Preclinical efficacy evaluations of XK-469: dose schedule, route and cross-resistance behavior in tumor bearing mice.

Abstract

XK-469 is advancing to Phase I clinical trials. Preclinical studies were carried out to assist in clinical applications. DOSE-SCHEDULE ROUTE TESTING: Single dose i.v. treatment with XK-469 produced lethality (LD20 to LD100) above 142 mg/kg. Optimum treatment required total dosages of 350 to 600 mg/kg. Furthermore, high individual i.v. dosages (100 to 142 mg/kg) were poorly tolerated, producing substantial weight loss (8 to 18% of body weight), poor appearance, and slow recovery (8 to 12 days). A 1-hour infusion of dosages more than 140 mg/kg, or BID injections 6 hrs apart, did not reduce lethality. However, lower individual dosages of 40 to 50 mg/kg/injection i.v. were well tolerated and could be given daily to reach an optimum total dose with minimal toxicities. Likewise, 75 mg/kg/injection i.v. could be used every other day to reach optimal treatment. The necropsy profiles of deaths from toxic dosages were essentially identical regardless of schedule (deaths 4 to 7 days post treatment). The profiles were: paralytic ileus or gastroparesis; GI epithelial damage; and marrow toxicity. Interestingly, the key lethal events were rapidly reversible and simple to overcome with lower dosages given daily or every other day. Based on these results, the high dose, Q21 day schedule should be avoided in clinical applications. Instead, a split dose regimen is recommended (e.g., daily, every other day, or twice weekly). XK-469 was also well tolerated by the oral route, requiring 35% higher dosages p.o. to reach the same efficacy and toxicity as produced i.v.. CROSS-RESISTANCE STUDIES: XK-469 resistance was produced by optimum treatments of i.v. implanted L1210 leukemia over seven passage generations. This leukemia subline (L1210/XK469) had reduced sensitivity to VP-16 (with a 4.0 log kill in i.v. implanted L1210/XK469 compared to an 8.0 log kill against i.v. implanted L1210/0). It also had a reduction in the sensitivity to 5-FU (with a 2.0 log kill in the implanted L1210/XK469 compared to a 4.0 log kill against i.v. implanted L1210/0). Other agents were approximately as active against the resistant tumor, including: Ara-C, Gemzar, Cytoxan, BCNU, DTIC, and CisDDPT. No case of collateral sensitivity was observed; i.e., no agent was markedly more active against the resistant subline L1210/XK-469 than against the parent tumor in mice.