Background: Acute Lymphoblastic Leukemia (ALL) remains a major cause of cancer-related deaths in children. We identified the AMP activated protein kinase (AMPK) as a potential target for ALL therapy due to its regulatory effects on the unfolded protein response (UPR), leading to increased vulnerability of ALL cells to endoplasmic reticulum (ER) stress inducers. In vitro, metformin leads to ALL cell death via AMPK-mediated inhibition of the UPR. Methods: Metformin was administered twice daily continuously on a 28 day cycle in addition to the Vincristine, Dexamethasone, PEG-Asparaginase and Doxorubicin (VPLD) systemic regimen and CNS-directed therapy. Metformin doses were increased in a standard 3+3 phase I design with three dose levels evaluated, 666, 1,000 and 1,333 mg/m²/day. Pharmacokinetic (PK) and pharmacodynamic evaluation of the AMPK and ER stress/UPR pathways were ascertained on days 1 and 7, and treatment response was assessed on day 29. Results: Twelve patients have been enrolled. DL3 was the maximum administered dose with 2 related DLT’s of diarrhea and acidosis. A single DLT of hypoglycemia and acidosis during an episode of sepsis was observed in DL2. Infectious SAE’s occurred in 7 patients and 2 patients had posterior reversible encephalopathy syndrome. Both died of disease progression within 30 days of coming off study. A single patient had stable disease, 2 had a partial response, and 3 achieved a complete response. PK studies demonstrated levels within the therapeutic range for patients with diabetes, and pharmacodynamics showed induction ER stress induction and inhibition of the UPR. Conclusions: This trial is ongoing.We found induction of ER stress with inhibition of UPR similar to that observed to mediate metformin-induced apopotosis in vitro. The chemotherapeutic backbone was tolerable and yielded responses in a heavily pretreated population. Toxicities attributable to metformin occurred in all dose levels, but DLT’s were only observed in dose levels above the standard dosing for diabetes. Clinical trial information: NCT01324180