Abstract Background: NCI-MATCH (EAY 131) assigns patients (pts) with refractory solid tumors, lymphomas, or multiple myeloma to targeted therapies based on somatic alterations identified in fresh tumor biopsies. Arm Z1B examined the cyclin dependent kinase 4 and 6 inhibitor palbociclib in pts whose tumors contained CCND1, 2 or 3 amplification. Methods: Pts with tumors containing CCND amplification and retinoblastoma (Rb) expression by immunohistochemistry were eligible. Pts with breast cancer were excluded. Pts received palbociclib 125mg daily by mouth on days 1-21 of a 28 day cycle until progression, death or intolerable toxicity. Restaging was performed every 2 cycles. The primary endpoint was objective response rate; secondary endpoints were 6-month progression free survival (PFS6) and identification of predictive biomarkers. Results: 40 pts were enrolled from 8/9/16 through 12/5/17 (39 with CCND1 amplification and 1 with CCND3 amplification); 4 pts were ineligible and/or did not receive protocol treatment which leaves 36 evaluable patients. 23 different tumor histologies were represented; 70% of pts had ≥3 prior therapies; 42% had >4 prior therapies. There were no responders. Stable disease (SD) was observed in 14 (38.9%) pts; 4 pts (squamous cell lung carcinoma, squamous cell esophageal carcinoma, dedifferentiated adenoid cystic carcinoma after pleomorphic adenoma of parotid and laryngeal squamous cell carcinoma) had SD ≥ 6 cycles (prolonged SD); these pts had 1 (n=2), 2 (n=1) and 4 (n=1) prior therapies. Median PFS was 1.8 months; estimated 6-month PFS was 13% (90% CI: 5-29%). The most common reason for discontinuation was progression (19, 53%). Toxicities included anemia (67%), leukopenia (47%), neutropenia (44%) and fatigue (28%). The most common grade 3 or 4 toxicity was neutropenia (30.6%). One grade 3 small bowel obstruction and one grade 3 urinary tract infection also occurred; both were possibly related to palbociclib. 8 deaths occurred, 1 prior to initiation of study treatment and 7 during cycle 1. All were unlikely or unrelated to palbociclib except 1 case of Death NOS (possibly related). In exploratory analyses, 2 of 3 pts with tumors containing a NOTCH1 mutation had prolonged SD. Conclusions: In a cohort of heavily pretreated pts with non-breast solid tumors selected for CCND1, 2 or 3 amplification and treated with palbociclib, prolonged stable disease was noted in 13% of patients. CCND1 or 3 amplification may not predict response to palbociclib in this cohort. No new palbociclib-related safety signals were observed. Acknowledgement: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: CA180820, CA180794, CA180858, CA180867, CA180870, CA189809, CA180888. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Citation Format: Amy S. Clark, Fangxin Hong, Richard S. Finn, Angela M. DeMichele, Edith P. Mitchell, James Zweibel, Fernanda I. Arnaldez, Lisa M. McShane, Shuli Li, Robert J. Gray, Larry V. Rubenstein, David Patton, P Mickey Williams, Stanley R. Hamilton, Mehmet S. Copur, Sameer S. Kasbari, Ravneet Thind, Barbara A. Conley, Peter J. O'Dwyer, Lyndsay N. Harris, Carlos L. Arteaga, Alice P. Chen, Keith T. Flaherty. Molecular analysis for therapy choice (NCI-MATCH, EAY131) arm Z1B: Phase II trial of palbociclib for CCND1, 2 or 3 amplified tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-010.