dianhydrogalactitol (VAL-083) / Kintara Therap, Zhongheng Group, Valent Tech - LARVOL DELTA

VAL-083 is effective in patients with newly-diagnosed MGMT-unmethylated glioblastoma: report of phase II study. (PubMed, Discov Oncol) - P2 | "VAL-083 (30 mg/m2/day) combined with radiation therapy was generally safe and well tolerated. Adverse events aligned with previous studies. This regimen, compared to standard-of-care TMZ, showed potential benefits in terms of disease progression and overall survival. Trial registration ClinicalTrials.gov ID NCT03050736, dated: February 13, 2017."

Journal • P2 data • Brain Cancer • Glioblastoma • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • MGMT

VAL-083 for treatment of Histone H3-Wild Type Diffuse Midline Glioma (SNO 2025) - "H3K27M mutation is associated with worse prognosis and O6-Methylguaninemethyl transferase (MGMT) is usually unmethylated, predicting a poor response to temozolomide in these patients...ONC201 is a selective dopamine receptor D2 (DRD2) antagonist showing preferential activity in H3K27M-mutant DMG, and has demonstrated significant survival benefit in patients with this mutation...VAL-083 will be co-administered with radiotherapy, and up to 12 cycles of treatment every 21 days. Further details on the study design will be presented at the conference."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Solid Tumor • DRD2 • MGMT

VAL-083 for treatment of Histone H3-Wild Type Diffuse Midline Glioma (WFNOS 2025) - "H3K27M mutation is associated with worse prognosis and O6-Methylguaninemethyl transferase (MGMT) is usually unmethylated, predicting a poor response to temozolomide in these patients...ONC201 is a selective dopamine receptor D2 (DRD2) antagonist showing preferential activity in H3K27M-mutant DMG, and has demonstrated significant survival benefit in patients with this mutation...VAL-083 will be co-administered with radiotherapy, and up to 12 cycles of treatment every 21 days. Further details on the study design will be presented at the conference."

Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • DRD2 • MGMT

Modeling glioblastoma treatment responses: insights into tumor plasticity and the role of the tumor microenvironment (EANO 2025) - "It is unclear to what extent the responses are patient- and treatment-specific, and how much they depend on the tumor microenvironment.Material and We applied a cohort of molecularly characterized patient-derived models to investigate patient-specific responses to chemotherapeutics (Temozolomide, VAL-083). Our findings highlight the critical roles of both tolerance and intrinsic resistance mechanisms. The responder groups appear to be specific to the type of treatment and the unique characteristics of each patient's tumor, emphasizing the need to evaluate treatment-induced plasticity in a patient-specific context. Glioblastoma cells are further supported by the adaptation of the microenvironment towards a tumor-supportive crosstalk."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting (clinicaltrials.gov) - P2 | N=118 | Completed | Sponsor: Kintara Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

Safety Study of VAL-083 and Radiotherapy in Patients With Newly Diagnosed GBM Having Unmethylated MGMT Expression (clinicaltrials.gov) - P2 | N=29 | Completed | Sponsor: Kintara Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Dec 2024

Trial completion • Trial completion date • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=1280 | Recruiting | Sponsor: Global Coalition for Adaptive Research | Trial completion date: Jun 2028 ➔ Jun 2030 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

Dual treatment with Val-083 and AZD1775 shows potent anti-tumor activity in diffuse midline glioma models. (PubMed, NPJ Precis Oncol) - "H3K27M diffuse midline gliomas (DMG) are characterized by p53 mutations and hypomethylation of MGMT, a DNA-repair enzyme, leading to resistance towards chemotherapeutic agents such as temozolomide (TMZ). In vivo, the combination of both drugs led to significant reduction in tumor growth in zebrafish xenograft models and prolongation of survival in mice xenograft models. Our findings indicate that Val-083 and AZD1775 in combination demonstrate promising efficacy in DMGs, providing a clinical rationale for positioning these arms in future therapies."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • CDK1 • MGMT • TP53

VAL-083 in patients with recurrent glioblastoma treated under expanded access program (SNO 2024) - P | "Background: Current standard-of-care for glioblastoma (GBM) includes surgery followed by chemoradiation with temozolomide (TMZ) followed by adjuvant TMZ...Twelve (12/26; 46.2%) patients had ≥2 recurrences and 9/26 (34.6%) had prior lomustine...Eight (8/26; 30.8%) patients received bevacizumab concurrently with VAL-083... Use of VAL-083 continues to show benefit in the treatment of GBM patients who have had multiple recurrences and have limited therapeutic options."

