On June 19, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported that China’s National Medical Products Administration (NMPA) has approved the clinical trial application for GFH375 (VS-7375) in an open-label, multi-center phase I/II study targeting advanced solid tumor patients with KRAS G12D mutation (Press release, GenFleet Therapeutics, JUN 19, 2024, View Source [SID1234644443]). G12D mutation is the most prevalent KRAS mutation detected in human cancers, and no G12D-targeted therapies have been approved yet.

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GFH375 is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. According to the latest preclinical findings posted at 2024 AACR (Free AACR Whitepaper) annual meeting, GFH375 demonstrated preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models; moreover, GFH375 holds the potential for treating G12D-mutant cancers with brain metastases.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three oncology programs. The first program selected is GFH375, which represents a significant milestone as the GenFleet’s first product to achieve overseas out-licensing at preclinical stage and the IND approval in China, underscoring the company’s expertise in the development of RAS-targeted therapies.

The study (GFH375X1101) will be conducted at ~40 hospitals, including the prominent Shanghai Chest Hospital. In phase I, the study aims to evaluate the safety/tolerability and preliminary efficacy of GFH375 in advanced G12D-mutant solid tumor patients. Additionally, the phase I trial will determine the recommended phase II dose (RP2D). Progressing into Phase II, the study will further assess the efficacy of GFH375 for patients of advanced solid tumors including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) – three cancer types with highest prevalence of G12D mutation; the study will also investigate the underlying mechanisms of patients’ response and resistance to the treatment.

"I am excited that the clinical trial application for GFH375 has been approved. The therapeutic landscape for G12D-mutant cancers remains challenging with limited treatment options, highlighting the significant unmet medical needs in this population. The G12D mutation is one of the most prevalent KRAS mutations and the development of G12D-targeted therapies has garnered significant attention recently. We eagerly await favorable safety and efficacy outcome for GFH375 in the upcoming trial, with the hope of introducing a novel life-saving treatment for patients." stated Dr. Shun Lu, professor of Dept. of Medical Oncology, Shanghai Chest Hospital.

"We are delighted to enter in a clinical trial to assess the clinical benefits of our G12D targeted program in monotherapy setting and explore the possibilities of synergistic effects that may arise from potential combination regimen in future. GenFleet’s expertise in developing RAS-targeted therapies has been exemplified by the successful development of fulzerasib (GFH925, a KRAS G12C inhibitor) and the NDA acceptance of its monotherapy for NSCLC in China. This allows GenFleet to be well positioned to advance our second RAS pathway inhibitor GFH375 into the clinical trial, as well as other RAS-inhibiting therapies in our pipeline." stated Yu Wang, Ph.D/M.D., Chief Medical Official of GenFleet.

References:

1. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma, NPJ Precision Oncology, Feb. 2024

2. Next batter up! Targeting cancers with KRAS G12D mutations, Trends in Cancer (Cell Press), Nov. 2023

3. Pan-KRAS inhibitor disables oncogenic signaling and tumor growth, Nature, May 2023

About KRAS G12D mutation and GFH375

RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans. Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitors hold promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alterations are the most frequently occurring somatic change in PDAC patients (about 40%) who are reported to have an overall 5-year survival rate lower than 10%.

GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated that the inhibition of GFH375 on tumor growth is enhanced along with the increase in dosage and duration of treatment; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS pathway-driven cancers. The risk-sharing structure of the collaboration provides Verastem Oncology a milestone-based option to license up to three compounds. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain rights inside of the Chinese mainland, Hong Kong, Macau, and Taiwan.

On June 19, 2024 Medivir AB (NASDAQ: MVIR) (STOCKHOLM: MVIR), a pharmaceutical company focused on developing innovative treatments for cancer in areas of high unmet medical need, reported that it has selected a global CRO partner for the planned phase 2b study evaluating fostroxacitabine bralpamide (fostrox) + Lenvima vs Lenvima alone in second line HCC (Press release, Medivir, JUN 19, 2024, View Source;lenvima-and-initiates-study-feasibility-302176636.html [SID1234644444]).

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In the next phase of development, Medivir is planning for a global, randomized phase 2b study aligned with its recent supportive Type C interaction with the FDA. The objective is to evaluate the combination of fostrox + Lenvima in second line advanced HCC with the aim of becoming the first, approved treatment alternative after current first line treatment.

