Safety and Efficacy Of BEZ235, a Dual PI3-Kinase /mTOR Inhibitor, In Adult Patients With Relapsed Or Refractory Acute Leukemia: Results Of a Phase I Study

Activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling plays a role in cell proliferation, survival, and drug resistance in solid tumors and hematologic malignancies including chronic myeloid leukemia (CML), B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-ALL and acute myeloid leukemia (AML). The investigational compound BEZ235 is a potent dual pan-class I PI3K and mTOR complex C1 and C2 inhibitor and an attractive agent for relapsed or refractory leukemias.

Primary objectives of this phase I study were determination of the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in pts. with advanced acute leukemia. Secondary objectives included assessment of pharmacokinetics (PK), pharmakodynamic (PD) parameters and preliminary evidence of anti-leukemic activity.

Inclusion criteria included age > 18years, relapsed or refractory AML, ALL or CML-BP considered ineligible for intensive or established treatment. Pts. with a fasting blood glucose >160mg/dl or an HbA1c >8% were excluded. The starting dose of BEZ235 was 400 mg twice daily (BID), administered orally during 28d cycles. Dose escalation was based on a “rolling-six”design, followed by an expansion phase at the RP2D. PK analyses were performed on days 1 and 15 by HPLC and fluorescence detection, PD analysis included assessment of phosphorylation of AKT, S6 and 4EBP1 by Western blotting (WB) and flow cytometry. The presence of PI3KCA, AKT or PTEN mutations was evaluated by direct sequencing of exons with known mutation hotspots. All pts. gave informed written consent, the study was approved by the Ethics Committee of the University of Frankfurt.

22 pts. (13m, 9f), median age 62.5 years (range 29-82), were enrolled. Types of leukemia were AML (n=11), BCP-ALL (n=9), T-ALL (n=1) and CML in myeloid blast phase (CML-BP, n=1). 6 pts. were in first and 9 pts. in second or later relapse, 7 refractory or in refractory relapse, 7 pts. had extramedullary leukemia, 14 pts. previously received an allogeneic stem cell transplant (SCT). Six pts. were evaluated at the starting dose of BEZ235 (400 mg BID). No DLTs were observed, but BEZ235-related AEs (stomatitis and GI toxicity grades 1-3) necessitated treatment interruptions in 3 of 6 pts. 400 mg BID was considered not tolerable for prolonged administration and 16 pts. were subsequently treated at dose level -1 (300 mg BID). The most frequent non-hematologic AEs were gastrointestinal primarily of grades 1 and 2 with diarrhea (n=20), nausea/vomiting (n=18/6), stomatitis/mucositis (n=20), decreased appetite (n=14), fatigue (n=10) and hyperglycemia (n=21). Grade 3/4 AEs included sepsis (n=6), pneumonia (n=4), diarrhea (n=3), hyperglycemia (n=2), mucositis and fatigue (2 each). No patient started at dose level -1 was dose-reduced and none discontinued BEZ235 because of toxicity, 300 mg BID was selected as the RP2D. Clinical responses were observed in 4 of 22 pts. (3/10 ALL): one pat. with pro-B ALL achieved a complete hematologic and molecular remission with full donor chimerism, ongoing after 11 cycles of BEZ235. Hematologic improvement was observed in two pts. with BCP-ALL (1 Ph+, 1 Ph neg) and stable disease of 4 mos. duration in an AML patient. Nineteen of 22 pts. discontinued because of disease progression, median time to progression was 28 days (5d-112d). PK analysis revealed substantial interpatient variability of peak and trough levels at steady state, with no clear dose-dependency. All three responders in whom PK data are already available had low steady state trough levels below 100 ng/ml. No activating mutations of PIK3CA, AKT or PTEN were identified in any of the 22 pts. Phospho-flow and WB analysis provided no evidence of PI3K pathway activation, even in responding pts.

In conclusion, the RP2D for BEZ235 was determined to be 300 mg BID, without formal definition of DLTs and an MTD. Single-agent anti-leukemic efficacy was most pronounced in ALL, with an overall response rate of 30% and a sustained molecular remission in one patient. Results of PK analysis and assessment of PD markers associated with PI3K signaling did not correlate with response. The PI3K pathway appears to be a “driver pathway” in only a small minority of pts. with ALL or AML, but more comprehensive genomic analysis may identify a subset of patients likely to benefit from treatment with dual PI3K-mTOR inhibitors.