Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Antineoplastic Agents

Valproic Acid

Topoisomerase I Inhibitors

Enzyme Inhibitors

Neurotransmitter Agents

All patients enrolled in the Phase II will be treated with Valproic Acid (VPA) and Karenitecin using the dosing schedule determined to be the Maximum Tolerated Dose (MTD) in Phase I.

Karenitecin

Adil Daud, M.D.

This is a Phase I study looking at the combination of Valproic Acid (VPA) and Karenitecin to treat patients with metastatic malignant melanoma. We will find the dose-limiting toxicity (DLT) and the highest dose (maximum tolerated dose) of this combination treatment that has acceptable side effects and recommend a Phase II dose level.

There will be seven escalating doses of Valproic acid and one dose escalation step of Karenitecin. Each patient shall receive one cycle of Karenitecin alone (cycle 1 days 1 - 5) followed by the same dose of Karenitecin given in combination with VPA (cycle 2 days 1-7). Patients will receive oral VPA in divided doses for 5 days and Karenitecin starting on the 3rd day every 3 weeks (a treatment cycle).

Treatment will continue until progression of disease or an unacceptable level of toxicity. After 2 cycles of treatment there will be the first efficacy evaluation or restaging of the disease. In the absence of disease progression and if there is continued safety and tolerability, treatment may continue.

Treatment cycles are every 3 weeks and there are 17 study visits in all.

During Phase I subjects will receive one cycle of Karenitecin alone (cycle 1 days 1-5) and then combination therapy with VPA + Karenitecin (cycle 2 days 1-7)followed by oral VPA in divided doses for 5 days and Karenitecin starting the third day (days 3-7) every 3 weeks. After 2 cycles of treatment there will be the first efficacy evaluation or restaging of the disease.

Dose escalations will continue until unacceptable dose limiting toxicity (DLT) occurs, then dose escalation will be stopped and the previous dose level will be explored. In each dose level, participants will undergo pharmacokinetic (PK) sampling to determine blood levels. The melanoma skin lesions will also be biopsied to measure the effect of the combination therapy.

All patients enrolled in the Phase II will be treated with VPA and Karenitecin using the dosing schedule determined to be the MTD in Phase I. In the absence of disease progression and if there is continued safety and tolerability, treatment may continue in consecutive 3 week cycles.

Phase I/II Trial of Valproic Acid and Karenitecin for Melanoma

Phase I/II Trial of Valproic Acid and Karenitecin for Metastatic Malignant Melanoma

BioNumerik Pharmaceuticals, Inc.

H. Lee Moffitt Cancer Center and Research Institute

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle

Indenoisoquinolines, such as LMP744, are potent inhibitors of the enzyme topoisomerase I (Top1). Top1 is necessary for transcription, replication, recombination, and the repair of double-strand DNA breaks. It relaxes the supercoiled DNA by introducing a single-strand break, generating a free strand that rotates around the Top1-bound DNA complex. In the absence of external triggers, Top1-DNA cleavage complexes are generally short lived. Top1 inhibitors are potent anticancer agents because they stabilize the formation of the Top1-DNA cleavage complex in tumor cells, which induces DNA damage, delays DNA repair, and results in cell cycle arrest and apoptosis. LMP744 exhibited antitumor activity with lower toxicity than other agents in preclinical studies. Treatment of patients with LMP744 is expected to reduce tumor burden at doses that are well-tolerated.

LMP744

Alice P Chen, M.D.

Background:

The new drug LMP744 damages DNA. This causes cell death. Researchers want to see if it can treat certain kinds of cancer. They want to understand how the drug works and how it affects the body.

Objective:

To test the safety of LMP744 and find out the dose of the drug that can be safely given to humans.

Eligibility:

Adults at least 18 years old who have metastatic solid tumors or lymphoma, which have progressed after other treatment.

Design:

Participants will be screened with:

* Vital signs taken
* Blood and urine tests
* Heart tests
* Scans or ultrasound

Some participants will have a tumor sample taken 2 times. A small piece of tumor is removed by a small needle. A scan or ultrasound will guide the process.

The study will be done in 28-day cycles.

Each cycle, participants will get the study drug in a vein for 60 minutes once a day for 5 days.

For day 1 of cycle 1, participants will be admitted to the clinic and have blood and urine taken several times.

At the beginning of each cycle, participants will have a clinic visit and repeat some screening tests. They will also do this twice in the middle of cycle 1 and once in the middle of cycle 2.

After participants stop taking the study drug, they will be followed for 30 days. They may give blood samples. They will be contacted by phone to see how they are doing....

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:

-To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC 706744) administered intravenously (IV) daily for 5 days (QD x 5) schedule in patients with refractory solid tumors and lymphomas.

Secondary Objectives:

-Characterize the pharmacokinetic (PK) profile of LMP744.

Exploratory Objectives:

* Evaluate the effect of LMP744 on markers of DNA damage (yH2AX, pNbs1, pATR, ERCC1, RAD51, Topo1cc, Top1, SLFN11) and epithelial-mesenchymal transition (EMT) in circulating tumor cells (CTCs) and pre- and post- treatment tumor biopsies in patients at the expansion cohort.
* Assess preliminary antitumor activity of LMP744.
* Examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with response or resistance to treatment

Eligibility:

-Adult patients must have histologically documented, relapsed solid tumors which have progressed after one line of therapy, or lymphoma which has progressed after initial therapy and without potentially curative options, or patient refuses potentially curative therapy.