Clinical • Brain Cancer • CNS Tumor • Glioblastoma • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • NF1 • PTEN • TERT • TP53

Assessment of molecular alterations in newly diagnosed GBM MGMT-unmethylated patients treated with VAL-083 (SNO 2024) - P2 | "VAL-083 was evaluated in an open-label, biomarker-driven, phase 2 trial in MGMT-unmethylated, bevacizumab-naïve GBM patients. None of the molecular alterations were predictors of number of treatment cycles or dose reductions. No specific molecular alterations were identified that predicted either improved or poorer patient outcome, during treatment with VAL-083."

Clinical • Glioblastoma • BRCA2 • CDK4 • CDKN2A • CDKN2B • EGFR • MDM4 • MGMT • NF1 • NOTCH1 • PIK3R1 • PTEN • RB1 • TP53

RELA fusion-positive ependymoma, diffuse midline glioma and Grade 4 IDH mutant astrocytoma treated with VAL-083 under expanded access: case reports (SNO 2024) - P | "IDHmut astrocytoma, and DMG refractory to other treatment regimens. Additional outcomes related to these cases will be presented at the meeting."

Case report • Clinical • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Ependymoma • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor • ATRX • MAP2K1 • RELA • TP53

Evaluation of VAL-083 in GBM AGILE, a phase 3 registration platform trial for newly diagnosed and recurrent glioblastoma (EANO 2024) - P2/3 | "C is temozolomide (in ND) & lomustine (in RD). GBM AGILE is an efficient & effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, & with fewer patients than typical registration trials & is currently evaluating several other arms."

P3 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Kintara Therapeutics Announces Preliminary Topline Results From GBM AGILE Study (PRNewswire) - P2/3 | N=1030 | GBM AGILE (NCT03970447) | "Kintara Therapeutics, Inc...announced that preliminary topline results from the Glioblastoma Adaptive Global Innovative Learning Environment (GBM AGILE) study showed that VAL-083 did not perform better than the current standards of care in glioblastoma. These topline results included preliminary safety data for VAL-083 that was similar to that of the current standards of care used to treat glioblastoma...With this study outcome, Kintara is suspending the development of VAL-083 and turning its focus to its second program, REM-001....All development activities and related costs for VAL-083 will be suspended while the Company awaits the full dataset from the GBM AGILE Study which is expected at the end of the first quarter/beginning of second quarter of calendar year 2024."

Discontinued • P2/3 data • Glioblastoma

Treatment resistance in the glioblastoma ecosystem: exploring the interplay between tumor cells and the microenvironment with advanced patient avatars (EACR 2024) - "Advanced models recapitulating the complex tumor ecosystem are required to assess clinically-relevant therapy responses.Material and Methods We applied a cohort of well-characterized patient-derived models, propagated as tumor organoids and orthotopic xenografts (PDOXs) to investigate GBM treatment responses to chemotherapeutic agents (temozolomide, VAL-083). Our study suggests a crucial role of phagocytosis mediated by microglia in supporting tumor resistance mechanisms. Further functional studies are needed to assess the treatment responses in time to unravel the molecular mechanisms or resistance."

Clinical • Metastases • Tumor cell • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Evaluation of VAL-083 in GBM AGILE, a phase 3 registration platform trial for newly diagnosed and recurrent glioblastoma. (ASCO 2024) - P2/3 | "C is temozolomide (in ND) & lomustine (in RD). GBM AGILE is an efficient & effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, & with fewer patients than typical registration trials & is currently evaluating several other arms."

