A multicenter phase II study of the cryptophycin analog LY355703 in patients with platinum-resistant ovarian cancer

Abstract

LY355703 is a synthetic product structurally related to the cryptophycin family isolated from the blue-green algae, which exerts a potent destabilization of microtubules during mitosis. This study was performed to determine the activity of LY355703 in patients with platinum-resistant advanced ovarian cancer and to characterize its toxicity profile. Twenty-six patients were enrolled in this study. Resistant disease was defined as a platinum-free interval of <6 months from primary treatment or rechallenge. LY355703 (1.5 mg/m(2)) was administered intravenously on days 1 and 8, every 3 weeks, infused over 2 h. From 24 patients evaluable for response, three partial responses (12.5%) and seven disease stabilizations were registered (29.2%), for an overall clinical benefit of 41.7%. Fourteen patients (58.3%) experienced a progression of the disease during treatment. Among the 25 patients evaluable for toxicity, two episodes of grade 3 anemia (8%); one, grade 3 thrombocytopenia (4%); one, grade 4 elevation of creatinine (4%); and one, grade 3 hyperbilirubinemia (4%) were reported. LY355703 has a modest activity in patients with platinum-resistant advanced ovarian cancer. Nevertheless, the considerable rate of disease stabilization in the absence of serious adverse events in this poor-prognosis study population suggests that this novel cryptophycin may deserve further investigation in this setting.

Microtubule Active Agents: Beyond the Taxane Frontier

“…Cryptophycins are naturally occurring compounds isolated from blue-green algae (61). LY355703 is a synthetic cryptophycin derivative, which has shown some activity in platinum-refractory ovarian cancer (61). Although the activity of these compounds in refractory malignancies may be modest, a future role in a variety of settings is possible.…”

“…Halichondrin B is a large polyether macrolide derived from the marine sponge Halichondria okadaic (60) Eribulin mesylate (E7389) is a synthetic derivative of halichondrin, which is currently in phase II trials in breast, prostate, and NSCLC (60). Cryptophycins are naturally occurring compounds isolated from blue-green algae (61). LY355703 is a synthetic cryptophycin derivative, which has shown some activity in platinum-refractory ovarian cancer (61).…”

Biological targets and mechanisms of action of natural products from marine cyanobacteria

“…57 Cryptophycin-52 (LY355703) reached Phase II clinical trials for non-small cell lung carcinoma (NSCLC) and ovarian cancer previously treated with platinum-based drugs. 58,59 Poor response and unacceptable toxicity was seen in NSCLC patients, while better prognosis was observed in ovarian cancer. This indicated that the dose and schedule of cryptophycin-52 treatment is crucial for activity and in minimizing undesired side effects.…”

“…This indicated that the dose and schedule of cryptophycin-52 treatment is crucial for activity and in minimizing undesired side effects. 58,59 …”

Design and synthesis of a new class of cryptophycins based tubulin inhibitors

“…They had been a subject of extensive research in past, prompting myriad total synthesis [3,4] and structural modifications [5]. The result of these efforts was the development of cryptophycin-52 (C-52), a synthetic analogue of cryptophycins, which reached phase 2 clinical trials [6,7]. Studies continued to develop new cryptophycin analogues through synthetic or biotechnological methods [8,9] and recently SanofieAventis published two patents on cryptophycin antibody-drug conjugates (ADCs) for treatment of lung cancer [10].…”