HGG-14. ACT001 – A PROMISING THERAPEUTIC FOR DIFFUSE INTRINSIC PONTINE GLIOMAS

Diffuse Intrinsic Pontine Gliomas (DIPGs) are a subset of Diffuse Midline Gliomas (DMG) and are the most devastating of all brain tumors. There are no effective treatments and all children die of their tumor within 12-months. We performed a high-throughput drug screen with 3,570 biologically active, clinically approved compounds against a panel of DIPG cultures. Parthenolide, a compound derived from the herb T.parthenium, was found to be one of the most effective drugs tested, demonstrating significant anti-tumor activity. However, parthenolide also affected healthy cell viability and showed no in-vivo efficacy. ACT001 is a novel agent in clinical development that is a fumarate salt form of dimethylamino-micheliolide, which is semi-synthesized from parthenolide. ACT001 is blood-brain-barrier permeable and exerts an anti-tumor effect via inhibition of NF-κB and STAT3 pathways. ACT001 demonstrated potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells and inhibited colony formation in-vitro. To determine whether this activity could be replicated in-vivo, we tested ACT001 in a DIPG-orthotopic model. ACT001 was well tolerated and significantly improved survival of tumor-bearing animals, extending survival by 33% in ACT001 treated mice. We have initiated a Phase 1 paediatric trial of ACT001 for children with relapsed/refractory solid or CNS tumors, with an expansion cohort planned for patients with DIPG/DMG. Eleven patients have been enrolled, and the dose escalated from dose level-1 at 188mg/m2 bd to dose level-4 at 700mg/m2 bd. To date, no dose limiting or Grade 3/4 toxicities have been observed. At the highest dose level, clinical activity has been demonstrated in two patients, one with DIPG with a reduction in tumor burden, and another with DMG with H3K27M mutation with an objective radiographic and clinical response. These combined preclinical and clinical results suggest that ACT001 is an active novel therapy for patients with DIPG/DMG.