The study is planned to enroll patients broadly in the US, EU and Asia, building on countries and sites participating in currently ongoing phase 1b/2a, which will ensure that recruitment requirements for a potential accelerated or conditional approval are fulfilled. A key next step is to initiate study feasibility to identify optimal sites and investigators to enable study start in early 2025. Already now, we have received high level of interest from experts in HCC regarding potential participation in the study.

"With the selection of a CRO partner, following our recent Type C meeting with the FDA, we are confidently moving forward with the enhanced phase 2b study design. It has been a thorough process to select the best possible partner to ensure optimal execution of the upcoming study across all geographies. The selected CRO partner has a global footprint, with a strong track record in performing oncology studies in general and HCC studies in particular. We are now moving forward with next steps, which include performing the feasibility, operational and regulatory study preparations as well as finalisation of the study protocol to open an IND in the USA.", says Malene Jensen, VP Clinical Development at Medivir.

About fostrox

Fostrox is a liver-targeted inhibitor of DNA replication that delivers the cell-killing compound selectively to the tumor while minimizing harmful effects on normal livercells. This is achieved by coupling a chemotherapy (troxacitabine) with a prodrug tail. This design enables fostrox to be administered orally and travel directly to the liver where the active substance is released locally in the liver. With this unique mechanism, fostrox has the potential to become the first liver-targeted, orally administered drug that can help patients with various types of liver cancer. A phase 1b monotherapy study with fostrox has been completed and a phase 1b/2a combination study in advanced HCC is ongoing where it has shown encouraging anti-cancer efficacy with a good safety and tolerability profile.

About primary liver cancer

Primary liver cancer is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common cancer that arises in the liver and it is the fastest growing cancer in the USA. Although existing therapies for advanced HCC can extend the lives of patients, treatment benefits are insufficient and death rates remain high. The unmet medical need is especially high in second line where there are no approved treatments post first line standard of care. There are approximately 660,000 patients diagnosed with primary liver cancer per year globally and current five-year survival is less than 20 percent1). HCC is a heterogeneous disease with diverse etiologies, and lacks defining mutations observed in many other cancers. This has contributed to the lack of success of molecularly targeted agents in HCC. The limited overall benefit, taken together with the poor overall prognosis for patients with intermediate and advanced HCC, results in a large unmet medical need.

On June 19, 2024 Researchers at the National Institutes of Health (NIH) reported a non-chemotherapy treatment regimen that is achieving full remissions for some people with aggressive B-cell lymphoma that has come back or is no longer responding to standard treatments (Press release, US NCI, JUN 19, 2024, View Source [SID1234644445]). The five-drug combination targets multiple molecular pathways that diffuse large B-cell lymphoma (DLBCL) tumors use to survive.

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In a clinical trial at NIH’s National Cancer Institute, researchers tested the combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (called ViPOR) in 50 patients with DLBCL, the most common type of lymphoma. The treatment shrank tumors substantially in 26 of 48 (54%) evaluable patients, with 18 (38%) of those patients’ tumors disappearing entirely, known as a complete response. At two years, 36% of all patients were alive and 34% were free of disease. These benefits were seen mainly in people with two specific subtypes of DLBCL.

The findings were published June 20, 2024, in the New England Journal of Medicine.

"Many of these patients who stopped responding to standard treatments would have otherwise died within a year, and now we have a good proportion who are still alive past two years, and some past four years," said Christopher J. Melani, M.D., of NCI’s Center for Cancer Research, who co-led the study. "It’s gratifying to see these long-term remissions and potential cures in patients."

Previous studies have identified various genetic pathways involved in the development and survival of the different molecular subtypes of DLBCL, such as activated B cell–like (ABC) DLBCL and germinal center B cell–like (GCB) DLBCL. Targeted drugs have shown effectiveness in blocking some of these pathways, but individual drugs rarely produced lasting responses in patients because the tumors may be resistant due to alternative survival pathways. Dr. Melani and his colleagues hypothesized that combining targeted drugs that block multiple survival pathways would lead to more durable responses.

