A Phase 2 Clinical Trial of AP23573, an mTOR Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies.

Background: AP23573 is a novel non-prodrug rapamycin analog that inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient-sensing pathways. In phase I clinical trials, AP23573 completely inhibited in vivo mTOR activity in peripheral blood mononuclear cells (PBMCs) as measured by decreased phosphorylation of the mTOR target protein 4E-BP1. Because the mTOR pathway has been implicated in the pathobiology of hematologic malignancies, this study is undertaken in this patient population to determine the safety and efficacy of AP23573 treatment. In addition, correlative studies in PBMC and bone marrow samples will examine if tumoral mTOR pathway status predicts clinical response.

Methods: Eligible patients with relapsed or refractory hematologic malignancies are being enrolled, stratified into 5 disease specific groups and given AP23573 12.5 mg I.V. daily x 5 days (QDx5) every 2 weeks. Enrollment into each group is proceeding according to a Simon’s two-stage design with a minimum of 21 patients per group and an overall maximum enrollment of 205. Efficacy is being assessed according to standard response criteria at the end of each 4-week cycle (leukemia patients) or every two cycles (lymphoma patients). In addition, pharmacodynamic (PD)/biomarker samples for correlative studies are collected during Cycle 1.

Results: At this time, a total of 51 patients have been enrolled. There are 35 males and 16 females with a median age of 61 years (range 31–83). Best or most recent response to treatment by disease cohort is shown below (5 are too early for response evaluation).

AP23573 is generally well tolerated with the most prevalent mild or moderate treatment-related adverse events (AEs) being nausea, mucositis, hyponatremia, pruritis, rash, and hypokalemia. Serious, possibly treatment-related AEs include diarrhea, mucositis, hypertriglyceridemia, neutropenic sepsis, dyspnea, syncope, pleural effusion and pneumonia. Analysis of correlative PD/biomarker studies is in progress.

Conclusions: QDx5, every other week administration of AP23573 has an acceptable side-effect profile with potential efficacy in some patients with advanced stage hematologic malignancies. Indications of anti-cancer activity have been observed in 4 of the 5 disease cohorts with 19 of the 46 evaluable patients (41%) showing at least stable disease. Patient enrollment, treatment and correlative biomarker analyses continue.