Solid TumorsPhase 1NCT03030417
Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas
A Phase 1 study testing LMP744, Ondansetron and Olanzapine in people with Solid Tumors and Lymphoma, run by National Cancer Institute (NCI) at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumors, Lymphoma
- What is being tested?
- LMP744, Ondansetron and Olanzapine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 2 sitesUnited States
- Study dates
- 27 Feb 2017to 12 Oct 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
Show all 23Show fewer
- 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
- OR
- 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.
- Patients receiving denosumab or bisphosphonates for any cancer or undergoing androgen deprivation therapy for prostate cancer are eligible for this therapy.
- Prior therapy with topoisomerase I inhibitors is allowed.
- Patients with known human immunodeficiency virus (HIV)-positive status are eligible provided the following criteria are met: cluster of differentiation 4 (CD4) count >350/mm^3, an undetectable viral load, and not receiving prophylaxis antibiotics. Diagnostic HIV testing will not be performed during screening or throughout this study.
- The effects of LMP744 (NSC 706744) on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women and men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of LMP744 administration.
- Ability to understand and the willingness to sign a written informed consent document.
- Willingness to provide blood and new tumor biopsy samples for research purposes if on the expansion phase of the study.
- Both men and women of all races and ethnic groups are eligible for this trial.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
University of Pittsburgh
Pittsburgh, Pennsylvania, 15260
About this study
Official title: A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas
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.
Read more
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....
Read the detailed description
Background:
- Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with improved characteristics over their predecessors. Indenoisoquinolines have better chemical stability, producing stable deoxyribonucleic acid (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, ATP-binding cassette super-family G member 2 (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 every day (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 phosphorylated H2AX (γH2AX), phosphorylated Nijmegen breakage syndrome 1 (pNbs1), pATR, excision repair cross-complementation group 1 (ERCC1), RAD51 recombinase (RAD51), Topo1cc, topoisomerase 1 (Top1), Schlafen family member 11 (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).
- Pharmacokinetic (PK) and pharmacodynamic (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-hour (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.
- Conditions
- Solid Tumors, Lymphoma
- Being tested
- LMP744, Ondansetron, Olanzapine, Lorazepam, Diphenoxylate hydrocholoride (HCL) + Atropine Sulfate
- Keywords
- Topoisomerase I Inhibitor, Epithelial-Mesenchymal Transition, Pharmacodynamics, DNA Damage, Pharmacokinetics
- Medical subject headings
- Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LMP744Drug
Also called NSC 706744
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.
OndansetronOther
Also called Zofran ODT, Zuplenz, Zofran
Anti-emetic for nausea or vomiting.
OlanzapineOther
Also called Zyprexa Relprevv, Zyprexa Zydis, Zyprexa
Persistent nausea or vomiting.
LorazepamOther
Also called Lorazepam Intensol, Ativan
Persistent nausea or vomiting.
Diphenoxylate hydrocholoride (HCL) + Atropine SulfateOther
Also called Lomocot, Lomotil, Lonox, Vi-Atro
Diphenoxylate hydrocholoride (HCL) 2.5 mg + Atropine Sulfate 0.025 mg/tablet for diarrhea.
LoperamideOther
Also called Imodium A-d, Diamode, Anti-Diarrheal (loperamide)
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.
DiphenhydramineOther
Also called Benadryl, Nytol, Banophen
Diphenhydramine 50 mg intravenous (IV) for allergic reaction.
SteroidOther
For allergic reaction at discretion of principal investigator.
EpinephrineOther
Also called Adrenaline
For allergic reaction at discretion of principal investigator.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: LMP744; Other: Ondansetron; Other: Olanzapine; Other: Lorazepam; Other: Diphenoxylate hydrocholoride (HCL) + Atropine Sulfate; Other: Loperamide; Other: Diphenhydramine; Other: Steroid; Other: Epinephrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
AUC is a measure of the serum concentration of LMP744 over time. It is used to characterize drug absorption.
Measured: 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)
Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Measured: 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)
Time to maximum (Tmax) concentration of LMP744 (NSC 706744).
Measured: 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)
To determine the maximum observed plasma concentration of LMP744, blood samples will be collected from participants and analyzed using a validated liquid chromatography-mass spectrometry (LC-MS) or liquid Chromatography with tandem mass spectrometry (LC-MS-MS) method and calculated by non-compartmental analysis.
Measured: 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)
Percent change in end of infusion drug concentration is a measure of LMP744 (NSC 706744) accumulation in the bloodstream from Day 1 to Day 5.