Based on laboratory studies in which they analyzed which targeted drugs could best be combined to kill DLBCL cells in a synergistic manner, the researchers designed the five-drug regimen to test in human trials. To allow for the targeted drugs to work synergistically in patients, the researchers gave the drugs simultaneously in two-week cycles. To limit the accumulation of side effects, they scheduled a weeklong break between each cycle.

"DLBCL is one of the most genetically heterogeneous forms of cancer, and as a result we don’t yet have the ability to identify exactly which combination of drugs would be most effective for any given patient," Dr. Melani said. "By putting five drugs together, we believe that there will be some drug combination—either two, three, or more drugs—that will be particularly effective against that patient’s tumor."

In the phase 1b/2 trial, 50 people with DLBCL that had relapsed or stopped responding to treatment were given six cycles of the ViPOR regimen. Responses to ViPOR varied by DLBCL subtype, with complete responses concentrated in two subtypes, including in 8 of 13 (62%) people with non-GCB DLBCL and 8 of 15 (53%) people with a form of GCB DLBCL known as high-grade B-cell lymphoma "double hit."

At two years, people with non-GCB DLBCL and double-hit GCB DLBCL had higher rates of both progression-free and overall survival than other people in the study. Non-GCB DLBCL and double-hit GCB DLBCL are highly reliant on the survival mechanisms targeted by ViPOR, so it makes sense that they responded particularly well to the combination therapy. ViPOR also helped 6 of 20 (30%) patients whose lymphomas had not responded to or had come back after CAR T-cell therapy—the current standard of care for people with relapsed DLBCL—achieve lasting remissions.

Side effects of the five-drug regimen were generally mild to moderate when compared with those of standard treatments and improved during the treatment breaks. Only five patients had to stop treatment early for various reasons, including side effects. Given these relatively mild to moderate side effects, additional drugs could potentially be added to ViPOR to improve its efficacy, the researchers said. The team is also studying the ViPOR regimen in people with other types of lymphoma that are resistant to previous therapies.

The researchers have developed a larger phase 2 study, which will be conducted at multiple centers, to confirm the activity of ViPOR in people with non-GCB DLBCL and double-hit GCB DLBCL. More work is needed to develop therapies for GCB DLBCL subtypes that aren’t as responsive to ViPOR.

NCI’s Center for Cancer Research investigators Wyndham H. Wilson, M.D., Ph.D., Mark Roschewski, M.D., and Louis M. Staudt, M.D., Ph.D., co-led the study with Dr. Melani. Investigators from NIH’s National Center for Advancing Translational Sciences and other institutions contributed to the study.

On June 19, 2024 TAE Life Sciences reported a significant presence at the 20th International Congress on Neutron Capture Therapy (ICNCT), taking place in Krakow, Poland, from June 24 to 28, 2024 (Press release, TAE Life Sciences, JUN 19, 2024, View Source [SID1234644438]). This biennial event is the premier conference for advancements in the field of boron neutron capture therapy (NCT) and serves as a vital platform for researchers, clinicians, and industry professionals to share their latest findings and technological advancements in all aspects of BNCT.

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The 20th ICNCT conference will feature presentations, workshops, and discussions on various aspects of neutron capture therapy, including basic research, clinical applications, technological advances, materials and compounds, and case studies.

TAE Life Sciences’ Contributions at ICNCT 2024:

Plenary Presentation by CEO Rob Hill:
When: Wednesday, June 26 at 11:00 AM
Topic: State of TAE Life Sciences and BNCT Future Directions
Oral Presentations:
Tuesday, June 25 at 3:00 PM: Warren Kilby will present "Pharmacokinetic modeling to extrapolate from mouse to human biodistribution data for new tissues and compounds."
Wednesday, June 26 at 3:50 PM: Chad Lee will present "Neutron Beam System for Accelerator BNCT in China: Status and Performance."
Poster Presentations:
Tuesday, June 25 from 1:30 to 3:00 PM:
Michael Torgov will present in the Chemistry of NCT Carriers poster session about "Antibody boron conjugates with a payload comprised of carborane-modified poly-L-lysine is capable of delivering boron to EGFR-expressing tumor cells."
Karen Morrison will participate in the Biology poster session about "First reported immunohistochemical studies and q-PCR expression of LAT-1 transporter in the hamster cheek pouch oral cancer model."
Thursday, June 27 from 12:00 – 1:30 PM
Chad Lee will present in the Engineering and Physics poster session about "Optical monitoring of the position and size of direct current particle beams."
Warren Kilby will present in the Medical Physics poster session about "The expected dose of radiation therapists at a high-throughput BNCT Center."
TAE Life Sciences is proud to contribute to the advancement of neutron capture therapy and to be part of this esteemed conference. We look forward to engaging with other professionals in the field, sharing our research and innovations, and exploring collaborative opportunities to further enhance the
effectiveness and application of NCT in the field of oncology.

