In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 3023-3023
Abstract:
3023 Background: Antiangiogenic therapy has been a successful clinical strategy for the treatment of various cancer types. To date, all approved antiangiogenic drugs primarily inhibit the VEGF/VEGFR pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis. A dual blockade of both VEGF and DLL4 could be a promising strategy to overcome anti-VEGF therapy resistance. ABL001 (NOV1501) has been developed as a bispecific antibody to bind and inhibit both DLL4 and VEGF thereby significantly suppressing tumor angiogenesis. Methods: In a classical 3+3 dose-escalation design, ABL001 was administered IV at doses ranging from 0.3, 1, 2.5, 5, and 7.5 mg/kg biweekly (NCT03292783: the next doses of ABL001 are 10 and 12.5 mg/kg). After the first administration of ABL001 in each cohort, DLT (dose limiting toxicity) was observed for 3 weeks. Tumor assessments were performed every 6 weeks and cardiac assessments were performed every cycle. Results: From 2017 November to February 2019, 18 patients were enrolled on this trial. All patients were heavily pre-treated with at least 3 prior lines of chemotherapy. All patients in cohort 4 and 5 were either metastatic colorectal cancer or gastric cancer. Of the 5 cohorts, there was no DLT observed during dose escalation. In addition, there was no maximum tolerated dose identified up to 7.5 mg/kg dose. The most common treatment-related adverse events (AEs) (including all dose levels and all grades) occurred were hypertension, anorexia, general weakness, headache and anemia. Preliminary results of pharmacokinetic (PK) analysis demonstrated slightly shorter mean half-life than conventional monoclonal tantibodies due to the bispecific nature of the ABL-001. In addition, preliminary pharmacodynamic (PD) biomarker analysis using PBMC and plasma samples showed engagement of both VEGF/VEGFR and DLL4/Notch1 pathway modulation after ABL001 administration. One gastric cancer patient at 7.5 mg/kg achieved unconfirmed partial response at the time of this writing. Conclusions: ABL001 therapy has been well tolerated up to 7.5 mg/kg with no significant treatment related adverse events and showed preliminary anti-tumor activity in heavily pre-treated cancer patients. After completion of this ongoing phase 1a study, phase 1b/2a study is planned in combination of ABL001 with chemotherapy or anti-PD-1 antibody. Clinical trial information: 03292783.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2019.37.15_suppl.3023
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2019
detail.hit.zdb_id:
2005181-5
