Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

NCT03030417 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 17004517-C-0045
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 2

Brief Summary

Background: The new drug LMP744 (NSC 706744) damages deoxyribonucleic acid (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....

Conditions

Solid Tumors; Lymphoma

Keywords

Topoisomerase I Inhibitor; Epithelial-Mesenchymal Transition; Pharmacodynamics; DNA Damage; Pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• Dose Escalation Phase: Maximum Tolerated Dose (MTD) of LMP744 (NSC 706744)

  Maximum tolerated dose (MTD) of LMP744 administered intravenously (IV) daily for 5 days (QD x 5) schedule in participants with refractory solid tumors and lymphomas. The MTD is the dose level at which no more than 1 in 6 participants experience dose-limiting toxicity (DLT), and the dose below that at which ≥ 2 (of ≤ 6) participants have DLT as a result of the drug. A DLT is Grade ≥3 non-hematologic toxicity except Grade 3 fatigue lasting ≤ 7 days. Grade 4 hematological toxicity if it meets the following criteria: Lymphopenia (any grade) will not be considered dose limiting for all participants; Anemia: Grade 4 anemia will be considered dose limiting. Any neurotoxicity Grade ≥2 that is not reversible to a Grade ≤1 within 2 weeks. Any non-hematologic Grade 2 toxicity that does not resolve to Grade ≤1 or baseline within 14 days despite adequate treatment, except for alopecia.

  Cycle 1 (28 days)

Secondary Outcomes (5)

• Dose Escalation & Dose Expansion Phase: Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF) of LMP744 (NSC 706744)

  Day 1, prior to drug administration, 2 minutes before end of infusion; 15 minutes, 30 minutes, and 1, 2, 4, and 6 hours post infusion on Day 1 and prior to start of infusion on Day 2.

• Dose Escalation & Dose Expansion Phase: Apparent Half-Life of LMP744 (NSC 706744)

  Day 1, prior to drug administration, 2 minutes before end of infusion; 15 minutes, 30 minutes, and 1, 2, 4, and 6 hours post infusion on Day 1 and prior to start of infusion on Day 2.

• Dose Escalation & Dose Expansion Phase: Time to Maximum (Tmax) Concentration of LMP744 (NSC 706744)

  Day(D)1, prior to drug administration, 2 minutes (min) before end of infusion; 15 min., 30 min., and 1, 2, 4, and 6 hours (hr) post infusion on D1. 24 hrs post D2, 3, & 4 start of infusion & 2 min. before end of infusion. 72 hrs post D5 start of infusion.

• Dose Escalation & Dose Expansion Phase: Maximum Concentration of LMP744 (NSC 706744)

  Day(D)1, prior to drug administration, 2 minutes (min) before end of infusion; 15 min., 30 min., and 1, 2, 4, and 6 hours (hr) post infusion on D1. 24 hrs post D2, 3, & 4 start of infusion & 2 min. before end of infusion. 72 hrs post D5 start of infusion.

• Dose Escalation & Dose Expansion Phase: Percent Change in End of Infusion Concentration of LMP744 (NSC 706744)

  Day 1 at end of infusion to Day 5 end of infusion.

Other Outcomes (10)

• Dose Escalation & Dose Expansion Phase: Percentage of Participants With Confirmed Objective Response Following Treatment With LMP744 (NSC 706744)

  Tumor re-staging was performed every 2 cycles for the first year on study then every 3 cycles thereafter until a participant met criteria to be removed from the study; a median of 2 cycles completed and a full range of 0-31 cycles completed.

• Dose Expansion Phase: Percent of Nuclear Area Positive (NAP) for Phosphorylated Nibrin (pNbs1) Staining

  Baseline (pre-treatment) and Cycle 1 Day 1 at 1-4 hours after the end of the LMP744 (NSC 706744) infusion.

• Dose Expansion Phase: Percent of Nuclear Area Positive (NAP) for RAD Recombinase (Rad51) Staining

  Baseline (pre-treatment) and Cycle 1 Day 1 at 1-4 hours after the end of the LMP744 (NSC 706744) infusion.

Study Arms (1)

Treatment Arm - LMP744 (NSC 706744)

EXPERIMENTAL

LMP744 (NSC 706744) will be administered intravenous (IV) over 1 hour on days 1-5 of each 28-day cycle.

Drug: LMP744; Other: Ondansetron; Other: Olanzapine; Other: Lorazepam; Other: Diphenoxylate hydrocholoride (HCL) + Atropine Sulfate; Other: Loperamide; Other: Diphenhydramine; Other: Steroid; Other: Epinephrine

Interventions

LMP744 DRUG

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 deoxyribonucleic acid (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.

Also known as: NSC 706744

Treatment Arm - LMP744 (NSC 706744)

Ondansetron OTHER

Anti-emetic for nausea or vomiting.

Also known as: Zofran ODT, Zuplenz, Zofran

Treatment Arm - LMP744 (NSC 706744)

Olanzapine OTHER

Persistent nausea or vomiting.

Also known as: Zyprexa Relprevv, Zyprexa Zydis, Zyprexa

Treatment Arm - LMP744 (NSC 706744)

Lorazepam OTHER

Persistent nausea or vomiting.

Also known as: Lorazepam Intensol, Ativan

Treatment Arm - LMP744 (NSC 706744)

Diphenoxylate hydrocholoride (HCL) + Atropine Sulfate OTHER

Diphenoxylate hydrocholoride (HCL) 2.5 mg + Atropine Sulfate 0.025 mg/tablet for diarrhea.

