On November 24, 2024 Alpheus Medical, Inc., a private, clinical-stage oncology company pioneering sonodynamic therapy (SDT) for the treatment of solid body cancers, reported positive results from their Phase 1/2 clinical trial in patients with recurrent or refractory high-grade gliomas (Press release, Alpheus Medical, NOV 24, 2024, View Source [SID1234648593]). The company’s proprietary therapy demonstrated a strong safety profile and extended median overall survival (OS) and progression-free survival (PFS) compared to historical data. The data were presented by Michael Schulder, MD, at the 2024 Society of Neuro-Oncology (SNO) Annual Meeting.

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"Glioblastomas are the most common and aggressive primary brain cancer, presenting a devasting diagnosis for patients and their familes," said David Reardon, MD, Clinical Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, and member of the Alpheus Medical Scientific Advisory Board. "Current treatment options are limited and often ineffective due to the diffuse spread of the disease across the blood-brain barrier and often across the entire hemisphere, making it universally fatal with a rapid timeline. The early clinical results of Alpheus’s therapy are promising, offering hope for this new approach. I look forward to further exploring the potential benefits of their SDT therapy for this patient population who is in critical need of an effective solution."

Alpheus Medical’s non-invasive SDT treatment, which can be delivered in an outpatient setting, combines low-intensity diffuse ultrasound (LIDU) with oral 5-aminolevulinic acid (5-ALA) to target and kill cancer cells across the entire hemisphere without the need for imaging or sedation. Key findings from the study include:

Median overall survival (OS): 15.7 months vs. historical ~6-8 months
Median progression-free survival (PFS): 5.5 months vs. historical 1.8 month
Safety: No treatment-related deaths, serious adverse events (SAEs), or duration-limited toxicities (DuLTs) reported
"In addition to the strong safety data and early indications of efficacy, Alpheus’ non-invasive SDT therapy stands out for its ease of use – a significant improvement over the uncomfortable and often toxic treatments currently available for this rapidly fatal condition," stated Dr. Schulder, Director of the Brain Tumor Center at Northwell Health, and one of the trial’s primary investigators. "We look forward to expanding the ability for patients to receive this promising therapy."

The Phase 1/2 trial (NCT05362409) is an open-label, multicenter, duration-escalation study evaluating the safety, optimal dose, and efficacy of Alpheus Medical’s proprietary SDT platform. Twelve patients were enrolled across three cohorts, with treatment durations escalating to 60, 90, and 120 minutes per monthly session.

The company plans to initiate a randomized, controlled trial at multiple centers across the U.S. in 2025.

On November 23, 2024 TME Pharma N.V. (Euronext Growth Paris: ALTME), a clinical-stage biotechnology company focused on developing novel therapies for treatment of cancer by targeting the tumor microenvironment (TME), reported the presentation of a poster featuring NOX-A12 data from preclinical studies performed at the U.S. National Cancer Institute (NCI) at the 2024 Society for Neuro-Oncology (SNO) Annual Meeting, taking place in Houston, Texas, USA, November 21-24, 2024 (Press release, TME Pharma, NOV 23, 2024, View Source [SID1234648583]).

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The presentation showed that combining CXCL12 inhibition with anti-PD-1/CTLA4 immune checkpoint inhibition increases the presence of anti-cancer immune cells in tumor tissues both inside and outside the brain, including activated cytotoxic ("killer") T cells. Importantly, improved long-term survival and immunological protection from tumor recurrence were seen in models of tumors growing outside but not inside the brain. This suggests that while the combination with anti-PD-1/CTLA4 immune checkpoint inhibitors is a promising therapy for tumors outside the brain, it may not be an optimal approach for treating brain tumors.

