Kim, Dae Won

3553 Background: Immuno-STATs are modular fusion proteins designed for the selective activation of tumor antigen specific CD8+ T cells. CUE-102, the second Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the Wilms Tumor 1 (WT1) protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2). In preclinical studies CUE-102 binds, activates and expands WT1-specific CD8+ T cells with the potential to enhance anti-tumor immunity in patients with WT1+ cancers. Here we present the results of the dose-finding portion (Part A) of the CUE-102-01 study. Methods: CUE-102-01 is a 2 part phase 1 study. HLA-A*02:01 positive patients with WT1+ advanced colorectal (CRC), gastric (GA) and gastroesophageal junction (GEJ), pancreatic (PDAC) or ovarian (OvCa) tumors refractory to standard therapies were eligible for participation. WT1 status is determined by IHC via central testing. CUE-102 monotherapy was administered intravenously every three weeks in doses ranging from 1 mg/kg to 8 mg/kg following 3+3 design rules with a Bayesian Logistic Regression Model overlay. Dose levels that exhibit an immune or tumor response may be expanded to further characterize activity and toxicity as allowed by safety rules. Results: Dose escalation was successfully completed in 28 patients with CRC (17), PDAC (6), GA/GEJ (3) and OvCa (2). No DLTs were observed. Three dose levels (2, 4 and 8 mg/kg) exhibited evidence of immune activity and were expanded up to 9 patients each for further evaluation. CUE-102 was well-tolerated with > 96% of treatment-related adverse events (TRAEs) grade ≤2. The most common TRAEs, were fatigue, infusion reactions, nausea and vomiting. There were no cases of CRS Grade ≥ 2. Preliminary PK data demonstrate dose dependent increases in exposure across the dose range assessed. Preliminary analysis of patient samples demonstrates selective expansion of WT1-specific CD8+ T cells. Stable disease of ≥ 6 weeks (range 6-36 weeks), as determined by RECIST 1.1, has been observed in 10 of 23 patients (DCR 43.5%). Conclusions: CUE-102 is a novel T cell engager that demonstrates acceptable tolerability, favorable PK, and supportive preliminary PD readouts. No DLTs or drug-related SAEs have been observed in doses up to 8 mg/kg as of the data cut-off. Adverse events have been manageable and consistent with the CUE-102 mechanism of action and underlying disease. Early signs of disease stabilization and anti-tumor activity in late-stage patients are encouraging. Part B is a dose expansion that further evaluates safety, PK/PD, recommended phase 2 dose (RP2D), antitumor efficacy and is currently enrolling patients. Clinical trial information: NCT05360680 .

2538 Background: Claudin 18.2 (CLDN18.2) is a highly selective cell lineage marker with limited expression in normal gastric tissues and significantly higher expression in primary gastric, pancreatic tumors and their metastases. Anti-CLDN18.2-targeted CAR T cells, termed CT041, were developed to evaluate tumor response and patient-reported outcomes in the gastric and pancreatic cancer. Preliminary results of the trial (NCT03874897) showed an objective response rate (ORR) of about 60% in gastric cancer from a non-Western population. Here we report the results of CT041 for metastatic gastric cancer after ≥ 2 prior lines of systemic therapy or pancreatic cancer ≥ 1 prior line from six centers in the United States. Methods: This single-arm, open-label, phase Ib study (NCT04404595) investigated autologous CT041 CAR T cells in patients with CLDN18.2 positive advanced gastric (including diffuse, signet-ring) or pancreatic adenocarcinoma. All patients completed a conditioning regimen consisting of fludarabine, cyclophosphamide, and nab-paclitaxel prior to CT041 CAR T cells. The primary objective was to assess the safety, efficacy and cytokinetic profile of CT041. Adverse Events (AEs) were graded according to CTCAE 5.0, and tumor response was assessed per RECIST 1.1. Results: As of February 15, 2022, 11 patients (5 gastric and 6 pancreatic) with a median of 2 prior lines of therapy (range 1- 4) were treated with CT041 at a dose between 2.5 and 4 x 108 cells. There were no dose limiting toxicities, treatment-related deaths, severe cytokine release syndrome (CRS), immune effector cell-associated neurologic syndrome (ICANS), or severe gastrointestinal (GI) related AEs. All CRS were grade 1 or 2. Only one patient received tocilizumab. No grade 4 AEs were observed except for hematologic toxicities related to conditioning. The first eight patients were evaluable for response by the date of data cut-off: 1 patient achieved a complete response after two CT041 doses (gastric), 2 had partial response (gastric), 2 had stable disease with tumor shrinkage (pancreatic) and 3 (pancreatic) had progression of disease after an initial biochemical response. ORR was 37.5% (3/8) in all patients including 100% (3/3) in the gastric subgroup (all ≥ 3 prior lines). The last three patients had not reached the time for response assessment. CAR T cell expansion correlated with ctDNA reduction. The median duration of response and the progression-free survival had not been reached. Conclusions: These preliminary results indicate that CT041 therapy was safe and had therapeutic efficacy in patients with advanced GI cancers. In heavily pre-treated gastric cancer, CT041 may have significantly improved anti-tumor activity compared to historical treatment regimens. Clinical trial information: NCT04404595.

