Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Recruiting
CT.gov ID
NCT03030417
Collaborator
(none)
53
2
1
67.1
26.5
0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

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 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.

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
53 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas
Actual Study Start Date :
Feb 27, 2017
Anticipated Primary Completion Date :
Oct 2, 2022
Anticipated Study Completion Date :
Oct 2, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment Arm

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

Drug: LMP744
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.

Outcome Measures

Primary Outcome Measures

  1. To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC 706744) [cycle 1]

    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

Secondary Outcome Measures

  1. Characterize the pharmacokinetic (PK) profile of LMP744 [cycle 1]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
  • INCLUSION CRITERIA:
  1. 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.

  2. Patients must have measurable or evaluable disease

  3. Age greater than or equal to 18 years.

  4. ECOG performance status less than or equal to 2

  5. Life expectancy of greater than 3 months.

  6. 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

AST(SGOT)/ALT(SGPT) less than or equal to 2.5 (SqrRoot) institutional upper limit of normal (ULN)

Serum creatinine less than or equal to 1.5 (SqrRoot) institutional ULN

OR

creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with serum creatinine levelsgreater than 1.5 x higher than institutional normal.

  1. Anticoagulation with low-molecular-weight heparin (LMWH) or any direct oral anticoagulant (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.

  1. 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 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.

  2. Patients receiving denosumab or bisphosphonates for any cancer or undergoing androgen deprivation therapy for prostate cancer are eligible for this therapy.

  3. Prior therapy with topoisomerase I inhibitors is allowed.

  4. Patients with known HIV-positive status are eligible provided the following criteria are met: CD4 count >350/mm3, an undetectable viral load, and not receiving prophylaxis antibiotics. Diagnostic HIV testing will not be performed during screening or throughout this study.

  5. The effects of LMP744 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.

  6. Ability to understand and the willingness to sign a written informed consent document.

  7. Willingness to provide blood and new tumor biopsy samples for research purposes if on the expansion phase of the study.

EXCLUSION CRITERIA:
  1. Patients who are receiving any other investigational agents.

  2. 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.

  1. 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.

  2. 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.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.

Contacts and Locations

Locations

Site City State Country Postal Code
1 National Institutes of Health Clinical Center Bethesda Maryland United States 20892
2 University of Pittsburgh Pittsburgh Pennsylvania United States 15260

Sponsors and Collaborators

  • National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Geraldine H O'Sullivan Coyne, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT03030417
Other Study ID Numbers:
  • 170045
  • 17-C-0045
First Posted:
Jan 25, 2017
Last Update Posted:
Jul 7, 2022
Last Verified:
May 2, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by National Cancer Institute (NCI)
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 7, 2022