These results support the different combination strategies pursued by TME Pharma in both brain and pancreas cancer. In pancreas cancer, a tumor originating outside the brain, NOX-A12 is combined with an anti-PD-1 immune checkpoint inhibitor and chemotherapy. In brain cancer (glioblastoma), TME Pharma pursues a different strategy combining NOX-A12 with anti-VEGF therapy and radiotherapy, which has already shown exceptional efficacy in animal models (100% complete response1) and in the GLORIA clinical trial where a statistically significant survival benefit over a matched standard of care cohort was shown with a doubling of median overall survival from 9.5 to 19.9 months2.

"The presented results confirm the activity of NOX-A12 on the tumor microenvironment and support TME Pharma’s strategy to focus on combination with the VEGF inhibitor bevacizumab in brain cancer that has yielded excellent results in newly diagnosed chemotherapy-resistant patients with residual tumor remaining after surgery," said Aram Mangasarian, CEO of TME Pharma. "The survival benefit shown at the SNO conference for the NOX-A12 combination with anti-PD1/CTLA4 immune checkpoint inhibitors suggests potential to treat multiple tumor types outside the central nervous system and supports our plans to combine NOX-A12 with the anti-PD-1 immune checkpoint inhibitor pembrolizumab and chemotherapy in the OPTIMUS pancreatic cancer study."

The research was conducted at the NCI, part of the National Institutes of Health, under the material transfer agreement established with TME Pharma in June 2022 to explore the effects of TME Pharma’s CXCL12 inhibitor NOX-A12 in brain tumors.3

Details of the poster presentation at the 2024 SNO Annual Meeting are as follows:

Title: Potentiating the efficacy of immune check-point inhibitors in glioblastoma by inhibition of CXCL12
Presenter: Dr. Chen Cam-El Makranz, Neuro-Oncology Research Fellow, National Cancer Institute, National Institutes of Health
Session: Poster Session, Poster number EXTH12
Time and Date: 7.30-9.30 p.m. CST, Friday, November 22, 2024

The abstract and poster presentation are available on the TME Pharma website.

On November 22, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that the National Medical Products Administration (NMPA) in China has approved WELIREG (belzutifan), for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery (Press release, Merck & Co, NOV 22, 2024, View Source [SID1234648579]). WELIREG is a first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor and is the first and only approved HIF-2α inhibitor in China. This approval is based on objective response rate (ORR) and median duration of response (DOR) results from the Phase 2 LITESPARK-004 trial and is the 17th approval of WELIREG for these patients globally.

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"This approval of WELIREG brings the first and only systemic therapy to adult patients in China with certain VHL disease-associated tumors who, to date, have not had access to a non-surgical treatment option to help manage manifestations of VHL disease," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. "We are committed to bringing innovative treatment options to patients in need around the world and are proud to offer eligible adult patients in China a first-in-class HIF-2α inhibitor as a possible treatment option."

In August 2021, WELIREG was approved in the U.S. for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas or pNET, not requiring immediate surgery. The efficacy of WELIREG was evaluated in LITESPARK-004, an open-label clinical trial in 61 patients with VHL-associated RCC. In the LITESPARK-004 trial, WELIREG showed an ORR of 49% (95% CI, 36-62) in patients with VHL-associated RCC (n=30/61); all responses were partial responses (PR). Median DOR for these patients was not reached, with ongoing responses ranging from 2.8+ to 22.3+ months; among responders, 56% (n=17/30) maintained a response for at least 12 months.

Patients enrolled in LITESPARK-004 had other VHL-associated tumors, including CNS hemangioblastomas and pNET. In patients with VHL-associated CNS hemangioblastomas (n=24) in this trial, WELIREG showed an ORR of 63% (95% CI, 41-81) (n=15/24), with a complete response (CR) rate of 4% (n=1/24) and a PR rate of 58% (n=14/24). Median DOR for these patients was not reached, with ongoing responses ranging from 3.7+ to 22.3+ months; among responders, 73% (n=11/15) maintained a response for at least 12 months. In patients with VHL-associated pNET (n=12) in this trial, WELIREG showed an ORR of 83% (95% CI, 52-98) (n=10/12), with a CR rate of 17% (n=2/12) and a PR rate of 67% (n=8/12). Median DOR for these patients was not reached, with ongoing responses ranging from 10.8+ to 19.4+ months; among responders, 50% (n=5/10) maintained a response for at least 12 months.

