Management of neuromuscular dose limiting toxicity at the early stage of drug development.

editorial Management of neuromuscular dose limiting toxicity at the early stage of drug development Non-hematological toxicities, including neuromuscular toxicity, occurring during phase I trials may prevent novel compounds from undergoing further drug development. Toxicity may also result in the recommendation of low doses and inappropriate schedules with no antitumor activity, rapidly reducing the interest of clinical investigators, pharmaceutical companies, and/or business investors. In the early stages of drug development a few compounds such as imatinib mesylate [1] and sunitinib malate [2] will provide straightforward evidence of efficacy in well characterized tumor types and good safety profiles, allowing fast-track drug registration. For those drugs, very little support would be sufficient for a convincing and unequivocal demonstration of their potential benefit as anticancer drugs. Many other compounds in development with a narrow spectrum of activity, sporadic activity in a limited number of (often undefined) tumor types, and risky toxicity profile will require deeper clinical tutoring from investigators and sustained support from sponsors to properly balance the benefits/risk and identify the clinical niche of activity. The occurrence of neuromuscular toxicity has been an issue over the last 10 years, compromising the development of several novel anticancer agents. Oxaliplatin-development remains an emblematic story of a drug in which cumulative neuropathy, and limited antitumor activity as a single agent in colorectal cancer, prevented it becoming a reference drug in this disease in combination with 5fluorouracil/folinic acid [3–6]. The increasing prevalence of oxaliplatin/cisplatin-and paclitaxel-based regimens as first/second line chemotherapy in several malignancies further exposed patients to neuromuscular toxicity. Therefore, neuromuscular toxicity became an important issue for the development of several novel anticancer agents with neurological and muscular toxicity [7]. Didemnin B was extensively investigated in the 1990s. In phase I trials, didemnin B was shown to induce severe neuromuscular toxicity that led to the recommendation of safe, although relatively low, doses for phase II studies. Further phase II studies showed sporadic responses but failed to demonstrate clinically relevant evidence of antitumor activity, preventing further development of didemnin B as an anticancer agent. In this issue of Annals of Oncology, Marroun et al. [8] report the results of a phase I clinical trial with aplidine, a novel marine compound derived from didemnin B, infusions given five times a day every four weeks. This trial was one of the five phase I schedules evaluated with aplidine in 215 patients with advanced cancers (Table 1). In several of these …