A phase 1 trial of E7974 administered on day 1 of a 21‐day cycle in patients with advanced solid tumors

Abstract

BACKGROUND: E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids). METHODS: In a phase 1 study, E7974 was given intravenously over a 2-to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT). RESULTS: Twentyeight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m 2 , 0.27 mg/m 2 , 0.36 mg/m 2 , 0.45 mg/m 2 , and 0.56 mg/m 2 ) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m 2 , where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours). CONCLUSIONS: This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m 2 .

Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications

“…Another derivative of hemiasterlin, peptide E7974, was found to be effective in a phase I study of colorectal, prostate, and larynx carcinomas. It acts by a similar mechanism, and is on its way to a phase II study [137,196]. …”

Marine Pharmaceuticals: A New Wave of Anti-angiogenic Drugs

“…In 2009, another synthetic hemiasterlins analogue E7974 was found which showed strong in vivo anti-tumour efficacy in many human xenograft cancer models along with decreased drug resistance in cancer cells [29]. It has cleared the phase I clinical trial for the treatment of advanced solid tumours in colorectal, pancreatic and liposarcoma cancer patients and is currently undergoing human clinical trial [30].…”

Complementary isonitrile-based multicomponent reactions for the synthesis of diversified cytotoxic hemiasterlin analogues

“…Further, since 4 binds predominantly to the α-subunit of the tubulin, with minor binding to the β-subunit, it offers significant promise of activity in taxane-resistant tumor types, regardless of whether the mechanism driving resistance is based on P-glycoprotein or tubulin mutations. 11 …”