<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03030417</url>
  </required_header>
  <id_info>
    <org_study_id>170045</org_study_id>
    <secondary_id>17-C-0045</secondary_id>
    <nct_id>NCT03030417</nct_id>
  </id_info>
  <brief_title>Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas</brief_title>
  <official_title>A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      The new drug LMP744 damages DNA. This causes cell death. Researchers want to see if it can&#xD;
      treat certain kinds of cancer. They want to understand how the drug works and how it affects&#xD;
      the body.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To test the safety of LMP744 and find out the dose of the drug that can be safely given to&#xD;
      humans.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Adults at least 18 years old who have metastatic solid tumors or lymphoma, which have&#xD;
      progressed after other treatment.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
        -  Vital signs taken&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Heart tests&#xD;
&#xD;
        -  Scans or ultrasound&#xD;
&#xD;
      Some participants will have a tumor sample taken 2 times. A small piece of tumor is removed&#xD;
      by a small needle. A scan or ultrasound will guide the process.&#xD;
&#xD;
      The study will be done in 28-day cycles.&#xD;
&#xD;
      Each cycle, participants will get the study drug in a vein for 60 minutes once a day for 5&#xD;
      days.&#xD;
&#xD;
      For day 1 of cycle 1, participants will be admitted to the clinic and have blood and urine&#xD;
      taken several times.&#xD;
&#xD;
      At the beginning of each cycle, participants will have a clinic visit and repeat some&#xD;
      screening tests. They will also do this twice in the middle of cycle 1 and once in the middle&#xD;
      of cycle 2.&#xD;
&#xD;
      After participants stop taking the study drug, they will be followed for 30 days. They may&#xD;
      give blood samples. They will be contacted by phone to see how they are doing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with&#xD;
           improved characteristics over their predecessors. Indenoisoquinolines have better&#xD;
           chemical stability, producing stable DNA-top1 cleavage complexes, and exhibit a&#xD;
           preference for unique DNA cleavage sites, compared with their camptothecin counterparts.&#xD;
&#xD;
        -  They have demonstrated activity against camptothecin-resistant cell lines and produce&#xD;
           DNA-protein crosslinks, which are resistant to reversal. They also show less or no&#xD;
           resistance to cells overexpressing the ATP-binding cassette (ABC) transporters, ABCG2,&#xD;
           and multidrug resistance (MDR-1).&#xD;
&#xD;
      Primary Objectives:&#xD;
&#xD;
      -To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC&#xD;
      706744) administered intravenously (IV) daily for 5 days (QD x 5) schedule in patients with&#xD;
      refractory solid tumors and lymphomas.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
      -Characterize the pharmacokinetic (PK) profile of LMP744.&#xD;
&#xD;
      Exploratory Objectives:&#xD;
&#xD;
        -  Evaluate the effect of LMP744 on markers of DNA damage (yH2AX, pNbs1, pATR, ERCC1,&#xD;
           RAD51, Topo1cc, Top1, SLFN11) and epithelial-mesenchymal transition (EMT) in circulating&#xD;
           tumor cells (CTCs) and pre- and post- treatment tumor biopsies in patients at the&#xD;
           expansion cohort.&#xD;
&#xD;
        -  Assess preliminary antitumor activity of LMP744.&#xD;
&#xD;
        -  Examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with&#xD;
           response or resistance to treatment&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      -Adult patients must have histologically documented, relapsed solid tumors which have&#xD;
      progressed after one line of therapy, or lymphoma which has progressed after initial therapy&#xD;
      and without potentially curative options, or patient refuses potentially curative therapy.&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
        -  Cycle 1 and subsequent cycles: Patients will receive LMP744 administered IV QD over 1&#xD;
           hour on days 1-5 followed by 23 days without drug (28-day cycle).&#xD;
&#xD;
        -  PK and PD samples will be collected. Tumor biopsies will be mandatory during the&#xD;
           expansion phase.&#xD;
&#xD;
      LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle&#xD;
&#xD;
      Blood samples for PK analyses will be collected at the following timepoints in cycle 1 only:&#xD;
&#xD;
      Day 1, prior to drug administration, 2 minutes (+/- 2 minutes) before end of infusion, and at&#xD;
      appropriate time points post infusion (15 minutes, 30 minutes, and 1, 2, 4, and 6 hours post&#xD;
      infusion)&#xD;
&#xD;
      Day 2, 24 hr post day 1 start of infusion (prior to day 2 infusion), and 2 minutes (+/- 2&#xD;
      minutes) before the end of infusion&#xD;
&#xD;
      Day 3, 24 hr post day 2 start of infusion (prior to day 3 infusion), and 2 minutes (+/- 2&#xD;
      minutes) before end of infusion&#xD;
&#xD;
      Day 4, 24 hr post day 3 start of infusion (prior to day 4 infusion), and 2 minutes (+/- 2&#xD;
      minutes) before end of infusion&#xD;
&#xD;
      Day 5, 24 hr post day 4 start of infusion (prior to day 5 infusion), and 2 minutes (+/- 2&#xD;
      minutes) before end of infusion&#xD;
&#xD;
      Day 8, 72 hr post day 5 start of infusion Blood for circulating tumor cells (CTCs) (optional)&#xD;
      will be collected at baseline, on day 3 of&#xD;
&#xD;
      cycle 1 (within 2 to 4 hours after the start of LMP744 infusion), on day 1 of every&#xD;