e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T > C, gCHEK2 c.1461+1 G > A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease > 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

Abstract Lessons Learned The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy. Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily. The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma. Background The RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC. Methods This was a phase I study with a 3+3 design in patients with treatment-naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy. Results A total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose-limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment-related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression-free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated-ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated-ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells. Conclusion Trametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.

Abstract Background: A wide range of cancers, including pancreatic cancer, display altered expression of amino acid transporter LAT-1. LAT-1 overexpression has been shown to be an important prognostic factor and predicts chemo resistance in pancreatic cancer (Kaira K, 2012; Altan B, 2018). Radiolabeled amino acids for PET imaging, including 3-18F-l-α-methyl-tyrosine ([18F] FAMT), have successfully leveraged cancer’s aberrant LAT1 expression and amino acid uptake for decades. SM-88 is a denatured D/L racemic form of α-methyl-tyrosine designed for selective uptake and disruption of protein synthesis in cancer cells, as well as disruption of catecholamine production via inhibition of tyrosine hydroxylase. Catecholamines have been reported to potentially have a role in driving pancreatic cancer progression and changes in the tumor immune status (Renz B, Cancer Cell 2018; Calvani M, Oncotarget 2014). Initial clinical and preclinical results with SM-88 indicate that this agent could pose a novel approach in the treatment of pancreatic cancer. Methods and Results: Initial xenograft models of human gastrointestinal cancers using monotherapy SM-88 showed a >50% decrease in tumor growth at three weeks of treatment (p<0.05). Ongoing preclinical experiments are testing the full pharmacodynamic effects of SM-88 on pancreatic cancer cells, as well as potential effects on the tumor microenvironment due to catecholamine interruption. In results from the ongoing phase 2 trial of SM-88 in heavily pretreated metastatic pancreatic cancer patients, SM-88 has shown monotherapy antitumor activity based on RECIST 1.1 criteria. Additionally, 16/24 patients demonstrated a reduction in circulating tumor cells, with the median nadir decline of 63%. LAT1 has been reported to be important in EMT transition and mesenchymal cell survival (Holldorsson S, Cancer letters 2017); examination of the impact of SM-88 on this important emerging biomarker is ongoing. Conclusion: Altered amino acid (LAT1) metabolism has been shown to be a negative prognosticator in pancreatic cancer outcomes and progression. Targeting LAT1 and amino acid pathways has been identified as a therapeutic approach in multiple cancers (Fuchs BC, Semin Ca Biol 2005). Initial and ongoing studies of SM-88 may clarify the potential utility of this approach in the treatment of pancreatic cancer. Citation Format: Martin Fernandez-Zapico, Dae Won Kim, Philip Philip, Alexander Vandell, Jonathan Eckard, Ron Korn, Giuseppe Del Priore, Diane Simeone. Therapeutic potential of targeting amino acid metabolism in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B15.