A phase 2 and pharmacological study of sapanisertib in patients with relapsed and/or refractory acute lymphoblastic leukemia

Abstract

BackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…Sapanisertib (MLN0128/TAK-228) is a pan-mTOR inhibitor that has demonstrated variable degrees of efficacy in clinical trials. Sapanisertib only showed limited activity as a single agent in R/R acute lymphoblastic leukemia and advanced pancreatic NETs, as well as in combination with paclitaxel in recurrent or persistent endometrial cancers [226][227][228]. However, it demonstrated some clinical activity in combination with exemestane or fulvestrant in previously treated postmenopausal women in combination with carboplatin and paclitaxel in mTOR pathway-altered advanced solid tumors, as a single agent in advanced solid tumors as well as in combination with cisplatin in nasopharyngeal carcinoma [40,[229][230][231].…”