scholarly journals A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

2011 ◽  
Vol 17 (19) ◽  
pp. 6304-6312 ◽  
Author(s):  
Francesco Atzori ◽  
Josep Tabernero ◽  
Andrés Cervantes ◽  
Ludmila Prudkin ◽  
Jordi Andreu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Insulin Like Growth Factor ◽  
Pharmacodynamic Study ◽  
Receptor Monoclonal Antibody

A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3505-3505 ◽  
Author(s):  
C. S. Higano ◽  
E. Y. Yu ◽  
S. H. Whiting ◽  
M. S. Gordon ◽  
P. LoRusso ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Human Insulin ◽  
Clinical Activity ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igg1 Monoclonal Antibody ◽  
Growth Factor I

3505 Background: IMC-A12 is a fully human IgG1 monoclonal antibody directed against the human insulin like growth factor-I receptor. The safety and maximum tolerated dose (MTD) of IMC-A12 are being evaluated in an on-going a phase I trial. Methods: Patients (pts) with ECOG PS = 2 and advanced refractory solid tumors receive IMC-A12 weekly for 4 infusions per cycle until progression. After cycle one only, there is a two week observation period. Six cohorts of IMC-A12 are planned at 3, 6, 10, 15, 21, 27mg/kg. Sampling for PK and human anti-human antibodies directed against IMC-A12 occurs before and after the first and fourth doses of each cycle. Results: Fifteen pts have been treated, 7 at 3 mg/g, 4 at 6 mg/kg, 3 at 10 mg/kg and 1 at 15 mg/kg. Data is available for the first 11 pts: 7 male, 4 female, median age 56 years (range: 45–70). Treatment related toxicities for the first 11 pts include: grade 1 pruritis, rash, discolored feces; grade 2 anemia, psoriasis, hyperglycemia, infusion-related reaction; grade 3 hyperglycemia. Four of 11 pts have stable disease: 2 at the 3 mg/kg dose remain stable for >9 months (1 male breast cancer,1 hepatocellular cancer) and 2 at the 6 mg/kg dose (1 bladder, 1 endometrial) were stable after cycle 1. One pt with prostate cancer had >25% decline in PSA and stable radiographic disease at time of study discontinuation (week 5) for DLT. Non-compartmental PK analysis reveals a mean t1/2 of 148 and 209 hrs, mean Cmax of 333 and 415 ug/mL, and mean AUC0-Inf of 51317 and 80727 hr*ug/mL at the 3 and 6 mg/kg dose levels, respectively. Target trough levels have been achieved. Conclusions: Weekly administration of IMC-A12 appears to be well tolerated and the MTD has not been reached. The PK profile is consistent with that of other Mab’s. There is early evidence of clinical activity and correlative IGF biomarker data will be available. IMC-A12 will be further evaluated in prostate, breast, and other cancers. No significant financial relationships to disclose.

Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor Receptor

2004 ◽  
Vol 22 (1) ◽  
pp. 175-184 ◽  
Author(s):  
Udo Vanhoefer ◽  
Mitra Tewes ◽  
Federico Rojo ◽  
Olaf Dirsch ◽  
Norbert Schleucher ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Dose Levels ◽  
Receptor Monoclonal Antibody

Purpose To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). Patients and Methods This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. Results Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000 . Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. Conclusion Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.

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