Phase I study of a third-generation selective estrogen receptor modulator,LY353381.HCl, in metastatic breast cancer

Purpose: We conducted this phase I trial to determine the safety and toxici ty profile of LY353381.HCl-a novel, potent, third-generation selective estr ogen receptor modulator (SERM)-because this benzothiophene derivative demon strated an SERM profile in preclinical studies. Patients and Methods: We studied 32 patients with recurrent or metastatic b reast cancer. Patients were treated in four cohorts with oral daily doses o f 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours a fter the day 57 dose. Eligibility criteria included Eastern Cooperative Onc ology Group performance status of 0 to 2; no significant major organ dysfun ction; and at least 3 weeks elapsed since most recent hormonal therapy, che motherapy, and estrogen replacement therapy. Results: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one ( range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estr ogen receptor (ER) positive and progesterone receptor (PR.) positive, 19 pa tients; ER positive and PR negative, eight patients; ER positive and PR unk nown, two patients; and ER and PR unknown, three patients. Dose-limiting to xicity wets not observed. Treatment was well tolerated with mild to moderat e hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal u ltrasound performed at baseline and after 12 weeks of treatment showed no e ndometrial thickening. Of the 32 patients evaluable for response, six patie nts had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of: LY35338 1.HCl were generally linear with respect to time and studied dose range. Conclusion: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically b eneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are u nder way. (C) 2001 by American Society of Clinical Oncology.