On June 20, 2024 Allogene Therapeutics Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products, and Foresight Diagnostics (Foresight), a leader in ultra-sensitive liquid biopsy-based minimal residual disease (MRD) detection, reported the initiation of the pivotal Phase 2 ALPHA3 trial evaluating the use of cemacabtagene ansegedleucel (cema-cel) as part of the first line (1L) treatment regimen for newly diagnosed LBCL patients who are likely to relapse after standard 1L treatment and need further therapy (Press release, Allogene, JUN 20, 2024, View Source [SID1234644448]).

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"The transformative impact that the ALPHA3 trial could have on the treatment of first line LBCL is hard to overstate," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "Our investigational allogeneic CAR T product is designed to eliminate the complex logistics that have hindered autologous CAR T adoption to date and open the door for access by doctors in the community setting. ALPHA3 will proactively offer this potentially curative modality only to those patients who are likely to relapse."

The ALPHA3 trial will screen patients who are likely to relapse after 1L treatment for enrollment in the trial by using the Foresight CLARITY Investigational Use Only (IUO) MRD test, powered by PhasED-Seq, which recently received Investigational Device Exemption (IDE) approval from the U.S. Food and Drug Administration (FDA). Leveraging CLARITY’s ultra-sensitive MRD technology, cema-cel will be administered as a one-time infusion immediately upon detection of MRD at the completion of six cycles of R-CHOP or other standard 1L chemoimmunotherapy regimen. When given as a "7th cycle" of frontline treatment to eligible patients with MRD, consolidation treatment with cema-cel has the potential to meaningfully improve 1L cure rates in LBCL.

"Following the FDA Advisory Committee’s recent recommendation to include MRD as an endpoint to accelerate clinical trials in multiple myeloma, the ALPHA3 trial is yet another step forward towards broader implementation of MRD detection in drug development and clinical decision making," said Dr. Sandra Close, Chief Operating and Compliance Officer at Foresight Diagnostics. "We believe the Foresight CLARITY MRD platform has the performance to enable actionable treatment decisions at end of therapy when residual disease levels are challenging to detect using conventional methods."

The ALPHA3 trial will be conducted in a wide array of cancer treatment centers, including community cancer centers where most earlier line patients seek care. This randomized study will enroll approximately 240 patients and is designed to demonstrate a meaningful improvement in event free survival (EFS) in patients treated with cema-cel relative to patients who receive the current standard of care (observation). Efficacy analyses are expected to occur in 2026 and will include an interim EFS analysis monitored by the independent Data Safety Monitoring Board (DSMB) in 1H 2026 and the data readout of the primary EFS analysis in 2H 2026 with a potential biologics license application (BLA) submission targeted for 2027.

About Foresight Diagnostics
Foresight Diagnostics is a privately-held cancer diagnostics company and CLIA-registered laboratory. Its liquid biopsy platform, Foresight CLARITY, is a novel assay that measures minimal residual disease (MRD) with reported detection limits in parts per million1. The improved sensitivity of Foresight CLARITY has the potential to provide actionable information to physicians and biopharmaceutical companies to enable more personalized treatment approaches for patients with solid tumor and hematologic malignancies. For more information, please visit foresight-dx.com and follow us on Twitter and LinkedIn. Foresight CLARITY IUO is an investigational device. Limited by United States Law to investigational use.

About Cemacabtagene Ansegedleucel (cema-cel)
Cemacabtagene ansegedleucel, or cema-cel is a next generation anti-CD19 AlloCAR T investigational product for the treatment of large B cell lymphoma (LBCL). In June 2022, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation to cema-cel in third line (3L) r/r LBCL. The ALPHA3 pivotal Phase 2 trial in first line (1L) consolidation for the treatment of LBCL launched in June 2024. Allogene has oncology rights to cema-cel in the US, EU and UK with options for rights in China and Japan.

