On March 5, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), reported that the latest results from three preclinical studies of the company’s novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin, FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and EED inhibitor APG-5918, have been selected for presentations at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024) (Press release, Ascentage Pharma, MAR 5, 2024, View Source;ascentage-pharma-to-present-three-preclinical-studies-at-2024-american-association-of-cancer-research-annual-meeting-302080735.html [SID1234640814]). These abstracts are now available on the AACR (Free AACR Whitepaper)’s official website.

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The AACR (Free AACR Whitepaper) annual meeting is one of the world’s largest and longest-standing scientific gatherings in the field of cancer research. Covering some of the most cutting-edge advances in all the areas of oncology research and innovation, the annual event attracts tremendous interest from the global cancer research community. This year’s AACR (Free AACR Whitepaper) annual meeting will be held from April 5-10 2024, in San Diego, California, USA.

These three preclinical abstracts from Ascentage Pharma include:

Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms

Abstract#: 1971
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 2
Session Time: Monday April 8, 2024, 9:00 AM – 12:30 PM, Pacific Time
Results from this preclinical study show that in SDH-deficient cancer cells, olverembatinib has superior efficacy compared to other approved tyrosine kinase inhibitors. Mechanistically, olverembatinib can exert its antitumor effects in SDH-deficient neoplasms by modulating multiple signal pathways involved in cell hypoxia, angiogenesis, proliferation, and survival. These results provide a scientific rationale for the future development of olverembatinib in SHD-deficient cancers with an urgent unmet medical need.

Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa)

Abstract#: 3223
Session Category: Experimental and Molecular Therapeutics
Session Title: Epigenetic Targets
Session Time: Monday April 8, 2024, 1:30 PM – 5:00 PM, Pacific Time
Results from this preclinical study show that in preclinical models of PCa, targeting both EED and MDM2 can synergistically enhance antitumor activities by modulating pathways related to DNA methylation, cell cycle, and apoptosis. These findings provide a scientific rationale for the future clinical development of APG-5918 in combination with alrizomadlin for the treatment of PCa.

APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC)

Abstract#: 4569
Session Category: Experimental and Molecular Therapeutics
Session Title: Drug Combinations
Session Time: Tuesday April 9, 2024, 9:00 AM – 12:30 PM, Pacific Time
Results from this preclinical study show that the novel FAK inhibitor APG-2449 can reduce the metastasis of tumor cells and achieve synergistic antitumor effects with PLD in xenograft mouse models of ovarian cancer. These results support the future clinical development of APG-2449 in combination with PLD for the treatment of ovarian cancer.

On March 5, 2024 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), a clinical-stage immunotherapeutics company focused on oncology, reported it has submitted an amendment to GOBLET to initiate a new Phase 1/2 cohort evaluating pelareorep in combination with modified FOLFIRINOX (mFOLFIRINOX) with and without atezolizumab (Tecentriq) in patients with newly diagnosed metastatic pancreatic ductal adenocarcinoma (PDAC) (Press release, Oncolytics Biotech, MAR 5, 2024, https://oncolyticsbiotech.com/press_releases/oncolytics-biotech-files-amendment-to-initiate-new-pancreatic-cancer-goblet-cohort-supported-by-pancan/ [SID1234640813]). This amendment will be reviewed by the Paul Ehrlich Institute (PEI; Germany’s regulatory body) for approval before patient enrollment can begin. The cohort, the fifth of the GOBLET gastrointestinal cancer study, is being supported by the US$5 million Therapeutic Accelerator Award from the Pancreatic Cancer Action Network (PanCAN), an innovative program established to accelerate the development of new treatments for pancreatic cancer. Evaluation of this novel treatment approach will complement Oncolytics’ ongoing development of pelareorep, atezolizumab, gemcitabine, and nab-paclitaxel in PDAC, which is expected to advance to a registrational study later this year.

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"We are enthusiastic to have the support of PanCAN to expand the evaluation of pelareorep in pancreatic cancer and explore mFOLFIRINOX as another combination that could improve outcomes for patients. Notably, this patient population is newly diagnosed patients who are receiving first-line treatment. Chemotherapies, including either mFOLFIRINOX or gemcitabine and nab-paclitaxel, are the backbone treatment regimens of pancreatic cancer therapy1. Evaluating pelareorep in combination with these widely used regimens is an important step in our broad clinical development program," said Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics. "Last fall, we reported a 62% objective response rate for the GOBLET PDAC cohort studying pelareorep in combination with the checkpoint inhibitor atezolizumab in addition to gemcitabine and nab-paclitaxel (link to the PR, link to the poster). This response is about three times that of historical controls and forms the basis of the registrational program, expected to begin this year. Therefore, we are enthusiastic about this new mFOLFIRINOX pancreatic cancer cohort and look forward to enrolling the first patient as soon as possible."

Dirk Arnold, M.D., Ph.D., Director of Asklepios Tumorzentrum Hamburg, and primary investigator of the GOBLET trial, commented, "One of the reasons for pancreatic cancer’s poor survival rate is that it effectively evades the immune system and can induce an immunosuppressive tumor microenvironment (TME)2. Pelareorep is an attractive combination partner because of its ability to address both issues by activating the innate and adaptive immune systems while driving the remodeling of the tumor microenvironment. Positive results from the Phase 2 study evaluating pelareorep combined with atezolizumab and chemotherapy reported last fall support the potential use of these agents together. I am hopeful that the combination of pelareorep and mFOLFIRINOX (with or without atezolizumab) will yield positive response data and advance the development of new treatment options for patients with pancreatic cancer."

"This study is designed to evaluate whether pelareorep can enhance outcomes in patients receiving mFOLFIRINOX, one of the most commonly used metastatic pancreatic cancer treatments. Combining pelareorep with mFOLFIRINOX represents an expansion of our existing pancreatic cancer program and maximizes the potential of pelareorep-based combination therapies to benefit pancreatic cancer patients," commented Thomas Heineman, M.D., Ph.D., Chief Medical Officer at Oncolytics. "The mFOLFIRINOX cohort utilizes a screened selection design within a Simon two-stage approach that will also allow evaluation of the contribution of atezolizumab to the pelareorep/mFOLFIRINOX combination. In addition, this study is designed to provide valuable translational assessments, such as the expansion of tumor-infiltrating lymphocytes (TILs) in the blood, which has been associated with tumor responses. We look forward to building on PanCAN’s strong relationships with the pancreatic cancer community and furthering our collaboration with AIO-Studien-gGmbH (AIO) on the GOBLET study."

References

Botta G, et al. SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer. JCI Insight. 2021;6(18):e150453. View Source
Yoon JH, et al. Immunotherapy for pancreatic cancer. World J Clin Cases. 2021 May 6;9(13):2969-2982. doi: 10.12998/wjcc.v9.i13.2969. PMID: 33969083; PMCID: PMC8080736.
About GOBLET cohort 5

The mFOLFIRINOX cohort of the Phase 1/2 GOBLET study is designed to evaluate newly diagnosed PDAC patients treated with pelareorep + mFOLFIRINOX with or without atezolizumab. There will be a three-patient safety run-in to evaluate the tolerability of each treatment arm – pelareorep + mFOLFIRINOX + atezolizumab and pelareorep + mFOLFIRINOX. A total of fifteen patients may be randomized to each arm in Stage one of the Simon-two stage design. The co-primary endpoints of the cohort are objective response rate and safety. The success criteria for Stage 1 is defined as six or more responses in one or both of the treatment groups. Successful completion of Stage one will support expansion into Stage two, which can include one or both treatment regimens, and would enroll 17 additional evaluable patients. A total of 13 or more responses from Stage 1 and 2 combined are required to achieve the success criteria. Translational data will also be generated.

About GOBLET

The GOBLET (Gastrointestinal tumOrs exploring the treatment comBinations with the oncolytic reovirus peLarEorep and anTi-PD-L1) study is a phase 1/2 multiple indication study in advanced or metastatic gastrointestinal tumors. The study is being conducted at 12 centers in Germany and is being managed by AIO-Studien-gGmbH. The co-primary endpoints of the study are objective response rate (ORR) and/or disease control rate assessed at week 16 and safety. Key secondary and exploratory endpoints include additional efficacy assessments and evaluation of potential biomarkers (T cell clonality and CEACAM6). The study employs a Simon two-stage design with Stage 1 comprising five treatment groups:

Pelareorep in combination with atezolizumab, gemcitabine, and nab-paclitaxel in 1st line advanced/metastatic pancreatic cancer patients;
Pelareorep in combination with atezolizumab in 1st line MSI (microsatellite instability)-high metastatic colorectal cancer patients;
Pelareorep in combination with atezolizumab and TAS-102 in 3rd line metastatic colorectal cancer patients
Pelareorep in combination with atezolizumab in 2nd line advanced and unresectable anal cancer patients; and
Pelareorep in combination with mFOLFIRINOX with and without atezolizumab in newly diagnosed metastatic PDAC patients.
Any cohort meeting pre-specified efficacy criteria in Stage 1 may be advanced to Stage 2 and enroll additional patients.

On March 5, 2024 iTeos Therapeutics, Inc. (Nasdaq: ITOS), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of immuno-oncology therapeutics for patients, reported a poster presentation of preclinical data on EOS-984, a first-in-class small molecule antagonist targeting equilibrative nucleoside transporter 1 (ENT1), at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held April 5-10, 2024 in San Diego, California (Press release, iTeos Therapeutics, MAR 5, 2024, View Source [SID1234640812]).

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Poster Presentation Details

Abstract 734, "Inhibition of equilibrative nucleoside transporter 1 relieves intracellular adenosine-mediated immune suppression"

Session: Experimental and Molecular Therapeutics: Tumor Microenvironment
Date and Time: Sunday, April 7, 2024, 1:30 PM – 5:00 p.m. PT
Location: Poster Section 29

On March 5, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients, reported that preclinical data will be presented in five posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 to be held on April 5-10 in San Diego, California (Press release, Verastem, MAR 5, 2024, View Source [SID1234640811]). The presentations will highlight anti-tumor efficacy of GFH375 (VS-7375), a potent and selective orally bioavailable KRAS G12D (ON/OFF) inhibitor, and will also show data of RAF/MEK clamp plus FAK inhibition in pancreatic ductal adenocarcinoma (PDAC) models supporting the ongoing RAMP 205 trial. Additional presentations will support the use of avutometinib and FAK inhibitor combination in cutaneous melanoma models to overcome resistance to BRAF and MEK inhibitors, resistance to immunotherapy, and brain metastasis.

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"For the first time, GenFleet and Verastem will present potency, selectivity, anti-tumor efficacy, and bioavailability data on GFH375 (VS-7375), a potential best-in-class orally active KRAS G12D (ON/OFF) inhibitor. We look forward to an IND submission by GenFleet in China in H1 2024," said Jonathan Pachter, Ph.D., chief scientific officer of Verastem Oncology. "Additionally, preclinical data will be presented demonstrating that the combination of avutometinib and a FAK inhibitor with standard-of-care chemotherapy can induce tumor regressions in pancreatic cancer models, providing the scientific rationale for the ongoing RAMP 205 Phase 1/2 study evaluating the combination of avutometinib, defactinib, gemcitabine, and nab-paclitaxel in first-line metastatic pancreatic ductal adenocarcinoma. Collectively, these data from the five posters build on our desire to advance treatments that target the RAS/MAPK pathway and provide new options for patients with RAS/MAPK driven cancers."

Key Data Presentations:

Title: GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy
Abstract #: 3318
Date/Time: Monday, April 8, 2024, 1:30 – 5:00 p.m. PDT
Sponsor: GenFleet Therapeutics

Title: Combined inhibition of RAF, MEK and FAK increases PDAC responsiveness to cytotoxic- and immune therapy
Abstract #: 2899
Date/Time: Monday, April 8, 2024, 1:30 – 5:00 p.m. PDT
Institution: Siteman Cancer Center, Department of Medicine, Washington University School of Medicine

Title: Combined Inhibition of RAF, MEK, and FAK attenuates melanoma brain metastases and prolongs survival in preclinical models
Abstract #: 4127
Date/Time: Tuesday, April 9, 2024, 9:00 a.m. – 12:30 p.m. PDT
Institution: Huntsman Cancer Institute, Department of Surgery, University of Utah School of Medicine

