In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. A091-A091
Abstract:
Background: We report dose escalation results from a phase 1/2 trial of ASTX660 (NCT02503423). This non-peptidomimetic, dual XIAP and cIAP antagonist inhibits tumor cell lines at nanomolar concentrations and is active against xenografts. Methods: Study ASTX660-01, an open-label, multi-center, dose-escalation study in subjects with advanced cancers and lymphomas, used a 3+3 dose escalation design. Study drug was administered orally once daily in 28 day cycles of alternating 7 days on, then 7 days off therapy. Dose escalation was planned from a starting fixed 15 mg dose until the maximum tolerated dose (MTD) was reached. Endpoints included safety, MTD, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and antitumor effects. Results: Forty-five subjects received at least 1 dose of ASTX660 (range 15 mg - 270 mg). Mean age was 62 years (range 36-77); 60% of subjects were female. Median duration of study therapy was 2 cycles (range 1-8). Four dose-limiting toxicities (DLTs) were observed: 3 at 270 mg QD (grade 3/4 lipase increased), and 1 at 210 mg QD (grade 3 lipase increased). These lipasemia DLTs were all asymptomatic. Most declined after dose interruption and did not recur after dose reduction. The MTD was 210 mg QD, and the RP2D was 180 mg QD. Common adverse events (AEs) included fatigue, lipasemia, and vomiting (29%); nausea and lymphopenia (27%); anemia (24%); rash and edema (20%); ALT increase and pruritus (18%); AST increase (16%); appetite decrease and diarrhea (13%); and amylasemia and hyponatremia (11%). Lipasemia and amylasemia appeared to be dose-related. Most AEs were CTCAE grades 1-2 and manageable with supportive treatment. Median time to peak plasma concentration (tmax) was 1 hour. ASTX660 t ½ was 15.3 hours at the RP2D. Day 1 and 7 AUC0-24h plasma exposures after 180 mg ASTX660 were 1450 (67%) and 2080 (62%) ng*hr/mL (geometric mean [CV] ), respectively. Modest accumulation (1.4 fold) at Day 7 vs Day 1 was observed for ASTX660 AUC0-24h exposures but not for Cmax. Human RP2D exposure levels reached the biologically active exposure range seen in preclinical models. ASTX660 at all dose levels suppressed cIAP1 in peripheral blood mononuclear cells (PBMCs). At 180 mg cIAP1 suppression was sustained beyond the off-therapy week. A clinical response in cutaneous T cell lymphoma was observed at the 180-mg dose level. Conclusions: In phase 1, ASTX660 caused manageable toxicities, achieved target study drug exposures, and demonstrated both biologic and clinical activity at the RP2D. Enrollment to phase 2 expansion cohorts in lymphoma and other selected cancers is ongoing. Citation Format: Monica Mita, Patricia LoRusso, Michael S. Gordon, Aram Oganesian, Xiaoping Zhang, Roberta Ferraldeschi, Simone Jueliger, Harold N. Keer, Purvee Kumar, Chihche Lin, Edwin P. Rock, Alain Mita, Anthony W. Tolcher. Phase 1 study of IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A091.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-17-A091
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2062135-8
SSG:
12
