Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03030417
Recruitment Status : Recruiting
First Posted : January 25, 2017
Last Update Posted : July 23, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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
Solid Tumors Lymphoma Drug: LMP744 Phase 1

Detailed Description:

Background:

  • Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) withimproved 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 ( >=H2AX, pNbs1, pATR, ERCC1, RAD51) 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 optional during the escalation phase and mandatory during the expansion phase.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated 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 : February 27, 2017
Estimated Primary Completion Date : October 2, 2022
Estimated Study Completion Date : October 2, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

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.




Primary Outcome Measures :
  1. To establish the safety, tolerability and the maximum tolerated dose(MTD) of LMP744 (NSC 706744) [ Time Frame: 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 [ Time Frame: cycle 1 ]
    Characterize the pharmacokinetic (PK) profile of LMP744



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

    7. 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.

    8. 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.
    9. Patients receiving denosumab or bisphosphonates for any cancer or undergoing androgen deprivation therapy for prostate cancer are eligible for this therapy.
    10. Prior therapy with topoisomerase I inhibitors is allowed.
    11. HIV-positive patients are eligible provided the following criteria are met: CD4 count >350/mm3, an undetectable viral load, and not receiving prophylaxis antibiotics.
    12. 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.
    13. Ability to understand and the willingness to sign a written informed consent document.
    14. 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.

  3. 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.
  4. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03030417


Contacts
Layout table for location contacts
Contact: Brooksley F Augustine (240) 858-3197 brooke.augustine@nih.gov

Locations
Layout table for location information
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15260
Contact: Anuradha Krishnamurthy, M.D.    412-864-7764    krishnamurthya2@upmc.org   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Geraldine H O'Sullivan Coyne, M.D. National Cancer Institute (NCI)
Additional Information:
Publications:
Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03030417    
Other Study ID Numbers: 170045
17-C-0045
First Posted: January 25, 2017    Key Record Dates
Last Update Posted: July 23, 2021
Last Verified: February 1, 2021

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Topoisomerase I Inhibitor
Epithelial-Mesenchymal Transition
Pharmacodynamics
DNA Damage
Pharmacokinetics
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases