VAL-083 Fails to Outperform SOC in Glioblastoma

The central nervous system–penetrating and DNA-targeting agent, VAL-083, did not improve efficacy compared with standard-of-care (SOC) approaches in patients with glioblastoma, according to preliminary topline results from the phase 2/3 GBM AGILE trial (NCT03970447).¹

Safety data for VAL-083 were similar to current SOC options for the treatment of this population.

Kintara Therapeutics, the developer of VAL-083, announced it will suspend all development activities and related costs for the agent. Further steps will be decided after the full dataset from GBM AGILE read out in the first half of 2024.

“GBM AGILE is a rigorous mechanism for us to efficiently evaluate investigational drugs in a well-controlled, randomized setting,” Meredith Buxton, PhD, MPH, chief executive officer and president of Global Coalition of Adaptive Research, the sponsor of GBM AGILE, stated in a news release.“While we are disappointed that the preliminary results for VAL-083 did not show benefit over SOC, GBM AGILE is operating as designed and we await final data for VAL-083 in 2024 to better understand if there are possible pathways for further development.”

VAL-083 is a DNA-targeting agent that can induce DNA double-strand breaks and cell death through the rapid induction of interstrand cross-links at N7-guanine. The agent features a unique cytotoxic mechanism designed to circumvent MGMT-mediated chemoresistance. In vitro and in vivo preclinical studies showed that VAL-083 overcame temozolomide (Temodar) resistance in glioblastoma.²

The ongoing GBM AGILE study is a response-adaptive randomization platform trial evaluating multiple therapies in patients with newly diagnosed or recurrent glioblastoma.³

The study is enrolling patients at least 18 years of age with histologically confirmed grade IV glioblastoma. All patients are required to have a Karnofsky performance status of at least 60% and tumor tissue representative of glioblastoma from definitive surgery or biopsy. Those with recurrent glioblastoma need to have evidence of recurrent disease per modified Response Assessment in Neuro-Oncology criteria, and they must undergo at least 1 scan at the time of disease progression and 1 scan prior to the time of progression.

All patients cannot have extensive leptomeningeal disease. Key exclusion criteria for those with recurrent disease include early disease progression prior to 3 months from the completion of radiotherapy; receipt of more than 2 prior lines of chemotherapy; any prior treatment with lomustine, agents included in any of the experimental arms, and bevacizumab (Avastin) or other VEGF/VEGF receptor–mediated targeted agents; any prior treatment with prolifeprospan 20 with carmustine wafer; or any prior treatment with an intracerebral agent.

Newly diagnosed patients who were randomly assigned to receive VAL-083 received 60 Gy of radiotherapy for 6 weeks and 75 mg/m² of oral temozolomide once per day during radiation therapy. Following a rest period of 4 weeks from the last day of radiation, patients received VAL-083 at 30 mg/m² on days 1, 2, and 3 of each 21-day cycle. Patients with recurrent glioblastoma received VAL-083 at 30 mg/m² on days 1, 2, and 3 of each 21-day cycle.

Newly diagnosed patients in control arm received radiotherapy and temozolomide. Those with recurrent disease were given lomustine (Gleostine) at 110 mg/m² on day 1 of each 42-day cycle for up to 6 cycles.

Overall survival serves as the trial’s primary end point. Secondary end points include progression-free survival, overall response rate, and duration of response.

“Glioblastoma represents a high unmet medical need, and patients with this disease have very few treatment options,” Robert E. Hoffman, president and chief executive officer of Kintara Therapeutics, added in the news release.1 “We are very disappointed that the VAL-083 GBM AGILE study preliminary results do not support continued development efforts to give patients additional treatment options. We sincerely appreciate the exceptional support from patients and their families as well as patient advocates, physicians, and our employees who have been committed to the rigorous study of VAL-083.”

References

1. Kintara Therapeutics announces preliminary topline results from GBM AGILE Study. News release. Kintara Therapeutics. October 31, 2023. Accessed October 31, 2023. https://www.kintara.com/news-media/press-releases/detail/1032/kintara-therapeutics-announces-preliminary-topline-results
2. Guo C, Yang Q, Li J, et al. Phase 2 study of VAL-083 and radiotherapy in newly diagnosed MGMT-unmethylated GBM: case study reports. Presented at: 2023 European Association of Neuro-Oncology Annual Meeting; September 21-24, 2023; Rotterdam, Netherlands. Abstract P11.41.B.
3. A trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma (GBM AGILE). ClinicalTrials.gov. Updated October 24, 2023. Accessed October 31, 2023. https://clinicaltrials.gov/study/NCT03970447