A single agent, phase I pharmacodynamic study of nimotuzumab (TheraCIM-h-R3) in patients with advanced refractory solid tumors
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14030 Background: Nimotuzumab (N) is a humanized mAb against the EGFR extracellular ligand binding domain. Although well tolerated when combined with radiotherapy in previous studies and lacking usual toxicities of EGFR-targeting agents, the pharmacodynamics (PD) of N has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of N. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and ECOG PS = 0 - 2. IV N was administered weekly x 6 and then every other week (6 weeks = 1 treatment cycle). Tumor, skin and liver biopsies obtained pre- and 2 and 7 weeks post-treatment were evaluated using computer-based, whole mount assessment of immunohistochemical staining. Results: Accrual was completed 21/09/06, 17 patients (11m/6f, median age 63, 13 colorectal cancer, ECOG 0:1:2 = 6:10:1, prior therapy 1:2:3+ = 2:6:9) were registered and 16 patients were treated on 4 dose levels (100, 200, 400 and 800 mg) for a total of 43 treatment cycles (1 patient deemed ineligible after registration did not receive study therapy). Treatment was well tolerated. One dose-limiting toxicity was observed (dose level 1 - grade 3 fatigue possibly attributable to N) . Skin toxicity was mild (Gr 1/2 in 7/1 patients). Confirmed stable disease was seen in 6 patients, a confirmed partial response in 1 patient with prolonged progression-free status observed in 3 patients for 5.8, 14.1 and 18.7 months (the latter two remain on study). Baseline and week 2 biopsies of tumor/skin/liver were evaluable in 12/13/7 pts. Week 7 tumor/skin/liver biopsies in initially responding or stable patients were evaluable in 6/8/6 pts. Post treatment (week 2), EGFR staining decreased in 8/12 matched tumor [mean ratio (post/pre): 0.79 range: (0.37, 1.91)], 8/13 skin [0.96 (0.40, 1.31)] and 5/7 liver [0.88 (0.62, 1.17)] biopsies. No significant relationship was detected between pre/post-treatment EGFR expression with either response or toxicity. Evaluation of downstream targets of EGFR (in tumor, skin and liver) is ongoing and will be presented. Conclusions: Overall nimotuzumab was well tolerated and exhibits mild skin toxicity. Prolonged progression free-survival was observed in 3/16 of these heavily pre-treated patients. No significant financial relationships to disclose.
