dianhydrogalactitol (VAL-083)

P2, N=29, Completed, Kintara Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Dec 2024

P2, N=118, Completed, Kintara Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2/3, N=1280, Recruiting, Global Coalition for Adaptive Research | Trial completion date: Jun 2028 --> Jun 2030 | Trial primary completion date: Jun 2026 --> Jun 2028

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.

P2/3, N=1030, Recruiting, Global Coalition for Adaptive Research

P2, N=119, Active, not recruiting, Kintara Therapeutics, Inc. | Trial completion date: Dec 2022 --> Mar 2024 | Trial primary completion date: Oct 2022 --> Dec 2023

P2, N=30, Active, not recruiting, Kintara Therapeutics, Inc. | Trial completion date: Sep 2022 --> Dec 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.

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.

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.

Additional safety and efficacy outcomes related to patient status will be presented at the meeting.Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for this EAP patient were approved by MD Anderson Cancer Center IRB.

He also received levetiracetam, alprazolam and prochlorperazine, with no drug interactions...This case highlights that VAL-083 may be a treatment option for recurrent RELA fusion-positive ependymoma refractory to temozolomide-based regimens. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for this EAP patient were approved by MD Anderson Cancer Center IRB.