WELIREG is also approved in the U.S. for the treatment of adult patients with advanced RCC following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI), based on results from the Phase 3 LITESPARK-005 trial. Merck is evaluating WELIREG in advanced RCC and other tumor types through a broad clinical development program, including in Phase 2 and 3 trials evaluating WELIREG as monotherapy and in combination with other medicines.

About LITESPARK-004

LITESPARK-004 is an open-label Phase 2 trial (ClinicalTrials.gov, NCT03401788) evaluating WELIREG for the treatment of patients with VHL disease who had at least one measurable solid tumor localized to the kidney and who did not require immediate surgery. The study enrolled 61 patients who received WELIREG (120 mg orally once daily) until disease progression or unacceptable toxicity. The primary endpoint is ORR in VHL disease-associated RCC. Secondary endpoints in RCC tumors include disease control rate, DoR, time to response, progression-free survival, time to surgery and safety. Additionally, this study evaluated response rates in other common VHL disease-associated tumors including pNET and CNS hemangioblastomas.

About von Hippel-Lindau disease

Von Hippel-Lindau disease is a rare genetic disease that impacts an estimated 200,000 people worldwide. Patients with VHL disease are at risk for recurrent, benign blood vessel tumors as well as some cancerous ones. The most commonly occurring tumor is renal cell carcinoma, a form of kidney cancer, which occurs in about 70% of patients with VHL disease.

About WELIREG (belzutifan) 40 mg tablets, for oral use

Indications in the U.S.

Certain von Hippel-Lindau (VHL) disease-associated tumors

WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Advanced Renal Cell Carcinoma (RCC)

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Selected Safety Information for WELIREG

Warning: Embryo-Fetal Toxicity

Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.

Anemia

WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG.

In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).

The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.

In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs.

Hypoxia

WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.

Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

In LITESPARK-004, hypoxia occurred in 1.6% of patients.

In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).

Embryo-Fetal Toxicity

Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Adverse Reactions

In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).

WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.

Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).

The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).

In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).

WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).

Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).

Drug Interactions

Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.

Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.

Females and Males of Reproductive Potential

WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.

Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.

Pediatric Use

Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established.

On November 22, 2024 Zenyaku Kogyo Co., Ltd. (Japanese-only website) and Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that Zenyaku obtained regulatory approval from the Ministry of Health, Labour and Welfare (MHLW), for an additional dosage and administration of an anti-CD20 monoclonal antibody Rituxan intravenous injection 100 mg and 500 mg [generic name: rituximab (genetical recombination)] (hereafter, "Rituxan"), which is co-marketed by both companies, for "chronic idiopathic thrombocytopenic purpura*1 in children" (Press release, Hoffmann-La Roche, NOV 22, 2024, View Source;category= [SID1234648562]).

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Chronic ITP had previously only been approved for use in adults with specified dosage and administration, and its use in children had not been approved. The Japanese Society of Pediatric Hematology/Oncology requested the addition of dosage and administration for Rituxan for "chronic ITP in children." It was evaluated that this request qualified for a public knowledge-based application at the "58th evaluation committee on unapproved or off-labeled drugs with high medical needs" held on March 22, 2024. It was officially decided that a public knowledge-based application could be submitted at the "Pharmaceutical Affairs Council’s First Committee on Drugs" held on April 26, 2024. In response to this, Zenyaku submitted a public knowledge-based application for the addition of dosage and administration on May 24, 2024, and obtained approval.