      subsequent cycle (prior to drug infusion), and at disease progression.&#xD;
&#xD;
      Tumor biopsies (mandatory in expansion phase) will be obtained at baseline and then on day 2&#xD;
      (1-4 hours after the LMP744 infusion) in cycle 1 only.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 27, 2017</start_date>
  <completion_date type="Anticipated">October 2, 2023</completion_date>
  <primary_completion_date type="Anticipated">October 2, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC 706744)</measure>
    <time_frame>cycle 1</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characterize the pharmacokinetic (PK) profile of LMP744</measure>
    <time_frame>cycle 1</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">53</enrollment>
  <condition>Solid Tumors</condition>
  <condition>Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LMP744</intervention_name>
    <description>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.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
               1. Patients must have histologically documented metastatic solid tumors which have&#xD;
                  progressed after one line of therapy, or lymphoma which has progressed after&#xD;
                  initial therapy and without potentially curative options, or patient refuses&#xD;
                  potentially curative therapy.&#xD;
&#xD;
               2. Patients must have measurable or evaluable disease&#xD;
&#xD;
               3. Age greater than or equal to 18 years.&#xD;
&#xD;
               4. ECOG performance status less than or equal to 2&#xD;
&#xD;
               5. Life expectancy of greater than 3 months.&#xD;
&#xD;
               6. Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
                  leukocytes greater than or equal to 3,000/mcL&#xD;
&#xD;
                  absolute neutrophil count greater than or equal to 1,500/mcL&#xD;
&#xD;
                  platelets greater than or equal to 100,000/mcL&#xD;
&#xD;
                  total bilirubin within normal institutional limits&#xD;
&#xD;
                  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 (SqrRoot) institutional upper limit&#xD;
                  of normal (ULN)&#xD;
&#xD;
                  Serum creatinine less than or equal to 1.5 (SqrRoot) institutional ULN&#xD;
&#xD;
                  OR&#xD;
&#xD;
                  creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with&#xD;
                  serum creatinine levelsgreater than 1.5 x higher than institutional normal.&#xD;
&#xD;
               7. Anticoagulation with low-molecular-weight heparin (LMWH) or any direct oral&#xD;
                  anticoagulant (DOAC, e.g., rivaroxaban, apixaban, dabigatran, or edoxaban) will&#xD;
                  be permitted. Patients receiving treatment with warfarin will be given the option&#xD;
                  to switch to LMWH or a&#xD;
&#xD;
                  DOAC.&#xD;
&#xD;
               8. Patients must have recovered to grade 1 or baseline from adverse events (AEs)&#xD;
                  and/or toxicity of prior chemotherapy or biologic therapy. They must not have had&#xD;
                  chemotherapy, biologic therapy, or definitive radiotherapy within 4 weeks (6&#xD;
                  weeks for nitrosoureas and mitomycin C) or 5 half-lives, whichever is shorter,&#xD;
                  prior to entering the study. Palliative-intent radiotherapy (30 Gy or less) must&#xD;
                  be completed at least 2 weeks prior to start of treatment, and may not be to a&#xD;
                  lesion that is included as measurable disease. Patients must be greater than or&#xD;
                  equal to 2 weeks since any investigational agent administered as part of a Phase&#xD;
                  0 study (where a sub-therapeutic dose of drug is administered) at the PI s&#xD;
                  discretion, and should have recovered to grade 1 or baseline from any toxicities.&#xD;
&#xD;
               9. Patients receiving denosumab or bisphosphonates for any cancer or undergoing&#xD;
                  androgen deprivation therapy for prostate cancer are eligible for this therapy.&#xD;
&#xD;
              10. Prior therapy with topoisomerase I inhibitors is allowed.&#xD;
&#xD;
              11. Patients with known HIV-positive status are eligible provided the following&#xD;
                  criteria are met: CD4 count &gt;350/mm3, an undetectable viral load, and not&#xD;
                  receiving prophylaxis antibiotics. Diagnostic HIV testing will not be performed&#xD;
                  during screening or throughout this study.&#xD;
&#xD;
              12. The effects of LMP744 on the developing human fetus are unknown. For this reason,&#xD;
                  women of child-bearing potential and men must agree to use adequate contraception&#xD;
                  (hormonal or barrier method of birth control; abstinence) prior to study entry&#xD;
                  and for the duration of study participation. Should a woman become pregnant or&#xD;
                  suspect she is pregnant while she or her partner is participating in this study,&#xD;
                  she should inform her treating physician immediately. Women and men treated or&#xD;
                  enrolled on this protocol must also agree to use adequate contraception prior to&#xD;
                  the study, for the duration of study participation, and 4 months after completion&#xD;
                  of LMP744 administration.&#xD;
&#xD;
              13. Ability to understand and the willingness to sign a written informed consent&#xD;
                  document.&#xD;
&#xD;
              14. Willingness to provide blood and new tumor biopsy samples for research purposes&#xD;