Also known as: Lomocot, Lomotil, Lonox, Vi-Atro

Treatment Arm - LMP744 (NSC 706744)

Loperamide OTHER

Antidiarrheal. 4mg by mouth (PO) after first unformed stool and 2mg PO every 2 hours as long as unformed stools continue. No more than 16mg during a 24-hour period.

Also known as: Imodium A-d, Diamode, Anti-Diarrheal (loperamide)

Treatment Arm - LMP744 (NSC 706744)

Diphenhydramine OTHER

Diphenhydramine 50 mg intravenous (IV) for allergic reaction.

Also known as: Benadryl, Nytol, Banophen

Treatment Arm - LMP744 (NSC 706744)

Steroid OTHER

For allergic reaction at discretion of principal investigator.

Treatment Arm - LMP744 (NSC 706744)

Epinephrine OTHER

For allergic reaction at discretion of principal investigator.

Also known as: Adrenaline

Treatment Arm - LMP744 (NSC 706744)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically documented metastatic 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.
• Patients must have measurable or evaluable disease
• Age greater than or equal to 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Life expectancy of greater than 3 months.
• Patients must have normal organ and marrow function as defined below:
• leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets greater than or equal to 100,000/mcL
• total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/ alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (SGPT) less than or equal to 2.5 institutional upper limit of normal (ULN)
• Serum creatinine less than or equal to 1.5 institutional ULN
• creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 for patients with serum creatinine levels greater than 1.5 x higher than institutional normal.
• Anticoagulation with low-molecular-weight heparin (LMWH) or any direct oral anticoagulant (direct oral anticoagulants (DOAC), e.g., rivaroxaban, apixaban, dabigatran, or edoxaban) will be permitted. Patients receiving treatment with warfarin will be given the option to switch to LMWH or a DOAC.
• Patients must have recovered to grade 1 or baseline from adverse events (AEs) and/or toxicity of prior chemotherapy or biologic therapy. They must not have had chemotherapy, biologic therapy, or definitive radiotherapy within 4 weeks (6 weeks for nitrosoureas and mitomycin C) or 5 half-lives, whichever is shorter, prior to entering the study. Palliative-intent radiotherapy (30 Gray (Gy) or less) must be completed at least 2 weeks prior to start of treatment and may not be to a lesion that is included as measurable disease. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (where a sub-therapeutic dose of drug is administered) at the PI's discretion and should have recovered to grade 1 or baseline from any toxicities.

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 1 month after treatment of the brain metastases. Patients on anti-seizure medications or steroid therapy may be enrolled at the discretion of the Principal Investigator.
• Pregnant women are excluded from this study because LMP744 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LMP744, breastfeeding should be discontinued if the mother is treated.
• Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15260, United States

Location

Related Publications (4)

• Antony S, Kohlhagen G, Agama K, Jayaraman M, Cao S, Durrani FA, Rustum YM, Cushman M, Pommier Y. Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison. Mol Pharmacol. 2005 Feb;67(2):523-30. doi: 10.1124/mol.104.003889. Epub 2004 Nov 5.

  PMID: 15531731 BACKGROUND

• Antony S, Agama KK, Miao ZH, Takagi K, Wright MH, Robles AI, Varticovski L, Nagarajan M, Morrell A, Cushman M, Pommier Y. Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance. Cancer Res. 2007 Nov 1;67(21):10397-405. doi: 10.1158/0008-5472.CAN-07-0938.

  PMID: 17974983 BACKGROUND

• Meng LH, Liao ZY, Pommier Y. Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem. 2003;3(3):305-20. doi: 10.2174/1568026033452546.

  PMID: 12570765 BACKGROUND

• O'Sullivan Coyne G, Kummar S, Rubinstein LV, Wilsker D, Moore N, Hogu M, Piekarz R, Covey J, Beumer JH, Ferry-Galow KV, Villaruz LC, Hollingshead MG, Holleran JL, Deppas JJ, Pommier Y, Ko B, Johnson BC, Parchhment RE, Ivy P, Doroshow JH, Chen AP. Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas. Cancer Chemother Pharmacol. 2025 May 29;95(1):58. doi: 10.1007/s00280-025-04778-5.

  PMID: 40439882 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma

Interventions

6-(3-(2-hydroxyethyl)amino-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno(1,2-)isoquinoline; Ondansetron; Olanzapine; Lorazepam; Atropine; atropine sulfate-diphenoxylate hydrochloride drug combination; Loperamide; Diphenhydramine; Steroids; Epinephrine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring; Benzodiazepines; Benzazepines; Benzodiazepinones; Atropine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring; Piperidines; Ethylamines; Amines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Fused-Ring Compounds; Polycyclic Compounds; Ethanolamines; Amino Alcohols; Alcohols; Biogenic Monoamines; Biogenic Amines; Catecholamines; Catechols; Phenols

Results Point of Contact

• Title: Dr. Alice P. Chen
• Organization: National Cancer Institute

chenali@mail.nih.gov

240-781-3320

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Investigator

Study Record Dates

• First Submitted: January 24, 2017
• First Posted: January 25, 2017
• Study Start: February 27, 2017
• Primary Completion: October 2, 2023
• Study Completion: October 12, 2023
• Last Updated: December 10, 2024
• Results First Posted: December 10, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Requests for all collected individual participant data (IPD) data from clinical trials, conducted under a binding collaborative agreement between National Cancer Institute (NCI)/Division of Cancer Treatment and Diagnosis (DCTD) and a pharmaceutical/biotechnology company, that are not under Data and Safety Monitoring Board (DSMB) monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).

Locations

US (2)