A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors
Tóm tắt
MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor (FcγRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the tumor cytotoxicity of bispecific antibodies. In group 1, patients received MDX-447 intravenously (IV) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5, 7, 10, 15, 20, 30, and 40 mg/m2. In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days −3 to +2, 5–9, 12–16, etc.). Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m2. Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups, with seven patients experiencing ≥grade 3 events. MDX-447 half-life (T1/2) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and peak levels of circulating tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447 alone was 30 mg/m2. When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns, with the last patient being treated at the 7 mg/m2 dose level. There were no objective complete or partial responses in either group. MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m2 weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation.
Tài liệu tham khảo
van Spriel AB, van Ojik HH, van de Winkel JG (2000) Immunotherapeutic perspective for bispecific antibodies. Immunol Today 21:391–397
Curnow RT (1997) Clinical experience with CD64-directed immunotherapy. Cancer Immunol Immunother 45:210–215
Harari PM (2004) Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer 11:689–708
Mendelsohn J, Baselga J (2006) Epidermal growth factor receptor targeting in cancer. Semin Oncol 33:369–385
Deo YM, Graziano RF, Repp R, van de Winkel JG (1997) Clinical significance of IgG Fc receptors and FcγR-directed immunotherapies. Immunol Today 18:127–135
Hulett MD, Hogarth PM (1994) Molecular basis of Fc receptor function. Adv Immunol 57:1–127
Faillot T, Magdelenat H, Mady E, et al (1996) A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas. Neurosurgery 39:478–483
Wersall P, Ohlsson I, Biberfeld P, et al (1997) Intratumoral infusion of the monoclonal antibody, mAb 425, against epidermal growth factor receptor in patients with advanced malignant glioma. Cancer Immunol Immunother 44:157–164
Elsasser D, Stadick H, Stark S, et al (1999) Preclinical studies combining bispecific antibodies with cytokine-stimulated effector cells for immunotherapy of renal cell carcinoma. Anticancer Res 19:1525–1528
Stockmeyer B, Valerius T, Repp R, et al (1997) Preclinical studies with FcγR bispecific antibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cells against HER-2/neu overexpressing breast cancer. Cancer Res 57:696–701
Repp R, Valerius T, Sendler A, et al (1991) Neutrophils express the high affinity receptor for IgG (FcγR1, CD64) after in vivo application of recombinant human granulocyte colony-stimulating factor. Blood 78:885–889
Stockmeyer B, Elsasser D, Dechant M, et al (2001) Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies. J Immunol Methods 248:103–111
Miller AB, Hogestraeten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214
Valone FH, Kaufman PA, Guyre PM, et al (1995) Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpress the proto-oncogene HER-2/neu. J Clin Oncol 13:2281–2292
Schwaab T, Lewis LD, Cole BF, et al (2001) Phase I pilot trial of the bispecific antibody MDXH210 (anti-Fcγ RI X anti-HER-2/neu) in patients whose prostate cancer expresses HER-2/neu. J Immunother 24:79–87
Pullarkat V, Deo Y, Link J, et al (1999) A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu. Cancer Immunol Immunother 48:9–21
Van Ojik HH, Repp R, Groenewegen G, Valerius T, van de Winkel JGJ (1997) Clinical evaluation of the bispecific antibody MDX-H210 (anti-FcγRI X anti-HER-2/neu) in combination with granulocyte-colony-stimulating factor (Filgrastim) for treatment of advanced breast cancer. Cancer Immunol Immunother 45:207–209
Lewis LD, Cole BF, Wallace PK, et al (2001) Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma: a multiple-dose phase I study in patients with advanced cancer which overexpress HER-2/neu. J Immunol Methods 248:149–165
Repp R, van Ojik HH, Valerius T, et al (2003) Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcγR1 X anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer. Br J Cancer 89:2234–2243
Baselga J, Pfister D, Cooper MR, et al (2000) Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904–914
Chung KY, Saltz LB (2005) Antibody-based therapies for colorectal cancer. Oncologist 10:701–709
Cohen EE (2006) Role of epidermal growth factor receptor pathway-targeted therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 24:2659–2665
Zhang W, Gordon M, Schultheis AM, et al (2006) Two immunoglobulin G fragment C receptor polymorphisms associated with clinical outcome of EGFR-expressing metastatic colorectal cancer patients treated with single agent cetuximab. J Clin Oncol, ASCO Annual Meeting Proceedings Part I. Vol 24, No 18S, abstract 3028
Nimmerjahn F, Ravetch JV (2006) Fcγ receptors: old friends and new family members. Immunity 24:19–28
Kiewe P, Hasmuller S, Kahlert S, et al (2006) Phase I trial of trifunctional anti-HER2 and anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin Cancer Res 12:3085–3091