P3 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=1030 | Recruiting | Sponsor: Global Coalition for Adaptive Research

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting (clinicaltrials.gov) - P2 | N=119 | Active, not recruiting | Sponsor: Kintara Therapeutics, Inc. | Trial completion date: Dec 2022 ➔ Mar 2024 | Trial primary completion date: Oct 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

Safety Study of VAL-083 and Radiotherapy in Patients With Newly Diagnosed GBM Having Unmethylated MGMT Expression (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Kintara Therapeutics, Inc. | Trial completion date: Sep 2022 ➔ Dec 2023

Trial completion date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

Global Coalition for Adaptive Research in Collaboration with Cure Brain Cancer Foundation Announce the Opening of Glioblastoma Clinical Trial in Australia (Businesswire) - "The Global Coalition for Adaptive Research (GCAR) in collaboration with Cure Brain Cancer Foundation (CBCF), today announced the opening of GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment – NCT03970447) in Australia. GBM AGILE is a revolutionary patient-centered, adaptive platform trial for registration that evaluates multiple therapies for patients with newly-diagnosed and recurrent glioblastoma (GBM) – the deadliest form of brain cancer."

Licensing / partnership • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Evaluation of post-progression treatments after VAL-083 in recurrent and newly diagnosed GBM MGMT-unmethylated patients (SNO 2023) - "VAL-083 was evaluated in an open-label two-arm biomarker-driven phase 2 trial in MGMT-unmethylated bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-radiation with TMZ (Group 2). Furthermore, receiving ≥5 cycles of adjuvant TMZ prior to VAL-083 in Group 1 didn’t affect patient’s ability to receive alkylating agents. For both groups, mOS and OS-6 from the last dose of VAL-083 were greater for those receiving alkylating agent post VAL-083, compared to those who didn’t.These data demonstrate that alkylating agents may be administered safely to patients who have progressed following therapy with VAL-083, and patients who have received an alkylating agent after VAL-083 therapy have a better outcome compared to those receiving other treatments."

Clinical • Hematological Disorders • MGMT

Post-Progression Treatment after VAL-083 with radiation in newly diagnosed GBM MGMT unmethylated patients (SNO 2023) - "In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and thus differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083."

Clinical • Glioblastoma • Oncology • MGMT

PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM: CASE STUDY REPORTS (EANO 2023) - P2 | "In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). CONCLUSIONThe results from the study and these patient cases, support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736."

Clinical • P2 data • Astrocytoma • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MGMT

Kintara Therapeutics Presents Case Studies of Glioblastoma Patients Treated with VAL-083 at 2023 European Association for Neuro-Oncology Annual Meeting (PRNewswire) - P2 | N=30 | NCT03050736 | Sponsor: Kintara Therapeutics, Inc. | "In the first case, a 32-year-old woman with grade four GBM (MGMT-unmethylated) received conventional radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083 for a total of 13 cycles of VAL-083. The patient was tumor-free and has survived more than four years as of the last follow-up in March 2023. In the second case, a 49-year-old man with grade four GBM (MGMT-unmethylated) received radiotherapy with concurrent chemotherapy with VAL-083 followed by VAL-083 as an adjuvant for a total of 12 cycles. Two years after the initial treatment with VAL-083 was discontinued, a new lesion was found, and the patient had a second resection, which revealed a grade four astrocytoma."

P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Kintara Therapeutics Announces Fiscal 2023 Year Financial Results and Provides Corporate Update (PRNewswire) - "Announced that the Company will be presenting a poster at the 2023 European Association of Neuro-Oncology (EANO) Annual Meeting taking place in Rotterdam, Netherlands, September 21-24, 2023. The presentation will include data from its lead program, VAL-083, for the treatment of recurrent GBM. (September 2023)."

Clinical data • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Kintara Therapeutics to Present at the 2023 European Association for Neuro-Oncology Annual Meeting (PRNewswire) - "Kintara Therapeutics, Inc...announced that it will be presenting a poster at the 2023 European Association for Neuro-Oncology (EANO) Annual Meeting, taking place in Rotterdam, September 21-24, 2023. The presentation will include data from its lead program, VAL-083, for the treatment of recurrent glioblastoma."

Clinical data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor