. Second,...

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“…No human antihuman antibodies have been reported to date. A large dose/schedule trial of single-agent panitumumab has been reported by Weiner and colleagues (24). This trial enrolled 96 EGFR-positive solid tumor patients (predominantly colorectal but 14 lung cancer patients were included).…”

Section: Panitumumabmentioning

confidence: 99%

Antibodies to the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer: Current Status of Matuzumab and Panitumumab

Socinski

2007

Clinical Cancer Research

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Matuzumab and panitumumab are antibodies against the epidermal growth factor receptor (EGFR) that are being evaluated in several malignancies including non^small cell lung cancer (NSCLC). In phase I trials of single-agent matuzumab in patients with EGFR-positive cancer, three tumor responses were documented in esophageal squamous cell carcinoma as well as colorectal carcinoma. A phase I trial of matuzumab in combination with paclitaxel has been reported in 18 patients with EGFR-positive advanced NSCLC. Objective responses were seen in 4 of 18 (23%) patients. A randomized phase II trial is currently ongoing in second-line NSCLC with matuzumab in combination with pemetrexed.

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Updated results from a dose and schedule study of Panitumumab (ABX-EGF) monotherapy, in patients with advanced solid malignancies

Cited by 36 publications

References 0 publications

Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer

Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer

Panitumumab, a Monoclonal Anti–Epidermal Growth Factor Receptor Antibody in Colorectal Cancer: Another One or the One?

Antibodies to the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer: Current Status of Matuzumab and Panitumumab

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