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

Place, Andrew E.; Pikman, Yana; Stevenson, Kristen E.; Harris, Marian H.; Pauly, Melinda; Sulis, Maria Luisa; Hijiya, Nobuko; Gore, Lia; Cooper, Todd M.; Loh, Mignon L.; Roti, Giovanni; Neuberg, Donna; Hunt, Sarah K.; Orloff-Parry, Sarah; Stegmaier, Kimberly; Sallan, Stephen E.; Silverman, Lewis B.

doi:10.1002/pbc.27062

Cited by 50 publications

(36 citation statements)

References 42 publications

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“…However, combination of MTIs with alternative salvage chemotherapy backbones that evoke fewer overlapping metabolic toxicities may increase successful delivery of this therapeutic strategy and reinduction of leukaemia remission. For example, in patients with first ALL relapse, preliminary data from a phase 1 trial combining the oral MTI everolimus with a 4‐drug ALL induction has reported CR2 rates approaching 90% with less severe mucosal and gastrointestinal toxicity than was observed in our trial (Place et al , ).…”

Section: Discussionmentioning

confidence: 50%

“…The study is based on the hypothesis that the combination of temsirolimus, etoposide and cyclophosphamide will result in less additive toxicity, such as hyperglycaemia, hypertriglyceridaemia and/or poor wound healing. In addition, oral formulations of MTIs, such as everolimus (NCT01523977) are being evaluated (Place et al , ). Furthermore, targeting of more proximal or multiple proteins in the PI3K/mTOR pathway with alternative tyrosine kinase inhibitors may result in greater sustained signalling inhibition and, possibly, to less dependence on conventional cytotoxic chemotherapy to achieve cure (Reismuller et al , ; Tasian et al , ).…”

Section: Discussionmentioning

confidence: 99%

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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)

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

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)

et al. 2017

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“…Fouladi et al reported what to our knowledge is the only previous single‐agent everolimus trial for pediatric patients with solid tumors, in which everolimus administered daily demonstrated tolerability and mTOR pathway signaling inhibition in PBMCs . Sporadic case reports have described everolimus use for patients with pediatric central nervous system tumors, acute lymphoblastic leukemia, kaposiform hemangioendothelioma, and vestibular schwannomas …”

Section: Discussionmentioning

confidence: 99%

“…23 Sporadic case reports have described everolimus use for patients with pediatric central nervous system tumors, acute lymphoblastic leukemia, kaposiform hemangioendothelioma, and vestibular schwannomas. [26][27][28][29] The COG performed a randomized study of temsirolimus as an mTOR inhibitor or bevacizumab combined with cyclophosphamide and vinorelbine (ARST0921; ClinicalTrials.gov identifier NCT01222715), 15 whereas the ADVL0918 trial (ClinicalTrials.gov identifier NCT01141244) 16 added temsirolimus to a regimen of irinotecan and temozolomide. Despite widespread interest in bevacizumab for adult cancers, to the best of our knowledge its development and indications for pediatric oncology remain uncertain, reflecting its somewhat disappointing responses in children.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors

Santana

Sahr

Tatevossian

et al. 2020

Cancer

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Background The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression‐free survival and is well tolerated in adults with solid tumors. Methods In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus‐mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. Results Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose‐limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24‐1.05 years). The mTOR biomarker phospho‐4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho‐AKT levels also decreased from those at baseline. Conclusions The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4‐week cycle for children with recurrent solid tumors.

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“…In a phase I study enrolling children and adolescents with ALL experiencing a first marrow relapse, RAD001 was tested with the natural alkaloid Vincristine and the GC Prednisone or Doxorubicin in subjects with bone marrow relapse occurring >18 months after first CR. With the four‐drug reinduction chemotherapy, the study reported acceptable tolerance and low end‐reinduction minimal residual disease (MRD) level …”

Section: Targeted Therapymentioning

confidence: 99%

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

Simioni

Bergamini

Ferioli

et al. 2019

Hematological Oncology

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Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematologic malignancies, and it is normally characterized by an aberrant proliferation of immature lymphoid cells. Moreover, dysregulation of multiple signaling pathways that normally regulate cellular transcription, growth, translation, and proliferation is frequently encountered in this malignancy. ALL is the most frequent tumor in childhood, and adult ALL patients still correlate with poor survival. This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies. Bi‐specific T‐cell Engagers (BiTE) antibodies, the chimeric antigen receptor (CAR)‐T cells, or CRISPR‐Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]–associated nuclease 9) represent other new innovative approaches for this disease. Target and tailored therapy could make the difference in previously untreatable cases, i.e., precision and personalized medicine. Clinical trials will help to select the most efficient novel therapies in ALL management and to integrate them with existing treatments to achieve durable cures.

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

Cited by 50 publications

References 42 publications

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)

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)

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

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