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.

Start Date15 Feb 2013

Sponsor / Collaborator

National Cancer Institute

NCT01051635 / CompletedPhase 1IIT

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

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.

Start Date25 Jan 2010

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Indotecan

100 Translational Medicine associated with Indotecan

100 Patents (Medical) associated with Indotecan

Literatures (Medical) associated with Indotecan

01 Mar 2023·Cancer chemotherapy and pharmacology

Evaluating the indotecan–neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions

Article

Author: Beumer, Jan H ; Doroshow, James ; Gobburu, Jogarao ; Kennard, Benjamin C ; Holleran, Julianne L ; Zlott, Jennifer ; Kummar, Shivaani ; Park, Wansu ; Moore, Nancy ; Miller, Brian M ; Chen, Alice ; Dunn, Allison

PURPOSE:

This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan-neutropenia relationship in patients with solid tumors.

METHODS:

Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner. Final model qualification included bootstrap simulation, visual and quantitative predictive checks, and goodness-of-fit. A sigmoidal E_max model was developed to describe the relationship between average concentration and maximum percent neutrophil reduction. Simulations at fixed doses were conducted to determine the mean predicted decrease in neutrophil count for each schedule.

RESULTS:

518 concentrations from 41 patients supported a three-compartment pharmacokinetic model. Body weight and body surface area accounted for inter-individual variability of central/peripheral distribution volume and intercompartmental clearance, respectively. Estimated typical population values were CL 2.75 L/h, Q3 46.0 L/h, and V3 37.9 L. The estimated value of Q2 for a typical patient (BSA = 1.96 m²) was 17.3 L/h, while V1 and V2 for a typical patient (WT = 80 kg) was 33.9 L and 132 L. The final sigmoidal E_max model estimated that half-maximal ANC reduction occurs at an average concentration of 1416 µg/L and 1041 µg/L for the daily and weekly regimens, respectively. Simulations of the weekly regimen demonstrated lower percent reduction in ANC compared to the daily regimen at equivalent cumulative fixed doses.

CONCLUSION:

The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect.

01 Aug 2020·Molecular cancer therapeuticsQ2 · MEDICINE

The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2

Q2 · MEDICINE

Article

Author: Pommier, Yves ; James, Amy ; Huang, Shar-yin N. ; Marzi, Laetitia ; Difilippantonio, Simone ; Sun, Yilun

Abstract:

The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)- and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.

15 Oct 2019·Clinical cancer research : an official journal of the American Association for Cancer ResearchQ1 · MEDICINE

The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib

Q1 · MEDICINE

Article

Author: Marzi, Laetitia ; Etemadi, Moudjib ; Beshiri, Michael L. ; Pommier, Yves ; Kelly, Kathleen ; Gordon, Melanie ; Murai, Junko ; Szabova, Ludmila ; Sharan, Shyam K. ; Weaver Ohler, Zoe

Abstract:

Purpose::

Irinotecan and topotecan are used to treat a variety of different cancers. However, they have limitations, including chemical instability and severe side effects. To overcome these limitations, we developed the clinical indenoisoquinolines: LMP400 (indotecan), LMP776 (indimitecan), and LMP744. The purpose of the study is to build the molecular rationale for phase II clinical trials.

Experimental Design::

CellMinerCDB (http://discover.nci.nih.gov.libproxy1.nus.edu.sg/cellminercdb) was used to mine the cancer cell lines genomic databases. The causality of Schlafen11 (SLFN11) was validated in isogenic cell lines. Because topoisomerase I (TOP1)-mediated replication DNA damage is repaired by homologous recombination (HR), we tested the “synthetic lethality” of HR-deficient (HRD) cells. Survival and cell-cycle alterations were performed after drug treatments in isogenic DT40, DLD1, and OVCAR cell lines with BRCA1, BRCA2, or PALB2 deficiencies and in organoids cultured from prostate cancer patient-derived xenografts with BRCA2 loss. We also used an ovarian orthotopic allograft model with BRCA1 loss to validate the efficacy of LMP400 and olaparib combination.

Results::

CellMinerCDB reveals that SLFN11, which kills cells undergoing replicative stress, is a dominant drug determinant to the clinical indenoisoquinolines. In addition, BRCA1-, BRCA2-, and PALB2-deficient cells were hypersensitive to the indenoisoquinolines. All 3 clinical indenoisoquinolines were also synergistic with olaparib, especially in the HRD cells. The synergy between LMP400 and olaparib was confirmed in the orthotopic allograft model harboring BRCA1 loss.

Conclusions::

Our results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11.

100 Deals associated with Indotecan

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	US	Gibson Oncology LLC	08 Mar 2020
Advanced Malignant Solid Neoplasm	Phase 1	US	National Cancer Institute	15 Feb 2013
Lymphoma	Phase 1	US	National Cancer Institute	25 Jan 2010
Relapsed Solid Neoplasm	Phase 1	US	National Cancer Institute	25 Jan 2010
Malignant glioma of brain	Preclinical	US	Gibson Oncology LLC	02 Nov 2023
Ewing Sarcoma	Preclinical	US	Gibson Oncology LLC	16 Sep 2020

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2017	Not Applicable	-	-	Indotecan (LMP400)	hajqhbiidp(btosxfkcal) = qmofnoneoy pophizyfjl (whbrpufful )	-	01 Jul 2017
				Imidotecan (LMP776)	hajqhbiidp(btosxfkcal) = qzbrtcqmsd pophizyfjl (whbrpufful )

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

Indotecan

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation