In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3590-3590
Kurzfassung:
3590 Background: IM156, a novel oral potent biguanide OXPHOS inhibitor of Protein Complex 1 (PC1) of the mitochondrial electron transport chain, causes AMPK phosphorylation, the downstream effects of which are detrimental to OXPHOS-dependent cancer cells prone to energy stress. Preclinical experiments with IM156 demonstrated activity in solid tumor and hematologic malignancy models as a single-agent and in combinations. Methods: This was an open label, first-in-human, multi-center, dose-escalation study ( NCT03272256 ) using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D) based on dose limiting toxicities (DLT), safety and tolerability. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD) and preliminary signals of efficacy. Eligible patients were adults with advanced solid tumors refractory to standard therapies with ECOG Performance Status 〈 2, adequate organ function, and measurable disease (RECIST 1.1 or RANO [gliomas]). IM156 was administered orally every other day (QOD) or daily (QD) in 28-day cycles. Results: 22 patients (gastric cancer: N = 8; ovarian cancer: N = 3; colorectal cancer: N = 3; endometrial cancer: N = 2; sarcoma: N = 2; other: N = 4) were enrolled in 7 dose cohorts (100, 200, 400, 800, and 1,200 mg QOD; 800 and 1,200 mg QD). The most frequent treatment-related adverse events (TRAEs) were gastrointestinal (nausea [N = 16, 73%] , diarrhea [N = 12, 55%], and vomiting N = 11, 50%] ). Nausea, reported in 3 (14%) patients, was the only Grade 3 TRAE. No DLTs were reported; the RP2D declared was 800 mg as 1,200 mg QD was associated with Grade 2/3 nausea requiring dose modifications. PK demonstrated dose-proportional increases in C max and AUC 0-last reaching the expected efficacious range. PD demonstrated a decrease in tumor growth rate in 3 patients (1,200 mg QOD: N = 2; 800 mg QD: N = 1), and a decrease in VEGF and tumor markers in a patient with gastric cancer with neuroendocrine differentiation treated at 800 mg QD who remains on study in Cycle 11. Best response was stable disease in 7 (32%) patients. Conclusions: IM156 is the first PC1 OXPHOS inhibitor to have been successfully tested in patients with cancer with the identification of a RP2D. It was well tolerated at dose levels active in preclinical models, and demonstrated modest clinical activity in an unselected population of patients. Subsequent development will focus on OXPHOS-dependent tumors and in combinations with agents in which OXPHOS metabolism is a mechanism of resistance. Clinical trial information: NCT03272256 .
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2020.38.15_suppl.3590
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2020
ZDB Id:
2005181-5
