Background: TPST-1120 is a first-in-class oral therapy that inhibits PPARα, a transcription factor that regulates fatty acid oxidation (FAO). TPST-1120 has diverse mechanisms of anti-tumor activity in preclinical studies, including inhibiting tumor proliferation, increasing the anti-angiogenic factor thrombospondin 1, and reducing T cell exhaustion. Methods: Subjects with advanced solid tumor malignancies received escalating doses of TPST-1120 as a single agent or in combination with nivolumab 480 mg IV every 4 weeks (combination cohort limited to RCC, cholangiocarcinoma [CCA] and HCC). Study objectives included evaluation of safety, pharmacokinetics, MTD, RP2D and anti-tumor activity as monotherapy and in combination with nivolumab. AEs were assessed per CTCAE v5 and efficacy per RECIST v1.1 Results: As of 14-Jan-2022, 35 subjects have been dosed (20 with TPST-1120 monotherapy at doses from 100 mg to 600 mg PO BID and 15 in combination with nivolumab at doses from 200 mg to 600 mg PO BID). Median prior lines of systemic therapy were 3 (2-11) in monotherapy and 2 (2-6) in combination cohorts. An MTD was not reached in monotherapy or combination, and the TPST-1120 RP2D was 600 mg PO BID for both cohorts. For TPST-1120 monotherapy, the most common treatment related AEs (TRAEs) were nausea (20%), fatigue (15%), and diarrhea (10%), all Grade 1-2. One monotherapy subject (5%) experienced a Grade 3 TRAE (hypertension). In the combination cohort the most common TRAEs related to either drug were fatigue (40%), diarrhea (27%) and nausea (20%), all Grade 1-2. Three combination subjects (19%) experienced Grade 3 TRAEs (one each arthralgia, hepatic enzyme increased, muscle spasms). A best response of stable disease was observed in 53% (10/19) of subjects treated with monotherapy. In combination, the ORR was 23% (3/13, all PRs) across all dose levels and 38% (3/8) at TPST-1120 dose levels ≥400 mg BID. These responses included 2 subjects with late-line RCC (2/2 RCC subjects enrolled, both with progression on prior anti-PD1 therapy) and one subject with heavily pre-treated CCA. At data cut off, 2 of 3 responding patients (CCA and one RCC) remained in PR and on study at 8.4 and 14 mo, respectively. Conclusions: TPST-1120 is a novel therapy designed to inhibit tumor proliferation and angiogenesis and stimulate anti-cancer immunity through inhibition of PPARα, a key regulator of FAO. The drug is well tolerated as a single agent and in combination with nivolumab. Promising objective responses have been observed in combination with nivolumab in subjects previously refractory to anti-PD-1 therapy, including 2/2 responders in late-line RCC, and a subject with heavily pretreated CCA, a tumor type generally not responsive to anti-PD-1 alone. Notably, all responders were treated at the two highest doses of TPST-1120 (ORR 38%). Updated study results including exploratory biomarkers will be presented. Clinical trial information: NCT03829436.