Clinical Trials /

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

NCT03030417

Description:

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.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas
  • Official Title: A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 170045
  • SECONDARY ID: 17-C-0045
  • NCT ID: NCT03030417

Conditions

  • Solid Tumors
  • Lymphoma

Interventions

DrugSynonymsArms
LMP7441

Purpose

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.

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.

        -  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 that are
      metastatic or unresectable, or lymphoma which had progressed after all FDA-approved therapy,
      therapy associated with overall survival benefit, or for which no standard of care therapy
      exists.

      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 and mandatory during the
           expansion phase.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalLMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle
  • LMP744

Eligibility Criteria

        -  ELIGIBILITY CRITERIA:

               1. Patients must have histologically documented metastatic solid tumors which have
                  progressed after one line of therapy, or lymphoma which has progressed after all
                  FDA-approved therapy.

               2. Patients must have measurable disease, defined as at least one lesion that can
                  be accurately measured in at least one dimension (longest diameter to be
                  recorded for non-nodal lesions and short axis for nodal lesions) as greater than
                  or equal to 20 mm (greater than or equal to 2 cm) with conventional techniques
                  or as greater than or equal to 10 mm (greater than or equal to 1 cm) with spiral
                  CT scan, MRI, or calipers by clinical exam.

               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

                  creatinine within normal institutional limits

                  OR

                  creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients
                  with creatinine levels above institutional normal.

               7. Anticoagulation with low-molecular-weight heparin (LMWH) will be permitted.
                  Patients receiving treatment with warfarin or any of the NOACs (rivaroxaban,
                  apixaban, dabigatran, or edoxaban) will be given the option to switch to LMWH.

               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 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.
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To establish the safety, tolerability and the maximum tolerated dose(MTD) of LMP744 (NSC 706744) administered intravenously (IV) dailyfor 5 days (QD x 5) schedule in patients with refractory solid tumorsand lymphomas
Time Frame:cycle 1
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Characterize the pharmacokinetic (PK) profile of LMP744
Time Frame:cycle 1
Safety Issue:
Description:
Measure:Evaluate markers of DNA damage in circulating tumor cells (CTCs)
Time Frame:throughout study
Safety Issue:
Description:
Measure:Evaluate markers of DNA damage in tumor biopsies
Time Frame:cycle 1
Safety Issue:
Description:
Measure:To assess preliminary anti-tumor activity of LMP744
Time Frame:throughout study
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Topoisomerase 1 Inhibitor
  • Epithelial-Mesenchymal Transition
  • Pharmacodynamics
  • DNA Damage
  • Pharmacokinetics

Last Updated

April 20, 2017