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Background: Axl, Mer and CSF1 receptor tyrosine kinases play vital roles in promoting the immunosuppressive tumor microenvironment (TME) by affecting myeloid functions (e.g., tumor associated macrophage [TAM], myeloid derived suppression cell [MDSC]) and promoting epithelial-to-mesenchymal transition (EMT). Thus, simultaneous inhibition of Axl, Mer and CSF1R may be an effective strategy for TME modification. Q702 is a novel Axl/Mer/CSF1R kinase inhibitor that affects the immune components (modulating TAM and MDSC populations, inducing CD8+ T cell infiltration and increasing IFN-ɣ in CD8+ T cell) as well as changes in malignant cells such as increasing MHC I on the tumor cells of syngeneic mouse models. These nonclinical results suggest that Q702 monotherapy or Q702 combination with conventional therapies may have considerable potential as a novel treatment strategy for patients with advanced solid tumors. Methods: This is a Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the recommended phase 2 dose (RP2D) in Patients with Advanced Solid Tumors (NCT04648254). Q702 was administered orally for seven days every other week. Peripheral blood samples were obtained on days 1,8,15, and 21. Axl, Mer and CSF1R target engagement is assessed by the quantifications of soluble Axl, Mer and M-CSF in plasma by Luminex xMAP® technology or ELISA. The pharmacodynamic biomarker changes are measured by flow cytometry for immune cell population shifts and IFN-ɣ levels in specific immune cells. Results: PK and PD biomarker samples from 22 patients with various tumor types (e.g. colon, pancreas, esophageal) from the dose escalation phase (4 mg to 240 mg) have been analyzed. Pharmacokinetic studies demonstrated dose proportional increase in Cmax and AUClast of Q702 and its two active metabolites which have activity against Axl and/or CSF1R. Axl and CSF1R target engagement by Q702 treatment is observed in a dose dependent manner. From the 60 mg cohort, target engagement for Axl and CSF1R reached a inhibitory level that was observed in nonclinical models. In the pharmacodynamic biomarker analysis, IFN-ɣ in CD8+ T cells and non-T cell populations is increased. Monocytes and M-MDSC population are decreased in peripheral blood. Conclusion: Up to 240 mg, Q702 has demonstrated the intended pharmacologic activity with acceptable safety profile. In biomarker analysis, immune modulation activity is exerted by Axl/Mer/CSF1R inhibition. Further assessment of pharmacokinetics, pharmacodynamics, safety and antitumor activity will be performed at the expansion phase at the RP2D in patients with selected advanced tumors. Citation Format: Bae Jung Choi, Devalingam Devalingam, Angela Alistar, Anthony El-Khoueiry, Alain Mita, Hwankyu Kang, Jinho Choi, Hyunji Ahn, Jeongjun Kim, Seung-Joo Lee, Yeong-In Yang, Jiye Ahn, Borami Jeon, Jaeseung Kim, Kiyean Nam. Patient pharmacodynamic biomarker and pk evaluation results from an ongoing phase I dose-escalation study of q702, an axl, mer and csf1r kinase inhibitor in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2255.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A medically supervised ketogenic diet (MSKD) defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies. A ketogenic diet combined with triplet chemotherapy (gemcitabine, nab-paclitaxel, cisplatin) was shown to inhibit murine pancreatic KPC tumor growth and to triple the survival benefit of chemotherapy alone. The ketogenic diet combined with triple chemotherapy was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Citation Format: Diana Hanna, Gayle S. Jameson, Drew W. Rasco, Angela Alistar, Richard C. Frank, Anthony B. El-Khoueiry, Julia E. Wiedmeier, Caroline Roberts, Brandon Fell, Sarah Hallberg, Denise Roe, Derek Cridebring, Joshua Rabinowitz, Stephen Thomas Gately, Daniel D. Von Hoff. Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT549.