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Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF–MEK–ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K–AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients. Mol Cancer Ther; 17(10); 2144–55. ©2018 AACR.

Supplementary Figure 1. Ulixertinib potentiates gemcitabine effect and this combination is well tolerated in mice; Supplementary Figure 2. Pharmacologic ERK inhibition increases p-MEK, ERK and AKT; Supplementary Figure 3. Ulixertinib synergizes with HER inhibitors; Supplementary Figure 4. Ulixertinib synergizes with PI3K Inhibitor

TPS4168 Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.

284 Background: Ramucirumab, a humanized monoclonal antibody targeting VEGFR2, is used for treatment of metastatic gastroesophageal adenocarcinoma after disease progression on first-line chemotherapy. Superior survival outcome is expected when combined with paclitaxel. However, many patients suffer from chemotherapy-induced peripheral neuropathy after oxaliplatin-containing first-line treatment and are unable to tolerate paclitaxel. Irinotecan has shown survival benefit as a single agent or in combination with other agents for treating gastroesophageal cancer, but has not been evaluated with ramucirumab. We hypothesized that the combination regimen of irinotecan and ramucirumab administered as second-line treatment for advanced gastroesophageal adenocarcinoma will be better tolerated than ramucirumab and paclitaxel with similar clinical efficacy. Methods: The primary objective of this multi-institutional, single-arm phase 2 clinical trial is to determine the progression-free survival (PFS) after disease progression on up to one line of cytotoxic chemotherapy. Secondary objectives include objective response rate, overall survival, time to progression, and clinical benefit; and to evaluate toxicity and tolerability. Patient-derived xenograft and organoid models generated in a subgroup of patients. Investigation of blood-based angiome profiling and cell-free DNA are planned. Patients received 8 mg/kg ramucirumab with 180 mg/m2 irinotecan IV every 14 days. A sample of 40 achieves 85.7% power at a one-sided significance level of 5% to detect a median PFS of 4 months compared to historic control of 2.5 months assuming the accrual time of 12 months and additional follow-up of 12 months and using a one-sample log rank test. NCT03141034. Results: Forty patients were enrolled from four institutions from December 2017 through May 2021. All patients received platinum-based chemotherapy prior to enrollment, 8 patients had HER2 positive disease, and 6 patients had received an immune checkpoint inhibitor. As of September 2021, median follow up time was 7.7 months. Median PFS was 4.6 months (95% CI 2.7 – 5.4). Of 31 patients evaluable for response, 9 patients (29%) had objective responses (1 complete response, 8 partial responses) and 5 patients (16%) had stable disease greater than 6 months. Diarrhea, nausea, vomiting, and neutropenia were common adverse events; no G3/4 neuropathy was reported. Patient-derived organoid and xenograft models were generated from 9 patient samples, treated in vitro to correlate with each patient’s disease response. Conclusions: Ramucirumab and irinotecan appears to be effective and well-tolerated in patients with previously treated gastroesophageal adenocarcinoma. This regimen is now part of standard guidelines and could be a preferred option for patients after disease progression on first-line chemotherapy. Clinical trial information: NCT03141034.

566 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, liposomal irinotecan and 5-FU/LV is currently an FDA-approved regimen in this setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and ORR 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5FU (2,400mg/m2)/LV (400mg/m2)/liposomal irinotecan (70mg/m2) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N = 10, dose level 1) or 7mcg/kg IV on day 1 weekly (N = 10, dose level 2). The primary endpoint was the occurrence of grade 3 and 4 toxicities. Dose-limiting toxicities (DLT) were assessed during cycle 1. Secondary endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Between 8/29/2019 to 5/6/2021, a total of 20 patients were enrolled in the study. No DLTs or grade 4 adverse events were observed in either paricalcitol cohort. The most common toxicities were gastrointestinal (nausea, diarrhea), fatigue and anemia and were similar in both cohorts. Only one grade 3 adverse event was possibly due to paricalcitol (spinal fracture). 2/10 patients experienced an objective response, one of which was confirmed. Median follow up was 6.1 months. At the time of analysis, one patient remains on liposomal irinotecan and 5-FU/LV and mPFS of all patients is 3.57 months and mOS is 6.15 months. The mPFS is 3.55 months for dose level 1 and 5.34 months for dose level 2 (p = 0.3). The mOS is 6.15 months for dose level 1 and 6.66 months for dose level 2 (p = 0.4). Conclusions: Administration of paricalcitol in combination with liposomal irinotecan and 5-FU/LV is well tolerated in patients with advanced pancreatic cancer, however does not appear to improve response rate or survival outcomes. Correlative analyses are ongoing. Clinical trial information: NCT03883919.