Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

Targeting the molecular target of rapamycin (mTOR)

“…The appropriateness of S6K1 activity as a biomarker of mTOR activity has been established in preclinical studies, and the validity of S6K1 activity as a surrogate marker has been assessed in PBMCs in a phase 2 trial of CCI-779 in RCC, in which S6K1 inhibition correlated strongly with TTP [103]. The results from this study, as well as those from clinical trials of RAD001 and AP23573, have resulted in more concerted studies of these potential biomarkers in disease-directed trials [93][94][95]99,100,102].…”

“…Rapid and protracted inhibition of mTOR activity, with at least 80% decrements in phosphorylated 4E-BP1, was demonstrated during treatment in PBMCs at dose levels associated with minimal toxicity [99,100]. In a preliminary report of the daily 5-day schedule involving 22 patients who were evaluable for antitumor response, regressions have been noted in patients with RCC, imatinibrefractory gastrointestinal stromal tumors, and metastatic uterine sarcoma, lymphoma, and non-small cell lung cancer, and 9 other patients had stable disease as their best response (2 to >6 months) [99] (Rowinsky EK, unpublished data). Disease-directed studies in both solid and hematologic malignancies known to have molecular aberrations that activate mTOR are planned.…”

“…Toxicologic, pharmacokinetic, and pharmacodynamic endpoints were evaluated in patients with advanced solid malignancies in phase 1 studies of AP23573 on the following schedules: (1) 30-minute intravenous infusion daily for 5 days every other week and (2) 30-minute intravenous infusion weekly [99,100]. In both studies, severe, albeit brief, mucositis precluded dose escalation; the rates of severe mucositis were unacceptably high at dosages of 28 mg/day and 100 mg/dat on the daily 5-day and weekly schedules.…”

The role of mTOR inhibitors for treatment of sarcomas

“…For the IV formulation, two schedules of administration were explored: weekly and daily times five every other week [36,37]. Toxicities included rash, mucositis, hypercholesterolemia, fatigue, and thrombocytopenia.…”

Mammalian target of rapamycin inhibitors in sarcomas

“…Rapamycin's anti-tumor activity is thought to occur through cell cycle arrest in the G1 phase. Presently there are three mTOR inhibitors in clinical development: AP23573 [11], RAD001 (everolimus) [12], and CCI-779 (temsirolimus) [13]. All three rapamycin analogs mediate their activity by binding to the intracellular protein FKBP12 and subsequently inhibiting the protein kinase of mTOR.…”