Background: The efficacy, safety, and feasibility of TMZ with VP (TE) have not been evaluated in pediatric patients (pts) and those of VNR with CPA (VC) have not been confirmed in Japanese pts. Methods: This multicenter, crossover randomized phase II study included children and young adults with recurrent or refractory solid cancer who received disease-specific standard chemotherapies. The study design has been reported in ASCO2010 (TPS328). In group A, VNR (25 mg/m²) and CPA (25 mg/m²) (VC) were administered intravenously on days 1, 8, and 15, and orally on days 1–28, every 28 days, then switched to TMZ (150 mg/m²) and VP (50 mg/m²) (TE) which were administered orally on days 1 - 5 and 1 - 12, every 28 days if they became progressive or intolerant. In group B, TE was given first, then switched to VC. Response was evaluated according to RECIST 1.1. Toxicity and complaints were assessed by using CTCAE v4.0. and face scales, respectively. Results: In group A, 34 pts (median age 15 years, range 3–29) included 8 neuroblastoma (NB), 4 rhabdomyosarcoma (RMS), 7 Ewing sarcoma family tumor (ES), 2 osteosarcoma (OS), 4 CNS tumors (BT), and 9 others. In group B, 33 pts (median age 14 years, range 3–30) included 7 NB, 5 RMS, 6 ES, 8 OS, 3 BT and 4 others. Treatment was well tolerated. No unexpected toxicities were observed. Febrile neutropenia occurred only in VC. In the first regimen, the response rates were 2.9% in VC with 1 PR and 18.2% in TE with 2 CR and 4 PR. The disease control rates were 29.4% in VC with 1 PR, 9 SD and 30.3% in TE with 2 CR, 4 PR and 4 SD. VC and TE improved pain, dyspnea, agitation, fatigue, and anorexia in 40%, 12%, 34%, 43% and 40%, and 38%, 23%, 33%, 28%, 33%, respectively. The 1-year overall survival for groups A and B were 35% (95% CI 21%-51%) and 45% (95% CI 31%-64%). The median survival days for A and B were 271.5 days (95% CI 164-411) and 354 days (95% CI 174-449). The 1-year last progression free survival for A and B were 24% (95% CI 11%-39%) and 21% (95% CI 9%-36%). Conclusions: In recurrent or refractory pediatric solid cancer with poor prognosis, VC, TE and those sequential administration are effective and alleviate tumor associated symptoms without severe toxicity. Clinical trial information: UMIN000003002.