In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 3031-3031
Abstract:
3031 Background: Indenoisoquinolines LMP 400 and LMP 776 form stable DNA-top1 cleavage complexes, have a preference for unique DNA cleavage sites, and are not substrates for ABC transporters compared to camptothecins. We conducted a randomized phase I trial of LMP 400 and LMP 776 in patients (pts) with refractory tumors to establish safety and MTD of LMP 400 and LMP 776 administered IV daily x 5 d, q 28d; determine PK; evaluate TOP1 and γH2AX levels in tumor biopsies (bx); and compare pharmacodynamic responses of LMP400 and LMP776. Methods: Pts had refractory malignancies; ≥ 18 yrs old; KPS 〉 70%; adequate organ function. DLT: drug-related gr ≥ 3 non-hem or gr 4 hem toxicities during C1. Pts assigned to receive either LMP 400 or LMP 776. Dose level (DL) in mg/m 2 /day for LMP 776: 1, 2, 3, 4.5 mg; LMP 400: 2.5, 5, 10, 20, 40, 80. Accelerated titration design with one pt per dose level (DL), 100% dose escalation until one DLT or 2 gr 2 toxicities, then 3+3 design. Tumor bx and circulating tumor cells (CTCs) were obtained at baseline and C1D3. Results: Twenty pts accrued to date [LMP 400 (11 pts); LMP 776 (9 pts)]; M/F 7/13; median age 59 (range 32-71 yrs); diagnosis (# of pts): colorectal (10), vaginal adenocarcinoma (1), head and neck (2), bladder (1), melanoma (1), pancreas (1), thyroid (1), small cell lung (1), sarcoma (1), lymphoma (1). DLTs: LMP 400- gr 4 myelosuppression, gr 3 fatigue at DL 6; DL 5 expanded to establish MTD; LMP 776 (DL2)- gr 4 hypercalcemia, no other DLTs, dose escalation continuing. One pt with irinotecan-refractory colon cancer had shrinkage of lung nodules post one cycle of LMP 400. Relative to baseline, 5 of 6 tumor bx demonstrated 20-50% reduction in TOP1 levels (LMP 776); an increase in γH2AX foci in tumor was observed in 2/6 LMP 776 and 1/1 LMP 400 pts. An increase in γH2AX was also observed in hair bulbs (3/3 pts) and CTCs (9/20 pts). PK for LMP 400 and LMP 776: mean T1/2 48 and 36 h; Cl 1.5 and 2.0 L/h/m 2 ; Vc 30 and 31 L/m 2 , respectively. Conclusions: POM, as assessed by reduction in TOP 1 levels and increase in γH2AX in tumor and CTCs, and preliminary evidence of activity, has been demonstrated in this first-in-human trial of indenoisoquinoline-class of TOP1 inhibitors. Accrual is ongoing.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.3031
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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