Measured: Day 1 at end of infusion to Day 5 end of infusion.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jan 2017 (estimated)
- Study start27 Feb 2017
- Primary completion2 Oct 2023
- Study completion12 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Solid TumorsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Alice Chen, M.D., National Cancer Institute (NCI)
- Investigators
- Alice P Chen, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03030417
- Sponsor's protocol ID
- 170045
- Other IDs
- 17-C-0045
- Status last verified
- Nov 2024
- First submitted
- 24 Jan 2017
- Last updated
- 10 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All individual participant data (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.
Publications
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.
PubMed 15531731Antony 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.
PubMed 17974983Meng 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.
PubMed 12570765O'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.
PubMed 40439882
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas
- ClinicalTrials.gov ID
- NCT03030417
- Acronym / sponsor ID
- 170045
- Conditions
- Solid Tumors, Lymphoma
- Keywords
- Topoisomerase I Inhibitor, Epithelial-Mesenchymal Transition, Pharmacodynamics, DNA Damage, Pharmacokinetics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 27 Feb 2017 (actual)
- Primary completion
- 2 Oct 2023 (actual)
- Study completion
- 12 Oct 2023 (actual)
- First posted
- 25 Jan 2017 (estimated)
- Results
- Posted 10 Dec 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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....
Detailed description
Background:
- Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with improved characteristics over their predecessors. Indenoisoquinolines have better chemical stability, producing stable deoxyribonucleic acid (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, ATP-binding cassette super-family G member 2 (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 every day (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 phosphorylated H2AX (γH2AX), phosphorylated Nijmegen breakage syndrome 1 (pNbs1), pATR, excision repair cross-complementation group 1 (ERCC1), RAD51 recombinase (RAD51), Topo1cc, topoisomerase 1 (Top1), Schlafen family member 11 (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).
- Pharmacokinetic (PK) and pharmacodynamic (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-hour (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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment Arm - LMP744 (NSC 706744) | Experimental | Drug: LMP744, Other: Ondansetron, Other: Olanzapine, Other: Lorazepam, Other: Diphenoxylate hydrocholoride (HCL) + Atropine Sulfate, Other: Loperamide, Other: Diphenhydramine, Other: Steroid, Other: EpinephrineLMP744 (NSC 706744) will be administered intravenous (IV) over 1 hour on days 1-5 of each 28-day cycle. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- 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)
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LMP744Also: NSC 706744Indenoisoquinolines, 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. | Drug | Treatment Arm - LMP744 (NSC 706744) |
| OndansetronAlso: Zofran ODT, Zuplenz, ZofranAnti-emetic for nausea or vomiting. | Other | Treatment Arm - LMP744 (NSC 706744) |
| OlanzapineAlso: Zyprexa Relprevv, Zyprexa Zydis, ZyprexaPersistent nausea or vomiting. | Other | Treatment Arm - LMP744 (NSC 706744) |
| LorazepamAlso: Lorazepam Intensol, AtivanPersistent nausea or vomiting. | Other | Treatment Arm - LMP744 (NSC 706744) |
| Diphenoxylate hydrocholoride (HCL) + Atropine SulfateAlso: Lomocot, Lomotil, Lonox, Vi-AtroDiphenoxylate hydrocholoride (HCL) 2.5 mg + Atropine Sulfate 0.025 mg/tablet for diarrhea. | Other | Treatment Arm - LMP744 (NSC 706744) |
| LoperamideAlso: Imodium A-d, Diamode, Anti-Diarrheal (loperamide)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. | Other | Treatment Arm - LMP744 (NSC 706744) |
| DiphenhydramineAlso: Benadryl, Nytol, BanophenDiphenhydramine 50 mg intravenous (IV) for allergic reaction. | Other | Treatment Arm - LMP744 (NSC 706744) |
| SteroidFor allergic reaction at discretion of principal investigator. | Other | Treatment Arm - LMP744 (NSC 706744) |
| EpinephrineAlso: AdrenalineFor allergic reaction at discretion of principal investigator. | Other | Treatment Arm - LMP744 (NSC 706744) |
Primary outcome
Dose Escalation Phase: Maximum Tolerated Dose (MTD) of LMP744 (NSC 706744)
Time frame: Cycle 1 (28 days)
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.
5 secondary outcomes
Dose Escalation & Dose Expansion Phase: Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF) of LMP744 (NSC 706744)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Day 1 at end of infusion to Day 5 end of infusion.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 15531731Antony 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.
- Background: PubMed 17974983Antony 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.
- Background: PubMed 12570765Meng 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.
- Derived from this study: PubMed 40439882O'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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. All individual participant data (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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alice P Chen, M.D. principal investigator
National Cancer Institute (NCI)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LMP744, Ondansetron and Olanzapine in people with Solid Tumors and Lymphoma, run by National Cancer Institute (NCI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Dose Escalation Phase: Maximum Tolerated Dose (MTD) of LMP744 (NSC 706744) (time frame: Cycle 1 (28 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03030417, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2024.