Background: Most patients with teratoma are managed by surgery and no standard medical therapy exists for progressive and/or unresectable teratoma. Teratomas have functional expression of retinoblastoma protein and clinical activity was observed with CDK4/6 inhibition (Vaughn DJ, et al. Cancer. 2015). Here, we report results with the CDK4/6 inhibitor ribociclib (RIBO) for unresectable teratoma. Methods: This multicenter, double-blind study enrolled patients (pts) ≥ 15 years old with unresectable, progressive teratoma without malignant transformation, ECOG PS 0-1, and ≥ 1 line of prior chemotherapy. Pts were randomized (2:1) to receive RIBO (600 mg/day, 3 weeks on/1 week off) or placebo (PBO). Crossover to RIBO was permitted following progressive disease (PD) on PBO. The primary endpoint was progression-free survival (PFS). Secondary endpoints included additional efficacy measures, safety, and tolerability. Results: The trial was closed prematurely in the setting of slow accrual. Ten pts were randomized (8 to RIBO, 2 to PBO). Median age was 33 years (range, 21-53). All pts received study treatment, and both pts in the PBO arm crossed over to RIBO following PD. Median exposure was 385 days for RIBO and 166 days for PBO. The PFS rates at 24 months were 71% and 0% in the RIBO and PBO arms, respectively. All 8 pts in the RIBO arm had stable disease (SD) as best response at first evaluation. In the PBO arm, 1 pt had best response of PD and the other SD with durations of treatment of 78 and 254 days, respectively. After crossover, both pts received RIBO, with a best response of SD, and durations of treatment of 943 and 133 days, respectively; the former entered a rollover protocol and the latter discontinued treatment due to an adverse event. The most common reason for discontinuation in both groups was PD. Grade ≥ 3 adverse events in the RIBO group included neutropenia and non-cardiac chest pain in 2 pts, and headache, decreased appetite, asthenia, fatigue, vomiting, and increased blood creatinine in 1 pt each; all but non-cardiac chest pain were suspected to be drug related. Conclusions: In this rare clinical setting, with a limited small sample size, RIBO prolonged PFS as compared to PBO and no new safety signals emerged. Clinical trial information: NCT02300987