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A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Sasaki Y, Miwa K, Yamashita K, Sunakawa Y, Shimada K, Ishida H, Hasegawa K, Fujiwara K, Kodaira M, Fujiwara Y, Namiki M, Matsuda M, Takeuchi Y, Katsumata N - Invest New Drugs (2014)

Bottom Line: Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed.No cumulative toxicity occurred in any patient.Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Saitama International Medical Center-Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan, yasutsuna@med.showa-u.ac.jp.

ABSTRACT
Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

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Relationship between dose and pharmacokinetic parameters of Cmax (a) and AUC(0-t) (b)
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Fig4: Relationship between dose and pharmacokinetic parameters of Cmax (a) and AUC(0-t) (b)

Mentions: Pharmacokinetic parameters, including Cmax and AUC(0-t), increased dose dependently. A low clearance and a low distribution volume characterized the PK profile of farletuzumab, which is similar to the PK profiles reported by other anti-receptor antibodies [14]. When the relationship between the dose and the PK parameters of Cmax and AUC(0-t) on cycle 0 day 1 was compared with corresponding parameters observed in the previous US phase I study [10], the comparison revealed similar PK profiles of farletuzumab between Japanese and US patients (Fig. 4). Although the t1/2 value seems to be different between the Japanese and US studies, the difference can be attributed to the different sampling points (up to 504 and 168 h after administration for the Japanese and US study, respectively). The serum trough concentrations of farletuzumab after weekly repeated administration at the 50 mg/m2 dose level were more than 10 μg/mL, which is beyond the minimum concentration needed to induce ADCC and CDC in an in vitro pharmacology study [5].Fig. 4


A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Sasaki Y, Miwa K, Yamashita K, Sunakawa Y, Shimada K, Ishida H, Hasegawa K, Fujiwara K, Kodaira M, Fujiwara Y, Namiki M, Matsuda M, Takeuchi Y, Katsumata N - Invest New Drugs (2014)

Relationship between dose and pharmacokinetic parameters of Cmax (a) and AUC(0-t) (b)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4387250&req=5

Fig4: Relationship between dose and pharmacokinetic parameters of Cmax (a) and AUC(0-t) (b)
Mentions: Pharmacokinetic parameters, including Cmax and AUC(0-t), increased dose dependently. A low clearance and a low distribution volume characterized the PK profile of farletuzumab, which is similar to the PK profiles reported by other anti-receptor antibodies [14]. When the relationship between the dose and the PK parameters of Cmax and AUC(0-t) on cycle 0 day 1 was compared with corresponding parameters observed in the previous US phase I study [10], the comparison revealed similar PK profiles of farletuzumab between Japanese and US patients (Fig. 4). Although the t1/2 value seems to be different between the Japanese and US studies, the difference can be attributed to the different sampling points (up to 504 and 168 h after administration for the Japanese and US study, respectively). The serum trough concentrations of farletuzumab after weekly repeated administration at the 50 mg/m2 dose level were more than 10 μg/mL, which is beyond the minimum concentration needed to induce ADCC and CDC in an in vitro pharmacology study [5].Fig. 4

Bottom Line: Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed.No cumulative toxicity occurred in any patient.Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Saitama International Medical Center-Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan, yasutsuna@med.showa-u.ac.jp.

ABSTRACT
Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

Show MeSH
Related in: MedlinePlus