Study Design:

* Cycle 1 and subsequent cycles: Patients will receive LMP744 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. Tumor biopsies will be mandatory during the expansion phase.

LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle

Blood samples for PK analyses will be collected at the following timepoints in cycle 1 only:

Day 1, prior to drug administration, 2 minutes (+/- 2 minutes) before end of infusion, and at appropriate time points post infusion (15 minutes, 30 minutes, and 1, 2, 4, and 6 hours post infusion)

Day 2, 24 hr post day 1 start of infusion (prior to day 2 infusion), and 2 minutes (+/- 2 minutes) before the end of infusion

Day 3, 24 hr post day 2 start of infusion (prior to day 3 infusion), and 2 minutes (+/- 2 minutes) before end of infusion

Day 4, 24 hr post day 3 start of infusion (prior to day 4 infusion), and 2 minutes (+/- 2 minutes) before end of infusion

Day 5, 24 hr post day 4 start of infusion (prior to day 5 infusion), and 2 minutes (+/- 2 minutes) before end of infusion

Day 8, 72 hr post day 5 start of infusion Blood for circulating tumor cells (CTCs) (optional) will be collected at baseline, on day 3 of

cycle 1 (within 2 to 4 hours after the start of LMP744 infusion), on day 1 of every subsequent cycle (prior to drug infusion), and at disease progression.

Tumor biopsies (mandatory in expansion phase) will be obtained at baseline and then on day 2 (1-4 hours after the LMP744 infusion) in cycle 1 only.

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

.All IPD recorded in the medical record will be shared with intramural investigators upon request. All collected IPD will be shared with collaborators under the terms of collaborative agreements.

Maximum tolerated dose (MTD) of LMP744 administered intravenously (IV) daily for 5 days (QD x 5) schedule in patients with refractory solid tumors and lymphomas

National Cancer Institute (NCI)

Gimatecan

Novartis Pharmaceuticals

CLBQ707A1101 assesses the tolerability, safety, efficacy and pharmacokinetics of gimatecan in Japanese patients.

An Extension Trial to a Phase I Dose Escalation Study of Gimatecan Administered Orally 5 Consecutive Days to Japanese Patients With Advanced Solid Tumor

An Extension Trial to a Phase I Dose Escalation Study of LBQ707 (Gimatecan) Administered Orally 5 Consecutive Days to Japanese Patients With Advanced Solid Tumor

Novartis

This study assesses the tolerability, safety, efficacy and pharmacokinetics of gimatecan in Japanese patients. Gimatecan is administered orally twice per week, every 28 days, to adult patients with advanced solid tumors who have progressed despite standard therapy or for whom standard systemic therapy dose not exist.

A Phase I Dose Escalation Study of LBQ707 (Gimatecan) Administered Orally Twice Per Week to Japanese Patients With Advanced Solid Tumors

A Phase I Dose Escalation Study of LBQ707 (Gimatecan) Administered Orally Twice Per Week to Japanese Patients With Advanced Solid Tumors.

External Affairs

This study assesses the tolerability, safety, efficacy and pharmacokinetics of gimatecan in Japanese patients. Gimatecan is administered orally for five consecutive days, every 28 days, to adult patients with advanced solid tumors who have progressed despite standard therapy or for whom standard systemic therapy does not exist.

A Dose Escalation of Gimatecan Administered Orally to Japanese Patients With Advanced Solid Tumor.

A Phase I Dose Escalation Study of LBQ707 (Gimatecan) Administered Orally 5 Consecutive Days to Japanese Patients With Advanced Solid Tumor.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I/II Trial of Valproic Acid and Karenitecin for Melanoma	NCT00358319	Malignant Melan...	Karenitecin Valproic Acid	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas	NCT03030417	Solid Tumors Lymphoma	LMP744	18 Years -	National Institutes of Health Clinical Center (CC)
An Extension Trial to a Phase I Dose Escalation Study of Gimatecan Administered Orally 5 Consecutive Days to Japanese Patients With Advanced Solid Tumor	NCT00441610	Advanced Solid ...	Gimatecan	20 Years -	Novartis
A Phase I Dose Escalation Study of LBQ707 (Gimatecan) Administered Orally Twice Per Week to Japanese Patients With Advanced Solid Tumors	NCT00487058	Advanced Solid ...	Gimatecan	20 Years -	Novartis
A Dose Escalation of Gimatecan Administered Orally to Japanese Patients With Advanced Solid Tumor.	NCT00410358	Advanced Solid ...	Gimatecan	20 Years -	Novartis
A Phase I Dose Escalation Study of LBQ707 (Gimatecan) Administered Orally Twice Per Week to Japanese Patients With Advanced Solid Tumors	NCT00487058	Advanced Solid ...	Gimatecan	20 Years -	Novartis

Spots Global Cancer Trial Database for topoisomerase i inhibitor