Phase I study of an anti-angiogenic agent with a novel mechanism of action E7820: Safety, pharmacokinetics (PK) and pharmacodynamic (PD) studies in patients (pts) with solid tumors
Abstract:3048 Background: E7820 is a first-in-class oral antiangiogenic sulfonamide that inhibits alpha-2 integrin expression, endothelial cell proliferation and is active against human breast and pancreatic cancer xenografts. Methods: The objectives of the study were to evaluate the safety, tolerability, to determine the maximum tolerated dose (MTD) to characterize the PK behavior, to assess PD markers and to explore the antitumor activity. Results: Thirty pts (18 male/12 female; age range 40–83) received E7820 at do… Show more
“…Only at the highest evaluated but toxic dose of 200 mg qd are 95% of patients expected to achieve inhibition of expression higher than both targets. This dose level has however been shown to induce non-tolerable hematological toxicity ( 15 ). Fig.…”
E7820 is an orally active inhibitor of α2-integrin mRNA expression, currently tested in phases I and II. We aimed to evaluate what levels of inhibition of integrin expression are needed to achieve tumor stasis in mice, and to compare this to the level of inhibition achieved in humans. Tumor growth inhibition was measured in mice bearing a pancreatic KP-1 tumor, dosed at 12.5–200 mg/kg over 21 days. In the phase I study, E7820 was administered daily for 28 days over a range of 0–200 mg, followed by a 7-day washout period. PK-PD models were developed in NONMEM. α2-Integrin expression measured on platelets, corresponding to tumor stasis at t = 21 in 50% and 90% of the mice (Iint,50, Iint,90) were calculated. It was evaluated if these levels of inhibition could be achieved in patients at tolerable doses. One hundred nineteen α2-Integrin measurements and 210 tumor size measurements were available from mice. The relationship between PK and α2-integrin expression was modeled using an indirect-effect model, subsequently linked to an exponential tumor growth model. Iinh,50 and Iinh,90 were 14.7% (RSE 7%) and 17.9% (RSE 8%). Four hundred sixty two α2-integrin measurements were available from 29 patients. Using the schedule of 100 mg qd (MTD), α2-integrin expression was inhibited more strongly than the Iint,50 and Iint,90 in greater than 95% and greater than 50% of patients, respectively. Moderate inhibition of α2-integrin expression corresponded to tumor stasis in mice, and similar levels could be reached in patients with the dose level of 100 mg qd.
“…Only at the highest evaluated but toxic dose of 200 mg qd are 95% of patients expected to achieve inhibition of expression higher than both targets. This dose level has however been shown to induce non-tolerable hematological toxicity ( 15 ). Fig.…”
E7820 is an orally active inhibitor of α2-integrin mRNA expression, currently tested in phases I and II. We aimed to evaluate what levels of inhibition of integrin expression are needed to achieve tumor stasis in mice, and to compare this to the level of inhibition achieved in humans. Tumor growth inhibition was measured in mice bearing a pancreatic KP-1 tumor, dosed at 12.5–200 mg/kg over 21 days. In the phase I study, E7820 was administered daily for 28 days over a range of 0–200 mg, followed by a 7-day washout period. PK-PD models were developed in NONMEM. α2-Integrin expression measured on platelets, corresponding to tumor stasis at t = 21 in 50% and 90% of the mice (Iint,50, Iint,90) were calculated. It was evaluated if these levels of inhibition could be achieved in patients at tolerable doses. One hundred nineteen α2-Integrin measurements and 210 tumor size measurements were available from mice. The relationship between PK and α2-integrin expression was modeled using an indirect-effect model, subsequently linked to an exponential tumor growth model. Iinh,50 and Iinh,90 were 14.7% (RSE 7%) and 17.9% (RSE 8%). Four hundred sixty two α2-integrin measurements were available from 29 patients. Using the schedule of 100 mg qd (MTD), α2-integrin expression was inhibited more strongly than the Iint,50 and Iint,90 in greater than 95% and greater than 50% of patients, respectively. Moderate inhibition of α2-integrin expression corresponded to tumor stasis in mice, and similar levels could be reached in patients with the dose level of 100 mg qd.
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