Phase I Study of Decitabine and Rapamycin in Relapsed/Refractory Acute Myelogenous Leukemia

Decitabine (5-aza-2'-deoxyctiidine) has demonstrated single agent activity in newly diagnosed acute myelogenous leukemia (AML). Complete response rates are low, however, and this agent has not been extensively studied in settings of relapsed or refractory disease where treatment responses are generally short in the absence of allogeneic stem cell transplantation. Most AML cases have activation of the mTOR pathway as evidenced by expression of phosphorylated p70S6 kinase or phopho-4EBP1. Since inhibitors of the mTOR pathway such as the tuberous sclerosis genes (TSC1 and TSC2) are hypermethylated in some cases of AML and there is evidence that decitabine may inhibit the PI3K/Akt pathway often activated after mTOR inhibition, we conducted a phase I study utilizing decitabine (DAC) followed by the mTOR inhibitor rapamycin in patients with relapsed/refractory AML to assess safety and feasibility.

Patients ≥ 18 years of age with non-M3 AML with relapsed or refractory disease were eligible for this protocol. Patients who had relapsed after allogeneic stem cell transplant were eligible if they did not have active graft vs. host disease >grade 1 of skin. Patients received DAC 20 mg/m2 intravenously daily for 5 days followed by rapamycin from day 6 to 25 at doses of 2mg, 4mg, and 6 mg/day in a 3+3 dose escalation design. Cycles were 28 days in duration, and in the absence of overt progression of disease, patients could receive up to 6 cycles of therapy. A marrow aspirate was performed at day 5 to assess effects of single agent decitabine on mTOR and Akt pathway mediators. Bone marrow responses were assessed after cycles 1 and 3.

Thirteen patients were treated, and 12 are available for safety evaluation. The median age of patients is 64 years (range 46–78). Median marrow blast percentage at enrollment was 35% (range 6–83%). In the 2 mg dose cohort, 1 patient had disease progression before completion of cycle 1 and another patient in the first cohort had a history of prolonged neutropenia at the time of enrollment and experienced reversible grade 3 mucositis, which was deemed a DLT. Three more patients enrolled at this dose, and no further DLTs were observed, allowing dose escalation to the 4 mg and 6 mg cohorts. The MTD has not yet been reached. Reversible grade 2–3 mucositis occurred in 7 patients, but no other recurrent non-hematologic toxicities were seen. On the 2 mg cohort, all patients achieved therapeutic rapamycin levels (5–15 ng/ml) during the first cycle, and in 5/7 patients, the therapeutic level was achieved within 4 days of beginning rapamycin. In the 2 mg cohort, no cumulative increase in rapamycin levels occurred over subsequent cycles (4/7 completed >1 cycle). In the 4 mg cohort, one patient had an elevated level at day 9, and one patient on concomitant voriconazole had supra-therapeutic levels at day 16 and day 23. At the end of one cycle, 4 patients demonstrated disease progression, 5 had stable marrow blasts, and 4 demonstrated a decline in marrow blast percentage. Median survival to date is 6 months (range 1 to 15+ months). Two patients proceeded to allogeneic stem cell transplant, and one patient who relapsed shortly after stem cell transplant survived 4 months and demonstrated stable donor chimerism during that time. As assessed by Western blotting in 9 patients with evaluable samples at baseline, 87% of these cases expressed phospho (p)-4EBP1 at diagnosis, 56% p70S6K, 67% peIF4E, and 44% pAKT. In the 7 patients with Western blot samples evaluable at the end of cycle 1, 3 had decreases in p4EBP1 after the first cycle, and 4 had increased expression. Of the 7 evaluable patients, only 3 expressed baseline p70S6K, and this decreased in 2 and was unchanged in 1 patient.

The combination of decitabine and rapamycin can be safely administered to patients with relapsed/refractory AML. Based on this phase I data, a phase II cohort to define efficacy can be conducted at the 2 mg rapamycin dosing given the therapeutic rapamycin levels demonstrated at this dose. Effects on mTOR mediators and on AKT can be serially assessed and are variable. Correlation with clinical response will require a phase II study. This trial is registered at clinical trials.gov as NCT00861874.

Liesveld:Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: This is a phase 1 study to see if rapamycin is safe in AML.