Background: Cyclin-dependent kinases 4/6 (CDK4/6) promote cell-cycle progression and cancer growth. CDK4/6 inhibitors (CDK4/6i), in combination with hormonal therapy, increase progression-free and overall survival (PFS and OS) in breast cancer but resistance to CDK4/6i is associated with genomic abnormalities including Rb-deficiency. Combined CDK4/6i/HSP90i has been shown to inhibit HIF1-alpha including in tumor cells with Rb-deficiency. Synergy between multiple CDK4/6i’s and HSP90i’s has suggested a drug class effect for combination. In CDK4/6i-treated cells, E3-ubiquitin ligase Smurf2 associates with and targets degradation of HIF1-alpha independent of VHL or hypoxia. BrUOG 387 investigates whether dual targeting of CDK4/6 and HSP90, through HIF1-alpha in patients with ER/PR+ Her2- advanced breast cancer progressing on CDK4/6i and patients with refractory Rb-deficient tumors is safe and reasonably tolerated. Methods: A phase Ib open-label single-arm dose de-escalation study is evaluating safety, tolerability as primary outcomes, recommended doses for cohort expansion and preliminary efficacy of CDK4/6i and HSP90i (IND163592; NCT05655598; the only HSP90i combination study in US). Patients with ER/PR+ Her2- advanced breast cancer progressing on CDK4/6i, and in cohort expansion, patients with Rb-deficient solid tumors (SCLC, soft tissue sarcoma, endometrial and bladder cancer) are included. CDK4/6i (palbociclib at dose previously tolerated up to 125 mg daily PO D1-21 of 28 day cycle) in combination with HSP90i (TAS-116/pimitespib starting at 120 mg 5 days on 2 days off, for D1-28 of cycle) is used in 3+3 dose-de-escalation design. The study includes PK analysis, and PD analysis will include HIF1/2, Smurf2, Rb, HIF targets VEGF, erythropoietin, Glut1, proliferation, cell death, cancer stem cells, NK, T-cells, RNA-seq and angiogenesis in pre- and post-treatment biopsies. Biostatistical design and analysis includes 3 dose levels of TAS-116 + palbociclib (level 0: TAS-116 120 mg, palbociclib 125 mg; level -1: TAS-116 80 mg, palbociclib 125 mg); level -2: TAS-116 40 mg, palbociclib 125 mg). Limiting Toxicities will include grade 4 neutropenia lasting > 7 days, neutropenic fever, grade 4 thrombocytopenia or Grade 3 non-hematologic toxicity not controlled with medical management. The study will enroll a total of approximately 15-27 patients (6-18 patients in dose de-escalation portion of the study and 9 additional patients in the cohort expansion phase). Secondary outcome analyses include response rate (CR, PR) measured by RECIST v.1.1 with exact two-sided 95% confidence intervals. OS, PFS, TTP, and DOR will be summarized using methods of Kaplan and Meier. Clinical trial information: NCT05655598.