A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114)

Abstract

Summary The phosphatidylinositol 3-kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re-induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m2 weekly × three doses. Subsequent patient cohorts received temsirolimus 7.5 mg/m2 weekly × three doses (DL0) or, secondary to toxicity, 7.5 mg/m2 weekly × two doses (DL-1). Sixteen patients were enrolled, 15 were evaluable for toxicity. Dose-limiting toxicity (DLT) occurred at all three dose levels and included hypertriglyceridaemia, mucositis, ulceration, hypertension with reversible posterior leucoencephalopathy, elevated gamma-glutamyltransferase or alkaline phosphatase and sepsis. The addition of temsirolimus to UKALL R3 re-induction therapy resulted in excessive toxicity and was not tolerable in children with relapsed ALL. However, this regimen induced remission in seven of fifteen patients. Three patients had minimal residual disease levels <0.01%. Inhibition of PI3K signalling was detected in patients treated at all dose levels of temsirolimus, but inhibition at an early time point did not appear to correlate with clinical responses at the end of re-induction therapy.

Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia

“…Rheingold et al. recently reported results from COG ADVL1114, a phase I study of the mTOR inhibitor temsirolimus in combination with the UK ALL R3 re‐induction backbone (a four‐drug regimen containing mitoxantrone and dexamethasone) in patients with second or greater relapse . Unfortunately, that combination resulted in excessive toxicity, including hypertriglyceridemia, hypertension, elevated gamma‐glutamyltransferase, mucositis, and infection (including grade 5 sepsis), at all DLs of temsirolimus tested, precluding further development.…”

“…23 End reinduction MRD levels have been shown to strongly predict long-term outcome in patients with first relapse B-ALL, with levels <0.1% significantly associated with a more favorable prognosis. 21,24,28 On COG AALL0433, a phase 3 trial for patients with first B-ALL 22,36 Unfortunately, that combination resulted in excessive toxicity, including hypertriglyceridemia, hypertension, elevated gammaglutamyltransferase, mucositis, and infection (including grade 5 sepsis), at all DLs of temsirolimus tested, precluding further development. Notably, the COG ADVL1114 study enrolled more heavily pretreated patients than DFCI 11-237 did and temsirolimus was combined with the more intensive UK ALL R3 chemotherapy backbone, which may have contributed to the higher rates of toxicity observed on that trial.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Interestingly, patients that had lower baseline 4EBP phosphorylation at Thr37/46 were associated with a better response to the therapy [300]. A phase I trial of temsirolimus and intensive re-induction chemotherapy in children with relapsed ALL also induced remission in about half of the patients, despite resulting in excessive toxicity at the dosages used [301]. In a study that used temsirolimus as maintenance therapy in castration-resistant prostate cancer after docetaxel induction, the regimen proved safe, and delayed the time to treatment failure to 6 months [274].…”

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

“…A phase 1 trial of the mTOR inhibitor, Temsirolimus, with intensive re-induction for relapsed ALL (COG study ADVL1114) induced remission in 50% of the patients. However, it resulted in excessive toxicity and was therefore not tolerable in these heavily pretreated children [89]. A potential strategy to overcome this drawback is to identify mTOR-responsive leukemias at diagnosis and incorporate lower doses of an mTOR inhibitor staggered to the chemotherapy backbone.…”