Safety and efficacy evaluation of ACT001 and WBRT treatment in patients with solid tumor and brain metastasis.
Authors: Zhang Tian , Zhang Wencheng , Zhang Kunning , Chen Xi , Cai Dongpo , Wang Ping , Pang Qingsong 
Published: June 2022

e14006

Background: Parthenolide-derived compounds, including ACT001, achieved radiation-enhancing and normal cell protection effects in pre-clinical studies through Nrf2, STAT3 and other pathways. Safety and efficacy data from 45 cancer patients with brain metastasis in a phase 1b/2a study were presented. Methods: Eligible patients with SCLC, NSCLC and other cancers complicated with more than three metastatic brain lesions (no up limit for SCLC) were randomized to placebo (Cohort C), ACT001 200mg (Cohort A) and 400mg,bid (Cohort B). Patients were treated with ACT001 or placebo in combination with WBRT (30 Gy/10f) in first two weeks followed by continuous treatment with ACT001 or placebo till disease progression. Treatment emergent adverse events (TEAEs, the primary endpoint) and survival events were monitored. TE-SAEs and OS events that happened within 3 months (for lung cancers) or 6 months (other cancers) after end of WBRT were also assessed. MRI scans were performed and evaluated in baseline, 30 and 90 days after end of WBRT during study per iRANO and RANO-BM criteria. Results: Study enrolled 22 patients with SCLC, 14 NSCLC, 7 breast cancer and 2 with other cancers. NSCLC patients were negative for EGFR, ALK and ROS1 mutations whereas breast cancer patients are negative for HER2. Patient characteristics were balanced in age, KPS and GPA scores. All subjects finished the required WBRT. As of Dec 31st, 2021, a total of 7 (9), 13 (13) and 10 (11) patients in Cohort C, A and B respectively had post-treatment MRI scans for objective response evaluation per iRANO (or RANO-BM) criteria. Of note, the patient numbers reflected those whose tumors met radiologically evaluable lesion requirements per iRANO (> 10mm) or RANO-BM criteria (≥10mm). 3 out of 7 patients (42.9%) in Cohort C, 11 out of 13 (84.6%) in Cohort A and 9 out of 10 (90.0%) patients in Cohort B presented with partial response for intracranial lesions per iRANO criteria whereas 3 out 9 (33.3%), 11 out of 13 (84.6%) and 10 out of 11 (90.9%) patients achieved a partial response per RANO-BM criteria. The increased objective response noted in two ACT001 cohorts was also associated with decreased percentage change of median SPD (sum of the products of perpendicular diameters )as compared with data in Cohort C: -66.1% (Cohort A, baseline 969.8 mm2), -72.3% (Cohort B, baseline 445.3 mm2) and -44.7% (Cohort C, baseline 506.9 mm2). There were 41, 30 and 20 WBRT-related grade 2 and 3 adverse events in Cohorts C, A and B. respectively. In total, there were 6, 4 and 2 TE-SAEs and death events reported in non-accumulative manner in Cohorts C, A and B respectively. As of this report, one year PFS for intracranial lesions has not been determined due to limited PD events. Conclusions: ACT001 seemed to ameliorate WBRT-induced adverse events and reduce intracranial burden of tumor metastasis. A pivotal study is warranted to further evaluate these effects. Clinical trial information: ChiCTR2000037739.