Table 3.
Main recent data on characteristics, pharmacokinetic data, side effects and efficacy of sorafenib and pazopanib in paediatric patients.
| Author | Series, TKI | MTD | PK/PD | Side effects | Efficacy |
|---|---|---|---|---|---|
| Widemann et al.73 |
Phase 1, sorafenib. 60 patients with solid tumours and refractory leukemia Median age 14 years (range, 4–21) |
200 mg/m2 BID for solid tumours and 150 mg/m2 BID for leukemias. | Substantial interpatient variability for day 1 and steady-state PK parameters. Sorafenib exposure was within the ranges reported in adults. Apparent sorafenib clearance (CL/f) increased significantly with patient age. No correlations of pharmacodynamic parameters to drug exposure or response were observed. | Most common diarrhoea, rash, fatigue, increased ALT/AST | SD for ≥4 cycles in 14 patients with solid tumours and achievement of M1 bone marrow in 2 patients with AML and FLT3ITD |
| Glade Bender et al.69 |
Phase 1, pazopanib. 51 patients with soft tissue sarcoma and other refractory solid tumours Median age 13 years (range, 4–24) |
450 mg/m2 for tablet once daily and 160 mg/m2 for suspension once daily. | There was marked interpatient variability in Cmax and AUC0-24 h. Steady-state trough concentrations Css were reached by day 15 and did not seem to be dose dependent. Mean AUC0-24 h and Css were significantly higher for patients with DLT compared with those without DLT (P = 0.039 and P = 0.04, resp.). | DLT are elevation of lipase, amylase, and ALT, proteinuria and hypertension | PR in 2 evaluable patients; SD for ≥6 cycles in 8 patients |
| Kim et al.75 |
Phase 1, sorafenib. 9 patients with type I neurofibromatosis and plexiform neurofibroma Median age 8 years (range, 6–12) |
Could not be determined. | There was little interpatient variability. | At the starting low dose of 115 mg/m2/dose (n = 5), two patients experienced DLT grade 3 pain. At the de-escalated 80 mg/m2/dose (n = 4), approximately 40% of the pediatric solid tumour MTD, two had DLT grade 3 rash and grade 4 mood alteration, exceeding the MTD. Toxicities appeared to correspond with decreases in quality of life. | No tumour shrinkage observed. |
| Navid et al.76 |
Phase 1, bevacizumab, sorafenib, and low-dose cyclophosphamide. 19 patients with various refractory/recurrent solid tumours. Median age 9 years (range, 1.2–24.5) |
90 mg/m2 BID. | Substantial interpatient exposure variability was observed (6- to 8-fold). Median apparent sorafenib clearance (Cl/f) at 90 mg/m2 was similar to that at 110 mg/m2 (44 vs 39 mL/min/m2). The same hold true for the median sorafenib steady-state concentrations at both dose levels. There was no correlation between sorafenib steady-state concentrations and the development of DLT. Sorafenib steady-state concentrations (day 21) were significantly inversely correlated with inhibition of serum VEGFR2 (P = 0.019) and circulating endothelial cells (P = 0.01). | DLTs during course 1 are grade 3 rash (n = 2), increased lipase (n = 1), anorexia (n = 1), and thrombus (n = 1). With an additional 71 courses of therapy, the most common toxicities ≥grade 3 included neutropenia (n = 9), lymphopenia (n = 9), and rashes (n = 4). | PR in 5/17 evaluable patients, SD in 5/17 |
| Karajannis et al.77 |
Phase 2, sorafenib. 11 patients with recurrent or progressive low-grade astrocytoma. Median age 8.8 years (ranges, 3.0–15.1) |
200 mg/m2 BID | Cmax was 5 µg/mL similar to PK data from a pediatric phase 1 trial using 200 mg/m2 BID (see ref. 68). | Grade 4 ALT elevation rash (n = 1), other grade 3 only each in one patient (HFSR, diarrhoea, AST elevation, headache, mucositis). | Median time to progression was 2.8 months (95% CI, 2.1 - 31.0). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. |
| Okada et al.81 |
Compassionate use, sorafenib. 4 patients with relapsed and refractory neuroblastoma Age 4 to 5 years |
250 mg/m2 BID | - | No adverse events were observed. | Transient anti-tumour activity with PD in all 4 patients |
| Kim et al.74 |
Phase 2, sorafenib. 20 patients with refractory solid tumours (10 rhabdomyosarcoma, 10 Wilms tumour) Median age 11 years [range, 5-21] |
