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A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas

2014-08-27 03:16:33 | BioPortfolio

Summary

Background:

- Indenoisoquinolines are experimental cancer treatment drugs that damage the DNA in cells, resulting in cell death. Researchers have been studying these drugs and their usefulness in treating types of cancer that have not responded well to standard therapies like surgery or radiation.

- LMP400 (NSC 743400) and LMP776 (NSC 725776) are indenoisoquinolines that have not been given to cancer patients before. These drugs have very similar chemical structures and work the same way, but researchers do not know which one will work best. More information is needed about how LMP400 and LMP776 are processed by the body and how effective they are in treating difficult-to-treat types of cancer.

Objectives:

- To determine the maximum tolerated dose of LMP400 (NSC 743400) and LMP776 (NSC 725776).

- To study how the body handles LMP400 and LMP776.

- To evaluate the effectiveness of LMP400 and LMP776 as a treatment for tumors and lymphoma that have not responded to standard treatment.

Eligibility:

- Individuals at least 18 years of age who have malignant solid tumors or Hodgkin s disease/non-Hodgkin lymphoma that has not responded to standard therapies.

Design:

- Participants will receive either LMP400 or LMP776. The treatment cycle will be 28 days. On the first 5 days of each cycle, participants will receive intravenous doses of their specific study drug, followed by 23 days without the drug. The 28-day cycle will be repeated as long as the drug does not cause severe side effects and the cancer remains stable or improves. The study doctor may increase or decrease the dose of study drug depending on how well it is tolerated.

- Blood, urine, and hair samples and skin and tumor biopsies will be collected during the first treatment cycle. Routine blood samples will be taken throughout the study.

- Other tests, including additional blood and urine samples, computed tomography (CT) or other scans, and bone marrow samples, may be performed as directed by the study doctors....

Description

Background:

- 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 counterparts.

- 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).

Primary Objectives:

- 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 and skin tissue samples 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 dose-response relationship.

Secondary Objectives:

- Obtain preliminary evidence of anti-tumor activity of LMP400 and LMP776.

- Characterize the pharmacokinetic (PK) profile of LMP400 and LMP776.

Eligibility:

-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.

Study Design:

- 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 (28-day cycle).

- 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.

Study Design

Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Neoplasms

Intervention

LMP 400, LMP 776

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda
Maryland
United States
20892

Status

Recruiting

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:16:33-0400

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