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A Phase I, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of ACT004 in Healthy Adult Subjects

开始日期2023-04-01

申办/合作机构

Accendatech AU Pty Ltd.

[+1]

ACTRN12621000093886 / Suspended临床2期IIT

A Phase 2, open label, multicentre study assessing the safety and efficacy of ACT001 in combination with whole brain radiation therapy (WBRT) for brain metastases from solid tumours.

开始日期2021-10-20

申办/合作机构

Accendatech AU Pty Ltd.

100 项与 Accendatech AU Pty Ltd. 相关的临床结果

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0 项与 Accendatech AU Pty Ltd. 相关的专利（医药）

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项与 Accendatech AU Pty Ltd. 相关的文献（医药）

2021-06-01·Neuro-Oncology

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

作者: Foresto, Steve ; Manoharan, Neevika ; Cai, Dongpo ; Ziegler, David ; Tsoli, Maria ; Upton, Dannielle ; Hassall, Tim ; Liu, Jie ; George, Sandra ; Su, Steven Yung-Chang

AbstractDiffuse 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.

2021-05-20·Journal of Clinical Oncology

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

作者: Kichenadasse, Ganessan ; Jennens, Ross ; Cai, Dongpo ; Su, Steven Yung-Chang ; Lickliter, Jason D. ; Lemech, Charlotte Rose

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

2018-05-20·Journal of Clinical Oncology

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.