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Camptothecin

LMP400 administered IV daily for 5 days per dose escalation table.

LMP776 administered IV daily for 5 days per dose escalation table.

Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 with improved characteristics such as better chemical stability, producing stable DNA-top1 cleavage complexes, and exhibiting a preference for unique DNA cleavage sites compared with their camptothecin counterparts.

LMP400

LMP776

Alice P Chen, M.D.

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.

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 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 not be collected during the escalation phase; however, tumor biopsies will be mandatory during the expansion phase.

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

Defined dose-limiting toxicities and toxicity profile associated with administration of LMP400 and LMP776

National Cancer Institute (NCI)

Open-label Phase I trial evaluating weekly administration of LMP400, on days 1, 8, and 15, in 28-day cycles.

Top1 inhibitors such as LMP400 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.

Background:

- Indenoisoquinoline LMP400 is an experimental cancer treatment drug. It damages DNA in tumor cells. Tumor cells with damaged DNA may die, resulting in cell death. Researchers want to see if this drug is a safe and effective treatment for solid tumors and lymphomas that have not responded to earlier treatment.

Objectives:

- To see if Indenoisoquinoline LMP400 is a safe and effective treatment for advanced solid tumors or lymphomas.

Eligibility:

- Individuals at least 18 years of age who have solid tumors or lymphomas that have not responded to treatment.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor samples may also be collected. The size and location of the tumors will be determined with imaging studies.
* Indenoisoquinoline LMP400 is given in a 28-day cycle. Participants will receive the drug by intravenous infusion on days 1, 8, and 15 of each cycle, followed by a break of 13 days without the drug.
* Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples will be optional.
* Participants will continue their cycles of treatment as long as the cancer does not grow and there are no severe side effects.

Background:

* 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.

Primary Objectives:

* 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.

Secondary Objectives:

* 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.

Eligibility:

-Patients with histologically confirmed metastatic solid tumors and lymphomas; adequate organ function.

Study Design:

* 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 apoptosis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas	NCT01051635	Neoplasms Lymphoma	LMP400 LMP776	18 Years -	National Institutes of Health Clinical Center (CC)
Indenoisoquinoline LMP400 for Advanced Solid Tumors and Lymphomas	NCT01794104	Neoplasm Lymphoma	LMP400	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Indenoisoquinoline LMP400 for Advanced Solid Tumors and Lymphomas	NCT01794104	Neoplasm Lymphoma	LMP400	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas	NCT01051635	Neoplasms Lymphoma	LMP400 LMP776	18 Years -	National Institutes of Health Clinical Center (CC)

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