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 centrosome and spindle maturation. Alisertib (MLN8237) is a potent 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 (UGT1A1*28), 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 μmol/L, exceeding the 1 μmol/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%.

Conflict of interest statement

Conflict of Interest Disclosure Statement: The authors declare no potential conflict of interest.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Sagittal and axial SPECT/CT images from 123I-MIBG examination performed at baseline, reporting periods (RP) 12 and 24; 123I-MIBG anterior projection planar images at baseline, RP10 and RP 20. Each reporting period is one cycle. Arrows indicate MIBG-avid neuroblastoma in the L3 vertebral body and proximal right femur. The other areas of MIBG positivity on planar imagines include physiologic uptake in liver, salivary glands, renal collecting system, GI tract, and excretion in bladder. Uptake projecting of the thorax at RP 10 and 10 is residual tracer at the port injection site.

Figure 2.

Percentage of huCD45 cells in peripheral blood over time (A), and event-free survival curves (B) for ALL-8 engrafted NOD/SCID mice treated with alisertib at 10.4 mg/kg twice daily for 7 days (Schedule A, red), or twice daily for 5 days repeated for 3 weeks (Schedule B, blue) in relation to vehicle-treated controls (dotted line).

Figure 3.

Percentage of huCD45+ cells in peripheral blood over time (A), and event-free survival curves (B) for ALL-19 engrafted NOD/SCID mice treated with alisertib at 10.4 mg/kg twice daily for 7 days (Schedule A, red), or twice daily for 5 days repeated for 3 weeks (Schedule B, blue) in relation to vehicle-treated controls (dotted line).