A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group Phase I and pilot Consortium (ADVL0921)

Yael P. Mosse, Elizabeth Fox, David T. Teachey, Joel M Reid, Stephanie L. Safgren, Hernan Carol, Richard B. Lock, Peter J. Houghton, Malcolm A. Smith, David Hall, Donald A. Barkauskas, Mark Krailo, Stephan D. Voss, Stacey L. Berg, Susan M. Blaney, Brenda J. Weigel

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centro-someandspindlematuration.Alisertib(MLN8237)isapotent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A128), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 mmol/L, exceeding the 1 mmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

Original languageEnglish (US)
Pages (from-to)3229-3238
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number11
DOIs
StatePublished - Jun 1 2019

Fingerprint

Leukemia
Aurora Kinase A
Neoplasms
Pharmacokinetics
Pharmacogenetics
Pediatrics
Heterografts
MLN 8237
Neuroblastoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Sarcoma
DNA Damage
Enzymes
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia : Children's Oncology Group Phase I and pilot Consortium (ADVL0921). / Mosse, Yael P.; Fox, Elizabeth; Teachey, David T.; Reid, Joel M; Safgren, Stephanie L.; Carol, Hernan; Lock, Richard B.; Houghton, Peter J.; Smith, Malcolm A.; Hall, David; Barkauskas, Donald A.; Krailo, Mark; Voss, Stephan D.; Berg, Stacey L.; Blaney, Susan M.; Weigel, Brenda J.

In: Clinical Cancer Research, Vol. 25, No. 11, 01.06.2019, p. 3229-3238.

Research output: Contribution to journalArticle

Mosse, YP, Fox, E, Teachey, DT, Reid, JM, Safgren, SL, Carol, H, Lock, RB, Houghton, PJ, Smith, MA, Hall, D, Barkauskas, DA, Krailo, M, Voss, SD, Berg, SL, Blaney, SM & Weigel, BJ 2019, 'A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group Phase I and pilot Consortium (ADVL0921)', Clinical Cancer Research, vol. 25, no. 11, pp. 3229-3238. https://doi.org/10.1158/1078-0432.CCR-18-2675
Mosse, Yael P. ; Fox, Elizabeth ; Teachey, David T. ; Reid, Joel M ; Safgren, Stephanie L. ; Carol, Hernan ; Lock, Richard B. ; Houghton, Peter J. ; Smith, Malcolm A. ; Hall, David ; Barkauskas, Donald A. ; Krailo, Mark ; Voss, Stephan D. ; Berg, Stacey L. ; Blaney, Susan M. ; Weigel, Brenda J. / A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia : Children's Oncology Group Phase I and pilot Consortium (ADVL0921). In: Clinical Cancer Research. 2019 ; Vol. 25, No. 11. pp. 3229-3238.
@article{23f8031fba9f4c9dade9bfb4a6b15280,
title = "A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group Phase I and pilot Consortium (ADVL0921)",
abstract = "Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centro-someandspindlematuration.Alisertib(MLN8237)isapotent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A128), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 mmol/L, exceeding the 1 mmol/L target trough concentration in 67{\%} of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5{\%}.",
author = "Mosse, {Yael P.} and Elizabeth Fox and Teachey, {David T.} and Reid, {Joel M} and Safgren, {Stephanie L.} and Hernan Carol and Lock, {Richard B.} and Houghton, {Peter J.} and Smith, {Malcolm A.} and David Hall and Barkauskas, {Donald A.} and Mark Krailo and Voss, {Stephan D.} and Berg, {Stacey L.} and Blaney, {Susan M.} and Weigel, {Brenda J.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1158/1078-0432.CCR-18-2675",
language = "English (US)",
volume = "25",
pages = "3229--3238",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia

T2 - Children's Oncology Group Phase I and pilot Consortium (ADVL0921)

AU - Mosse, Yael P.

AU - Fox, Elizabeth

AU - Teachey, David T.

AU - Reid, Joel M

AU - Safgren, Stephanie L.

AU - Carol, Hernan

AU - Lock, Richard B.

AU - Houghton, Peter J.

AU - Smith, Malcolm A.

AU - Hall, David

AU - Barkauskas, Donald A.

AU - Krailo, Mark

AU - Voss, Stephan D.

AU - Berg, Stacey L.

AU - Blaney, Susan M.

AU - Weigel, Brenda J.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centro-someandspindlematuration.Alisertib(MLN8237)isapotent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A128), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 mmol/L, exceeding the 1 mmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

AB - Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centro-someandspindlematuration.Alisertib(MLN8237)isapotent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A128), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 mmol/L, exceeding the 1 mmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

UR - http://www.scopus.com/inward/record.url?scp=85066633090&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066633090&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-2675

DO - 10.1158/1078-0432.CCR-18-2675

M3 - Article

C2 - 30777875

AN - SCOPUS:85066633090

VL - 25

SP - 3229

EP - 3238

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 11

ER -