ITP is an autoimmune disease in which autoantibodies against platelet membrane proteins are expressed1) 2) 3), leading to thrombocytopenia due to platelet destruction and impaired production. It is recognized as a designated intractable disease (designated intractable disease 63) by the national government. The etiology of ITP is unknown, and the mechanism of autoantibody production has not been clearly elucidated.
Many newly diagnosed pediatric ITP patients often exhibit severe thrombocytopenia. However, serious bleeding such as intracranial hemorrhage is rare4) 5) 6), and often resolve spontaneously. It is estimated that 30-56%7) 8) 9) of cases require treatment. On the other hand, some cases may show resistance to primary treatments such as corticosteroids or intravenous immunoglobulin therapy10). Both domestic and international clinical guidelines10) 11) 12) recommend Rituxan as one of the treatment options for such pediatric ITP patients.

Rituxan is an anti-CD20 monoclonal antibody that specifically binds to CD20, a protein expressed on B cells, excluding hematopoietic stem cells and plasma cells. It attacks target B cells using the immune system equipped with the human body, and damages cells. The influence of B cells has been suggested as a pathogenic factor in ITP13) 14) 15), and by eliminating B cells with Rituxan, therapeutic effects are expected for chronic ITP that shows resistance to primary treatments.

Zenyaku and Chugai will continue working closely together so that Rituxan can further contribute to the treatment of chronic ITP not only in adults but also in children.

Trademarks used or mentioned in this release are protected by law.

*1 Idiopathic thrombocytopenic purpura is considered an autoimmune disease targeting platelets, and it has also been referred to as "immune thrombocytopenia" in recent years.
*2 Approved dosage and administration
Chronic idiopathic thrombocytopenic purpura
The usual dose is 375 mg/m2 of rituximab (genetical recombination) administered as an intravenous infusion once weekly for four weeks.
*3 Rituxan’s indication for chronic ITP was initially approved for adults in June 2017, and now additional approval has been obtained for use in children.
Sources

Cooper N, Bussel J. The pathogenesis of immune thrombocytopenic purpura. Br J Haematol 2006; 133(4): 364-374.
Berchtold P, McMillan R, Tani P, Sommerville-Nielsen P, Blanchette VS. Autoantibodies against platelet membrane glycoproteins in children with acute and chronic immune thrombocytopenic purpura. Blood 1989; 74(5): 1600-1602.
Taub JW, Warrier I, Holtkamp C, Beardsley DS, Lusher JM. Characterization of autoantibodies against the platelet glycoprotein antigens IIb/IIIa in childhood idiopathic thrombocytopenia purpura. Am J Hematol 1995; 48(2): 104-107.
Neunert CE, Buchanan GR, Imbach P, et al. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood 2008; 112(10): 4003-4008.
Neunert CE, Buchanan GR, Imbach P, et al. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood 2013; 121(22): 4457-4462.
Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3(22): 3780-3817.
Grimaldi-Bensouda L, Nordon C, Leblanc T, et al. Childhood immune thrombocytopenia: A nationwide cohort study on condition management and outcomes. Pediatr Blood Cancer 2017; 64(7). doi: 10.1002/pbc.26389.
Grainger JD, Rees JL, Reeves M, Bolton-Maggs PHB. Changing trends in the UK management of childhood ITP. Arch Dis Child 2012; 97(1): 8-11.
Bennett CM, Neunert C, Grace RF, et al. Predictors of remission in children with newly diagnosed immune thrombocytopenia: Data from the Intercontinental Cooperative ITP Study Group Registry II participants. Pediatr Blood Cancer 2018; 65(1). doi: 10.1002/pbc.26736.
The Japanese Society of Pediatric Hematology/Oncology. Clinical Practice Guidelines for Childhood Immune Thrombocytopenia 2022 from the Japanese Society of Pediatric Hematology/Oncology. The Japanese Journal of Pediatric Hematology/Oncology 2022; 59(1): 50-57.
Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3(22): 3780-3817.
Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 guidelines for immune thrombocytopenia. Blood Adv 2019; 3(23): 3829-3866.
Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura: role in production of antiplatelet autoantibody. J Clin Invest 1998; 102(7): 1393-1402.
Chang M, Nakagawa PA, Shirley A, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood 2003; 102(3): 887-895.
Li X, Zhong H, Bao W, et al. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood 2012; 120(16): 3318-3325.

