Acylfulvene Prodrug LP-184 Shows Tolerability in Recurrent Glioblastoma

LP-184 (zirdafulven) was well tolerated at the recommended dose for expansion (RDE) in patients with recurrent glioblastoma, according to results from a phase 1a study (NCT05933265) published in Cancer Research Communications and announced in a press release from Lantern Pharma.^1,2 The findings also established a plan for dosing spironolactone with LP-184 in a planned phase 1b/2a trial (NCT07431216). No objective radiographic responses occurred with single-agent LP-184.

What did the phase 1a study show in recurrent glioblastoma?

Of 63 patients with advanced solid tumors enrolled in the study, 16 had recurrent isocitrate dehydrogenase wild-type, WHO grade 4 glioblastoma. Their median age was 56 years (range, 22-72), and the median number of prior systemic regimens was 2 (range, 1-4). Eight of 14 patients with known MGMT status (57%) had an unmethylated promoter. The broader study met its primary end points in advanced solid tumors, according to a news releasefrom Lantern Pharma in September 2025.³

Dose level 10 (0.39 mg/kg) was established as the RDE based on safety and pharmacokinetic data. Treatment-related adverse effects in patients with glioblastoma were similar to those in the larger cohort, and none occurred exclusively in patients with glioblastoma. Nausea occurred in 75% of patients and vomiting in 50%, all grade 1 or 2. Increased alanine aminotransferase occurred in 44% (grade 3, 6%; grade 4, 6%), and decreased platelet count occurred in 38%. Both grade 3 or 4 alanine aminotransferase elevations occurred at dose level 12, the highest dose. One patient there discontinued treatment for transient transaminitis and elevated total bilirubin meeting Hy's law, which was a dose-limiting toxicity.

No objective responses were seen per RANO 2.0, and the median progression-free survival (PFS) was 1.3 months (range, 0.3-22). One patient had stable disease for 4 months. Another, with MGMT-methylated glioblastoma, received 6 months of LP-184 and remained clinically and radiographically stable more than 22 months after enrollment, including more than 17 months off treatment.

“Glioblastoma is especially difficult to treat because a therapy must both reach the brain at effective levels and overcome the tumor's ability to repair the damage,” said Reginald Ewesuedo, MD, MBA, vice president of clinical development at Lantern Pharma, in a press release.¹ “This study shows LP-184 is well tolerated in patients with recurrent [glioblastoma] and points directly to how we can improve its activity in the tumor. By removing a key DNA repair protein with spironolactone, we aim to make the LP-184 that reaches the tumor considerably more effective.”

What was the design of the phase 1a trial?

The first-in-human study used a Bayesian optimal interval dose-escalation design starting at 0.01 mg/kg. Patients received LP-184 intravenously over 30 minutes (±5) on days 1 and 8 of each 21-day cycle. Eligible adults had relapsed or refractory disease, a Karnofsky performance status above 60, measurable disease per RANO v2.0 for glioblastoma, and a life expectancy longer than 3 months. Patients with glioblastoma were required to be on a stable dexamethasone dose and to have received prior surgery and temozolomide-based chemoradiotherapy plus adjuvant temozolomide, with no limit on other prior therapies.

The primary objectives were safety, tolerability, and determining the maximum tolerated dose and RDE. Secondary end points included pharmacokinetics and preliminary antitumor activity (objective response rate, duration of response, and PFS).

How does spironolactone fit into the combination plan?

LP-184 is an acylfulvene prodrug activated by prostaglandin reductase 1 (PTGR1), and its DNA lesions are repaired mainly by transcription-coupled nucleotide excision repair (TC-NER), independent of MGMT status. Plasma concentrations at all dose levels did not reach the levels projected to be effective in the brain, assuming about 20% tumor penetration.

Spironolactone degrades ERCC3, a TC-NER protein. In orthotopic glioblastoma patient-derived xenograft models, 3 daily doses reduced tumor ERCC3 by about 80%, vs 49% to 57% with 1 or 2 doses, and LP-184 given 8 hours after the third dose roughly doubled tumor cell death compared with LP-184 alone. Spironolactone lowered the concentration of LP-184 needed to kill cells by 3- to 6-fold in glioblastoma cell models, and modeling projected intratumoral LP-184 levels about 2 to 3 times the cell-killing concentration at the RDE.

The phase 1b/2a trial will evaluate LP-184 plus spironolactone in supratentorial glioblastoma at first recurrence after temozolomide-based therapy. LP-184 has fast track designation for glioblastoma and triple-negative breast cancer, and orphan drug designations for malignant gliomas and atypical teratoid rhabdoid tumors.¹

Panna Sharma, president and chief executive officer of Lantern Pharma, concluded, “Rather than push the dose higher, we used patient pharmacokinetic data, insights from our RADR® AI platform and our collaborators' models at Johns Hopkins to design a combination that makes the drug reaching the tumor work harder. We now have a defined dose and schedule to carry into the planned Phase 1b/2a study with our [central nervous system]-focused subsidiary, Starlight Therapeutics.”¹

References

1. Lantern Pharma announces peer-reviewed publication of phase 1a LP-184 data in recurrent glioblastoma, supporting a phase 1b/2a combination trial with spironolactone. News release. Lantern Pharma. November 10, 2026. Accessed November 10, 2026. https://tinyurl.com/2apx75ax
2. Schreck KC, Lal B, Zhou J, et al. Phase Ia evaluation of LP-184 in recurrent glioblastoma: safety, pharmacokinetics, and translational optimization of CNS exposure. Cancer Res Commun. 2026;6(10):2519-2528. doi:10.1158/2767-9764.CRC-26-0518
3. Lantern Pharma's LP-184 phase 1a clinical trial achieves all primary endpoints with robust safety profile and promising antitumor activity in multiple advanced solid tumors. News release. Lantern Pharma. September 16, 2025. Accessed November 10, 2026. https://tinyurl.com/f65whzmt