                  if on the expansion phase of the study.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Patients who are receiving any other investigational agents.&#xD;
&#xD;
          2. Patients with clinically significant illnesses which would compromise participation in&#xD;
             the study, including, but not limited to active or uncontrolled infection, immune&#xD;
             deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled&#xD;
             hypertension, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or&#xD;
&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          3. Patients with known brain metastases or carcinomatous meningitis are excluded from&#xD;
             this clinical trial, with the exception of patients whose brain metastatic disease&#xD;
             status has remained stable for greater than or equal to 1 month after treatment of the&#xD;
             brain metastases. Patients on anti-seizure medications or steroid therapy may be&#xD;
             enrolled at the discretion of the Principal Investigator.&#xD;
&#xD;
          4. Pregnant women are excluded from this study because LMP744 is an agent with the&#xD;
             potential for teratogenic or abortifacient effects. Because there is an unknown but&#xD;
             potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with LMP744, breastfeeding should be discontinued if the mother is treated.&#xD;
&#xD;
        INCLUSION OF WOMEN AND MINORITIES:&#xD;
&#xD;
        Both men and women of all races and ethnic groups are eligible for this trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alice P Chen, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Murielle Hogu</last_name>
    <phone>(240) 858-3335</phone>
    <email>murielle.hogu@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Alice P Chen, M.D.</last_name>
    <phone>(240) 781-3320</phone>
    <email>chenali@mail.nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact National Cancer Institute Referral Office</last_name>
      <phone>888-624-1937</phone>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15260</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kristen Lunn</last_name>
      <phone>412-623-4004</phone>
      <email>lunnke@upmc.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-C-0045.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>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.</citation>
    <PMID>15531731</PMID>
  </reference>
  <reference>
    <citation>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. Erratum In: Cancer Res. 2007 Dec 15;67(24):12034.</citation>
    <PMID>17974983</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>12570765</PMID>
  </reference>
  <verification_date>August 3, 2023</verification_date>
  <study_first_submitted>January 24, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 25, 2017</study_first_posted>
  <last_update_submitted>August 16, 2023</last_update_submitted>
  <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Topoisomerase I Inhibitor</keyword>
  <keyword>Epithelial-Mesenchymal Transition</keyword>
  <keyword>Pharmacodynamics</keyword>
  <keyword>DNA Damage</keyword>
  <keyword>Pharmacokinetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.All 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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Requests for all collected IPD data from clinical trials, conducted under a binding collaborative agreement between NCI/DCTD and a pharmaceutical/biotechnology company, that are not under 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 ETCTN Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03030417
org study id: 170045
secondary id: 17-C-0045
nct id: NCT03030417
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
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.
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.

        -  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).

        -  PK and 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 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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC 706744)
time frame: cycle 1
description: 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
measure: Characterize the pharmacokinetic (PK) profile of LMP744
time frame: cycle 1
arm group label: Treatment Arm
arm group type: Experimental
description: LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle
intervention type: Drug
intervention name: LMP744
description: 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.
arm group label: Treatment Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alice P Chen, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
last name: Murielle Hogu
phone: (240) 858-3335
email: murielle.hogu@nih.gov
last name: Alice P Chen, M.D.
phone: (240) 781-3320
email: chenali@mail.nih.gov
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-C-0045.html
description: NIH Clinical Center Detailed Web Page
citation: 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
citation: 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. Erratum In: Cancer Res. 2007 Dec 15;67(24):12034.
PMID: 17974983
citation: 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
responsible party type: Sponsor
mesh term: Lymphoma
sharing ipd: Yes
ipd description: .All 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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Requests for all collected IPD data from clinical trials, conducted under a binding collaborative agreement between NCI/DCTD and a pharmaceutical/biotechnology company, that are not under 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 ETCTN Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).