dianhydrogalactitol (VAL-083)

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.

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). These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.

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.

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

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

P2, N=30, Active, not recruiting, Kintara Therapeutics, Inc. | Trial completion date: Aug 2021 --> Jun 2022 | Trial primary completion date: Jun 2021 --> Nov 2021

P2, N=119, Active, not recruiting, Kintara Therapeutics, Inc. | Trial completion date: Dec 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Jun 2022

No abstract available

Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Enrollment, safety data and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

No abstract available

Regorafenib, paxalisib, and dianhydrogalactitol (VAL-083) are showing initial promise to decrease disease progression...Selinexor, recombinant nonpathogenic polio-rhinovirus, and GBM-vaccine of autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector have all also shown initial clinical benefit in terms of prolonging survival. Most trials observe modest improvement in outcomes with a positive safety profile. Nevertheless, the need for further studies is warranted, along with the trending of post-therapeutic biomarkers in order to better access future patient outcomes.

P2, N=30, Active, not recruiting, Kintara Therapeutics, Inc. | Trial completion date: Aug 2020 --> Aug 2021 | Trial primary completion date: Aug 2020 --> Jun 2021

Combination of TMZ and Val-083 shows a synergic cytotoxic effect in tumor cells in vitro, ex vivo and in vivo. We propose this combinatorial treatment as a potential approach for GBM patients.

We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

1,2:5,6-Dianhydrogalactitol (DAG) is a bi-functional DNA-targeting agent currently in phase II clinical trial for treatment of temozolomide-resistant glioblastoma (GBM)...Acting in S phase, DAG displayed selective synergy with topoisomerase I (camptothecin and irinotecan) and topoisomerase II (etoposide) poisons in GBM, PCa, and lung cancer cells with no synergy observed for docetaxel. Importantly, DAG combined with irinotecan treatment enhanced tumor responses and prolonged survival of tumor-bearing mice. This work provides mechanistic insight into DAG cytotoxicity in GBM and PCa cells and offers a rational for exploring combination regimens with topoisomerase I/II poisons in future clinical trials.