Alistar, Angela

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.

723 Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial OxPhos to generate ROS and activate apoptosis. An MTD of BPM31510-IV in combination with gemcitabine was established at 110mg/kg in a Phase I clinical trial, which determined the dose for the Phase 2 investigation. Methods: Eligible patients (aged ≥ 18 y) with relapsed/refractory PDAC to standard treatment (ST) and met inclusion/exclusion criteria were recruited. Patients received 110mg/kg IV BPM31510 in combination with gemcitabine in a 144-hour infusion. Tumor response was evaluated at week 10 and then every 8 weeks. Study endpoints assessed were Overall Response Rate (ORR), Overall Survival (OS), Progression-Free Survival (PFS), Time to Progression (TTP), Tumor Response using Adaptive Molecular Responses (multi-omic molecular profiling), changes in CA 19-9 levels and patient reported Quality of Life (QOL) using the validated FACT-HEP PRO. A comprehensive multi-omic profiling for identification of biomarkers for patient stratification was explored. Results: Of the 35 patients enrolled to receive therapy, 18 patients met criteria of an adequately treated cohort (ATC- received BPM31510-IV + gemcitabine for 30 days over 2 cycles and had a RECIST 1.1 evaluation) while remaining (n = 17) had progressive disease (PD). Half of the ATC population (n = 9/18, 50%) achieved best ORR of stable disease (SD); 10/18 (55 %) demonstrated SD as best response at target lesions and 8/18 demonstrated SD at end of Cycle 2. The mTTP was 121 days (70 – 147, 95% CI); PFS 118 days (70 – 131, 95% CI) and OS 218 days (131 – 228, 95% CI), respectively. Overall, BPM31510-IV was well tolerated; the most common AE’s were GI related. Conclusions: The efficacy signal observed in this heavily pretreated population in addition to the toxicity profile warrants further clinical investigation of BPM31510-IV + gemcitabine in advanced PDAC. Clinical trial information: NCT02650804 . [Table: see text]