A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas
- Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with
improved characteristics over their predecessors. Indenoisoquinolines have better
chemical stability, producing stable DNA-top1 cleavage complexes, and exhibit a
preference for unique DNA cleavage sites, compared with their camptothecin
- They have demonstrated activity against camptothecin-resistant cell lines and produce
DNA-protein crosslinks, which are resistant to reversal. They also show less or no
resistance to cells overexpressing the ATP-binding cassette (ABC) transporters, ABCG2,
and multidrug resistance (MDR-1).
- Define the maximum tolerated dose (MTD) of LMP400 (NSC 743400) and LMP776 (NSC 725776)
administered intravenously (IV) daily for 5 days (QDx5).
- Define the dose-limiting toxicities (DLTs) and toxicity profile associated with
administration of LMP400 and LMP776.
- Evaluate the effect of LMP400 and LMP776 on the pharmacodynamic (PD) endpoint,
gamma-H2AX, in tumor biopsy pre- and post-treatment. In particular, compare the PD
response, defined as the mean percent nuclear area that is gamma-H2AX positive (%NAP)
in tumor biopsies, at the MTD for LMP400 and LMP776, and the toxicity profile versus PD
- Obtain preliminary evidence of anti-tumor activity of LMP400 and LMP776.
- Characterize the pharmacokinetic (PK) profile of LMP400 and LMP776.
-Adult patients must have histologically confirmed relapsed solid tumor malignancy or
lymphoma that is metastatic or unresectable for which standard curative measures do not
exist or are associated with minimal patient survival benefit.
- Cycle 1 and subsequent cycles: Patients will be randomized to receive either LMP400 or
LMP776 administered IV QD over 1 hour on days 1-5 followed by 23 days without drug
- PK and PD samples will be collected in cycle 1 only. Tumor biopsies will be optional
until a consistent PD response is observed in surrogate tissue skin biopsies or
toxicity is encountered (one DLT or two Grade 2 events on the same dose level), at
which point tumor biopsies will become mandatory.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Define the MTD and DLTs of NSCs 743400 and 725776 administered IV daily for 5 days (QDx5) in patients with relapsed solid tumors and lymphomas. Compare the agents PD response at the MTD and the toxicity profile versus PD dose-response relationsh...
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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