About the ALPHA3 Trial
Over 60,000 patients are expected to be treated for LBCL annually in the US, the EU and the UK. While first line (1L) R-CHOP or other chemoimmunotherapy is effective for most patients, approximately 30% will relapse and require subsequent treatment. The current standard of care (SOC) after 1L treatment has been simply to "watch and wait" to see if the disease relapses. The pivotal Phase 2 ALPHA3 study takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD following six cycles of R-CHOP or other chemoimmunotherapy, positioning it to become the standard "7th cycle" of frontline treatment available to all eligible patients with MRD.

On June 20, 2024 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported it will present positive Phase 2 data on its lead drug candidate mitazalimab in first line metastatic pancreatic cancer at the European Society for Medical Oncology Gastrointestinal Cancers Congress 2024 (ESMO GI 2024), taking place in Munich, Germany from June 26-29 (Press release, Alligator Bioscience, JUN 20, 2024, View Source [SID1234644447]).

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The oral presentation outlines OPTIMIZE-1, an open-label, multicenter, Phase 1b/2 study, assessing the safety and efficacy of mitazalimab (CD40 mAb agonist) in combination with standard of care chemotherapy mFOLFIRINOX. The trial study met its primary endpoint, with mitazalimab showing a manageable safety profile and promising DoR associated with a clinically meaningful survival benefit.

Furthermore, there was a significant correlation between treatment-induced increases in natural killer T (NKT) cells and T cells expressing CD38 and depth of response, strongly suggestive of a mitazalimab-dependent contribution to deep anti-tumor responses.

The 5-year overall survival rate for metastatic pancreatic ductal adenocarcinoma (mPDAC) is less than 5%, and current systemic therapies are associated with poor outcomes. The OPTIMIZE-1 data have also recently been published in the peer-reviewed The Lancet Oncology and presented in two posters at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Alligator expects to report 18-month survival follow-up data from OPTIMIZE-1 at the end of June 2024, and that these will provide further insights into the potential of mitazalimab.

"We are pleased to present these exciting results with mitazalimab to the scientific community at ESMO (Free ESMO Whitepaper) GI. It is an important validation of the potential of our product candidate to make a meaningful difference to pancreatic cancer patients, who currently have a very poor prognosis and limited treatment options," said Dr. Sumeet Ambarkhane, CMO of Alligator Bioscience. "In particular, the long-lasting responses and related biomarker associations reported in OPTIMIZE-1 demonstrate a critical immunomodulatory contribution of mitazalimab. The increase in ORR and PFS, compared to FOLFIRINOX alone, are superior outcomes and mitazalimab also showed a favorable safety profile. Taken as a whole, these are very encouraging data which form the basis of planning mitazalimab’s development in a randomized Phase 3 study."
About the OPTIMIZE-1 data
Results from the OPTIMIZE-1 trial showed mitazalimab in combination with mFOLFIRINOX had a confirmed ORR of 40.4% in 57 evaluable patients (unconfirmed ORR was 50.9%). Median DoR was 12.5 months and the median OS was 14.3 months. Median Progression Free Survival (PFS) was 7.7 months. These data compare favorably to the historically reported outcomes with FOLFIRINOX (ORR 31.6%, mDoR 5.9 months, mOS 11.1 months and mPFS 6.4 months)[1]. The recently approved new treatment regimen of NALIRIFOX was associated with an ORR of 42%, mDoR of 7.3 months, mPFS 7.4 months and a mOS of 11.1 months[2].

Details of the presentation:
Title: CD40 agonist mitazalimab combined with mFOLFIRINOX (mFFX) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Primary analysis of the OPTIMIZE-1 phase 1b/2 study

Type: Oral presentation

Time: Saturday, June 29, 8:45am CET

Location: Room 13a

Presenter: Prof. Teresa Macarulla Mercade, MD, PhD, Vall d’Hebron, Barcelona

About pancreatic cancer
Pancreatic cancer is the 12th largest cancer by number of patients. It is expected to become the second leading cause of cancer death in the western world by 2030. There are about 200,000 annual cases in the U.S. and the EU, with very poor prognosis: five-year survival is about 10% and median survival about 6 months. For 80% of patients, the only option is chemotherapy that offers only marginal benefit. FOLFIRINOX is expected to be the preferred first line regimen in the U.S. and the EU for patients with good performance status.
Sources: POLARIS Market Research, KOL event.

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 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 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.