If you’re interested in learning more about our presence at ICNCT or are planning to attend and would like to meet with the team, please email Anna Theriault at [email protected].

On June 19, 2024 Theralase Technologies Inc. ("Theralase" or the "Company") (TSXV: TLT) (OTCQB: TLTFF), a clinical stage pharmaceutical company dedicated to the research and development of light and/or radiation activated small molecules and their formulations, intended for the safe and effective destruction of various cancers, bacteria and viruses, reported that it’s lead drug formulation, Rutherrin, has demonstrated an ability to provide a complete response in a Non-Small Cell Lung Cancer ("NSCLC") animal model (Press release, Theralase, JUN 19, 2024, View Source [SID1234644441]).

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Theralase recently press released its latest research, using a well-established Lewis Lung Cancer ("LLC1") orthotopic model, representing NSCLC. In this model, mouse lungs are implanted with lung cancer cells, inducing these mice to develop very aggressive, fast growing and metastatic lung tumors.

The mice were treated with x-ray radiation only as a control and x-ray activated Rutherrin as the active arm. The mice treated with x-ray activated Rutherrin demonstrated up to a 4-fold reduced tumor progression, based on Computerized Tomography ("CT") scan assessment of tumor volumes.

These results demonstrate that animals treated with a combination of Rutherrin and radiation therapy showed an increase in median survival from 26 to 35 days, versus radiation only. In scientific publications, mouse survival of 9 days has been equated to the equivalent of 1 year survival in humans, but more importantly, is that one animal treated with the x-ray activated Rutherrin (which had a positive lung tumor verified by CT scan) demonstrated a complete response and is now considered cancer free.

Dr. Arkady Mandel, M.D., Ph.D., D.Sc., Chief Scientific Officer of Theralase stated, "The latest preclinical research demonstrates the ability of x-ray activated Rutherrin to eradicate lung cancer in an animal model. This is initial research and through optimization, Theralase hopes to achieve a complete response in a much greater percentage of animals, but this initial data is extremely encouraging. As a result of this latest success, Theralase has committed to bringing this technology to market through the systematic research and development of this cutting-edge clinical therapy to safely and effectively destroy various cancers in patients. As a direct result, our list of cancer targets has increased from bladder cancer, which in the late stage of clinical development, to encompass brain cancer, lung cancer and various blood-based cancers, such as: leukemia, lymphoma and multiple myeloma."

Roger DuMoulin-White, B.E.Sc., P.Eng., Pro.Dir., President and Chief Executive Officer of Theralase stated, "This latest research symbolizes the significant progress Theralase has made over the last few years in the research and development of world-class systemic and targeted therapies for the treatment of various hard-to- treat cancers, such as: bladder cancer, brain and lung cancer. Pending sufficient capitalization and completion of a Good Laboratory Practice ("GLP") toxicology analysis for Rutherrin, Theralase plans to commence clinical studies for brain cancer, lung cancer and various blood-based cancers. If proven safe and effective in humans, Theralase hopes to change the paradigm of how patients diagnosed with cancer are treated in the future."

About Lung Cancer:

Lung cancer is the leading cause of cancer death worldwide. Most patients die of progressive metastatic disease despite aggressive local and systemic therapies. The survival rate for lung cancer depends on the type, stage and age of the patient, with the overall 5-year survival rate for all types of lung cancer about 26.6%. Lung cancer is histologically classified into two main types: Small Cell Lung Cancer ("SCLC"), which accounts for approximately 15% of the patients diagnosed with lung cancer and Non-Small Cell Lung Cancer ("NSCLC"), which accounts for approximately 85%.