On Nov. 22, 2024 The Global Coalition for Adaptive Research (GCAR) reported that they have executed an agreement with AstraZeneca for the evaluation of AstraZeneca’s compound, AZD1390, in GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment – NCT03970447), the world’s first global adaptive platform trial for glioblastoma (Press release, Global Coalition for Adaptive Research, NOV 22, 2024, View Source [SID1234648581]). The AZD1390 arm will be evaluated for the treatment of newly diagnosed glioblastoma, with recruitment of patients expected to begin by Q2 2025.

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Glioblastoma is the most aggressive and common form of primary brain cancer. Treatment options and patient outcomes have seen little progress over the past several decades. Since launching in July 2019, the GBM AGILE trial has evaluated multiple therapies and has screened over 2000 patients at trial locations in six countries.

GBM AGILE is designed to more rapidly identify and confirm effective therapies for patients with glioblastoma through response adaptive randomization and a seamless phase 2/3 design. Conceived by over 130 key opinion leaders, GBM AGILE is conducted under a master protocol, allowing multiple therapies or combinations of therapies from different pharmaceutical companies to be evaluated simultaneously against a common control arm. With its innovative design and efficient operational infrastructure, data from GBM AGILE can potentially be used as the foundation for a new drug application (NDA) and biologics license application (BLA) submissions and registrations to the US FDA and other health authorities.

Professor Anthony Chalmers, Chair of Clinical Oncology at the University of Glasgow and Dr. Patrick Wen, Director, Center for Neuro-Oncology at Dana-Farber Cancer Institute, and Professor of Neurology at Harvard Medical School, will serve as arm Principal Investigators for AZD1390’s evaluation in GBM AGILE. Dr. Timothy Cloughesy, Director, Neuro-Oncology Program and Distinguished Professor of Neurology at the University of California, Los Angeles, is the Global Principal Investigator for the overall study.

"There is an urgent need for new, tolerable and effective therapies to treat glioblastoma. GBM AGILE is a revolutionary, patient-centered, potentially registration-enabling, adaptive platform trial for glioblastoma," said Dr. Patrick Wen. "We are excited to include AZD1390 in GBM AGILE, based on encouraging data from previous studies, showing encouraging preliminary efficacy in heavily treated recurrent glioblastoma patients and potential for AZD1390 to act as a radiosensitizer. This investigational drug has the potential to support improved outcomes for glioblastoma patients."

AZD1390 is brain penetrant ataxia telangiectasia mutant (ATM) kinase inhibitor that blocks ATM-dependent signaling and repair of DNA double strand breaks (DSBs) in the genome. Preclinically, AZD1390 exhibits activity in combination with agents such as irradiation that induce DSBs. AZD1390 has also been shown to achieve clinically relevant concentrations in resected glioblastoma tissue and suppress the natural repair of the DNA damage that is mediated by radiation. Furthermore, in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, AZD1390 with radiotherapy showed a manageable safety profile and preliminary efficacy for patients with glioblastoma in a Phase I trial.

"GCAR is committed to accelerating the development of life-changing treatments for patients with rare and deadly diseases such as glioblastoma. We believe that adaptive platform trials have the potential to achieve that mission and make a profound difference for patients," said Dr. Meredith Buxton, Chief Executive Officer and President of GCAR. "We are delighted to collaborate with AstraZeneca and look forward to expediting the evaluation of AZD1390 in GBM AGILE for the treatment of glioblastoma, a devastating disease with a critical need for more effective treatments."