Interim results of phase II trial of the cyclin-dependent kinase 4/6 inhibitor PD-0332991 in refractory retinoblastoma protein positive germ cell tumors.

Abstract

4596 Background: Deregulation of the retinoblastoma pathway in germ cell tumors (GCT) has been well documented. We previously reported that PD-0332991, a selective oral inhibitor of cyclin-dependent kinase 4/6, led to prolonged disease control in 3 patients (pts) with unresectable growing teratoma syndrome (NEJM, 2009). For these reasons, we initiated a phase II trial of PD-0332991 in pts with refractory retinoblastoma protein (Rb) positive (+) GCT. Methods: Pts with incurable refractory GCT that expressed Rb by immunohistochemistry were treated with PD-0332991 125 mg orally daily for 21 days followed by a 7 day break (cycle = 28 days). Tumor assessments were performed every 2 cycles. The primary endpoint was 6-month progression-free survival (PFS) rate. Results: As of 1/12/2012, archived tumors from 36 pts with refractory GCT were stained for Rb and 35 had ≥ 1+ staining. 18 of planned 24 pts have been enrolled and treated. Pt characteristics: 17 male, 1 female; median age, 31 years (range, 17-56); median ECOG performance status, 1 (range, 0-1); median number of prior chemotherapy regimens, 2 (range, 1-6); median number prior surgeries, 3 (range, 1-6). Pt pathology: mature teratoma (MT), 7; teratoma with malignant transformation (TMT), 7; mixed GCT, 2; late relapse (LR), 2. 16 pts are evaluable; 2 pts are too early to evaluate. 5 of 16 evaluable pts achieved 6-month PFS (3 MT, 1 TMT, 1 LR). Median PFS was 2 months (range, 0-17). No objective radiological responses were observed; 7 patients had best response of stable disease by RECIST criteria (3 MT, 3 TMT, 1 LR). Grade 3 toxicity included neutropenia (4 pts), thrombocytopenia (3 pts), anemia (1 pt), mucositis (1 pt). No grade 4 toxicity was seen. Analysis of archival tumor for predictive biomarkers including Rb and p16 expression is being performed. Conclusions: PD-0332991 has resulted in 6-month PFS in pts with refractory Rb + GCT, including pts with incurable teratomas.