A Phase I Trial of Weekly Indenoisoquinoline LMP400 in Adults With Relapsed Solid Tumors and Lymphomas
- Indenoisoquinolines are non-camptothecin topoisomerase (Top1) inhibitors that form
stable DNA-Top1 cleavage-complexes, have a preference for unique DNA cleavage sites,
and are active against camptothecin-resistant cell lines. Unlike camptothecins,
indenoisoquinolines are chemically stable and active in cells that over-express
ATP-binding cassette (ABC) transporters ABCG2 and multidrug resistance (MDR-1). Top1
inhibitors are potent anticancer agents because stabilizing cleavage complex formation
induces replication-and transcription-mediated DNA damage and delays DNA repair,
leading to apoptosis. Preclinical and clinical data indicate that baseline tumor levels
of Top1 correlate strongly with ability to respond to Top1 inhibitor therapy.
- A first-in-human Phase I study conducted at the NCI of the indenoisoquinoline LMP400
(NSC 743400) on a QD x 5 q28 schedule in patients with refractory solid tumors and
lymphomas (10-C-0056) established that this agent is well tolerated. LMP400 shows
linear pharmacokinetics with evidence of drug accumulation following 5 days of dosing.
We hypothesize that weekly dosing (days 1, 8, 15 q28-day cycle) will increase LMP400
peak levels and exposures, improving clinical activity and safety.
- To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400
in patients with refractory solid tumors and lymphomas.
- To establish the maximum tolerated dose (MTD) of weekly LMP400 in patients with
refractory solid tumors and lymphomas.
- To evaluate the pharmacokinetic profile of weekly LMP400.
- Evaluate the level of Top1 in tumor biopsies pre- and post- administration of LMP400.
- Evaluate the effect of LMP400 on markers of DNA damage and apoptosis, such as ?H2AX and
caspase 3, in tumor biopsies pre- and post- LMP400 administration.
-Patients with histologically confirmed metastatic solid tumors and lymphomas; adequate
- This is an open-label Phase I trial evaluating weekly administration of LMP400, on days
1, 8, and 15, in 28-day cycles.
- Starting dose is based on the MTD determined from the QD x 5, q28 day schedule
currently being evaluated. The study will follow a 3 plus 3 design.
- Once the MTD is established, 10 additional patients will be enrolled at the MTD to
further define the pharmacokinetics and evaluate effect of study drug on DNA damage and
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Define safety and tolerability of weekly LMP400 (NSC 743400).
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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