Title: A novel combination therapy targeting RAF, MEK, and FAK to overcome skin cutaneous melanoma treatment resistance
Abstract #: 4745
Date/Time: Tuesday, April 9, 2024, 9:00 a.m. – 12:30 p.m. PDT
Institution: Moores Cancer Center-Department of Pharmacology, University of California San Diego

Title: The SOS1 Inhibitor MRTX0902 Demonstrates Activity Across Cancer Models with Mutations in Proximal Components of the RAS-MAPK pathway
Abstract #: 7268
Date/Time: Wednesday, April 10, 2024, 9:00 a.m. – 12:30 p.m. PDT
Sponsor: Mirati Therapeutics, Inc.
The accepted abstracts are available on the AACR (Free AACR Whitepaper) conference website: View Source

About GFH375 (VS-7375)

GFH375 (VS-7375) is a potential best-in-class, potent and selective oral KRAS G12D (ON/OFF) inhibitor, identified as the lead program from the Verastem Oncology discovery and development collaboration with GenFleet Therapeutics. GenFleet plans to submit an IND in China for GFH375 (VS-7375) in the first half of 2024, and upon approval GenFleet is expected to initiate a Phase 1 trial in China in the second half of 2024. The collaboration includes three discovery programs, the first being the KRAS G12D inhibitor, and will provide Verastem Oncology with exclusive options to obtain licenses to each of the three compounds in the collaboration after successful completion of pre-determined milestones in Phase 1 trials. The licenses would give Verastem Oncology development and commercialization rights outside of the GenFleet markets of mainland China, Hong Kong, Macau, and Taiwan.

About the Avutometinib and Defactinib Combination

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, a selective FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS/MAPK driven tumors as part of its (Raf And Mek Program). RAMP 301 (NCT06072781) is a Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC. RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization, expansion phase, and low-dose evaluation cohorts.

Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 (NCT05074810) and RAMP 204 (NCT05375994) trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, the Company is conducting RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.

On March 5, 2024 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing multimodal biological immunotherapies to help patients fight cancer, reported the Company will present a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 5-10, 2024, in San Diego, CA (Press release, Candel Therapeutics, MAR 5, 2024, View Source [SID1234640810]). The presentation will describe the second candidate from the enLIGHTEN Discovery Platform, a first-in-class multimodal immunotherapy candidate for induction of tertiary lymphoid structures as a novel therapeutic strategy for solid tumors. This abstract presentation at AACR (Free AACR Whitepaper) accelerates the milestone associated with the unveiling of the second enLIGHTEN program, which was originally planned for the third quarter of 2024.

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Presentation details are as follows:

Presentation Title: A first-in-class multimodal immunotherapy for induction of tertiary lymphoid structures as a novel therapeutic strategy for solid tumors
Presenter: Anne R. Diers, PhD, Senior Director, Research, Candel Therapeutics
Abstract Number: LB263
Session Date and Time: Tuesday, April 9, 2024; 9:00 AM – 12:30 PM PT
Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 3
Location: San Diego Convention Center
All regular abstracts are available for viewing via AACR (Free AACR Whitepaper)’s online itinerary planner, located here.

About the enLIGHTEN Discovery Platform

The enLIGHTEN Discovery Platform is a systematic, iterative herpes simplex virus (HSV)-based discovery platform leveraging human biology and advanced analytics to create new multimodal biological immunotherapies for solid tumors. The enLIGHTEN Discovery Platform has been designed to deconvolute the characteristics of the tumor microenvironment related to clinical outcomes. These discoveries are rapidly translated into optimized multi-gene payloads of tumor modulators that can be delivered to the tumor microenvironment for specific indications, disease stages, and rationally designed therapeutic combinations. In 2022, the Company announced a discovery partnership with the University of Pennsylvania Center for Cellular Immunotherapies to create new viral immunotherapies that could enhance the efficacy of chimeric antigen receptor T cell (CAR-T) therapy in solid tumors. During the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2023 Annual Meeting and the 2023 International Oncolytic Virus Conference, Candel presented encouraging data on the first candidate from this platform, Alpha 201-macro-1, which was designed to interfere with the CD47/SIRP1a pathway, in mouse models of breast cancer and lung cancer.