200 mg/m2 BID | Mean (± SD) steady state concentration during cycle 1 day 15 in 10 patients was 6.5 ± 3.9 µg/mL. No relationship between steady-state trough concentrations and change in VEGF and VEGFR2 plasma levels | Seven patients demonstrated DLT during the first cycle of therapy: palmar-plantar erythrodysesthesia, pain, maculo-papular rash, anorexia, fatigue, dyspnea, elevation of ALT, hypoalbuminemia. Five patients with DLT 5 received dose reduction which was tolerable. | No objective responses (RECIST) were observed in 10 evaluable patients. |
| Inaba et al.78 |
Phase 1/2, sorafenib with various other drugs (e.g. bevacizumab, cyclophosphamide, clofarabine, cytarabine). 74 patients, 35 patients with refractory/relapsed leukemia (RELHEM protocol) and 39 patients with refractory/relapsed solid tumours (ANGIO1 protocol) Age ≤31 years (RELHEM) and ≤21 years (ANGIO1) |
200 mg/m2 BID (RELHEM) and 90 mg/m2 BID (ANGIO1) | Older age, Bev/Cyclo regimen, and higher creatinine level were significantly associated with decreased apparent clearance (CL/f, P < 0.0001). Concurrent Clo/AraC administration was associated with sorafenib N-oxide CL/f (P = 7e-4). Sorafenib population apparent clearance was 50% higher and the sorafenib glucuronide population apparent clearance was 22% lower in individuals who received OATP1B1 inhibitors. | A shorter time to development of grade 2/3 HFSR was associated with concurrent Clo/AraC administration (P = 0.0015) but not with sequential Clo/AraC administration, compared with Bev/Cyclo, and with higher stead-state concentrations of sorafenib (P = 0.0004). PK simulations showed that once daily and every-other day sorafenib schedules minimize exposure to steady-state concentrations associated with HFSR. | - |
| Federico et al.80 |
Phase 1, sorafenib with bevacizumab and low-dose cyclophosphamide. 24 patients with solid tumours; Median age 14.5 years (range, 1–22) |
90 mg/m2 BID. | Only PK data for bevacizumab are presented. | Two patients experienced a DLT (grade 3 QTc prolongation, HFSR) during course 1. Most common grade 3/4 non-hematological toxicities were hypertension (n = 4), HFSR (n = 3) and elevated lipase (n = 3), and grade 3/4 hematological neutropenia (n = 7) and lymphopenia (n = 17). Seven patients required 50% dose reduction of sorafenib due to HFSR | 21 patients were evaluable for response. PR in 3 patients, SD in 15 patients, PD in 3 patients. |
| Weiss et al.70 |
Phase 2, pazopanib with ifosfamide-doxorubicin. 81 children and adults patients with advanced soft tissue sarcoma. Median age: 19 years (pazopanib group, n = 42) and 25 years (control group, n = 39); 40% <18 years |
350 mg/m² once daily (patients <18 years) or 600 mg once daily (patients ≥18 years) | Doxorubicin PK data was collected during the dose-finding phase of the study in 7 patients receiving chemotherapy and pazopanib. Doxorubicin clearance (L/h/m2) was similar in study patients and historic controls (24.2 and 24.1, respectively) supporting the safety of administration of pazopanib with doxorubicin-containing chemotherapy. | The most common grade 3/4 toxicities were leukopenia (43%), neutropenia (41%), and febrile neutropenia (41%) in the pazopanib group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. | On the basis of an interim analysis the number of patients with a ≥90% pathological response was 58% in the pazopanib group and 22% in the control group (P = 0.081, 83.8% CI, 16.5–55.8%). Adding pazopanib to neoadjuvant chemo-radiotherapy improved the rate of pathological near complete response. |
AML acute myeloid leukemia, AUC area under the curve, BID bis in die, CI confidential intervals, Cmax maximum concentration, Css steady-state concentration, CL/f apparent total clearance of the drug from plasma after oral administration, COG Children’s Oncology Group, CR complete response, CWS Cooperative Weichteilsarkom Studiengruppe, DLT dose-limiting toxicity, EFS event-free survival, EpSSG European pediatric Soft tissue sarcoma Study Group, FLT3ITO FLT3 internal tandem duplication, HFSR hand-foot skin reaction, MTD maximum tolerated dose, OS overall survival, PD pharmacodynamics, PK pharmacokinetics, PR partial response, PD progressive disease, SD stable disease.