NeoplasmPhase 1NCT01794104
Indenoisoquinoline LMP400 for Advanced Solid Tumors and Lymphomas
A Phase 1 study testing LMP400 in people with Neoplasm and Lymphoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Indenoisoquinoline LMP400 is an experimental cancer treatment drug. It damages DNA in tumor cells. Tumor cells with damaged DNA may die, resulting in cell death. Researchers want to see if this drug is a safe and effective treatment for solid tumors and lymphomas that have not responded to earlier… Read more about this study
- Who is it for?
- Ages 18 to 120 years
- What is being tested?
- LMP400
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Feb 2013to 27 Oct 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically-documented (confirmed at the Laboratory of Pathology, NCI), solid tumor malignancy, or Hodgkin's disease/non-Hodgkin lymphoma, that is metastatic or unresectable and for which standard curative measures do not exist or are associated with minimal patient survival benefit.
- The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
- Life expectancy >3 months.
- Patients must have normal or adequate 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/microL
Show all 19Show fewer
- Platelets greater than or equal to 100,000/microL
- Total bilirubin less than or equal to 2.0 x institutional upper limit of normal (we will allow patients with Gilbert s syndrome with total bilirubin up to 2.5 mg/dL)
- AST (SGOT)/ALT (SGPT) less than or equal to 3 x institutional upper limit of normal
- ---patients with metastatic disease in the liver less than or equal to 5 x ULN
- Creatinine <1.5 x upper limit of normal
- OR
- Creatinine clearance
- greater than or equal to 60 mL/minute for patients with creatinine levels
- greater than or equal to 1.5 x institutional upper limit of normal
- Age greater than or equal to 18
- The effects of indenoisoquinolines 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, for the duration of study participation, and for 3 months after completion of indenoisoquinolines administration. 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. 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 3 months after completion of indenoisoquinolines administration
- Ability to understand and the willingness to sign a written informed consent document.
- Both men and women of all races and ethnic groups are eligible for this trial.
Who cannot join
- Patients must have recovered to at least eligibility levels due to adverse events (AEs) and/or toxicity of prior chemotherapy or biologic therapy. They must not have had major surgery, chemotherapy, radiotherapy, or biologic therapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C, or 2 months for UCN-01). Patients must be greater than or equal to2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a subtherapeutic dose of drug is administered) at the PI s discretion, and should have recovered to eligibility levels from any toxicities. However, patients receiving 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 who are receiving any other investigational agents.
- Patients with known active brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastasis stable for at least 4 weeks following surgery and/or radiation are eligible.
- Uncontrolled incurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LMP400. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Phase I Trial of Weekly Indenoisoquinoline LMP400 in Adults With Relapsed Solid Tumors and Lymphomas
Background:
- Indenoisoquinoline LMP400 is an experimental cancer treatment drug. It damages DNA in tumor cells. Tumor cells with damaged DNA may die, resulting in cell death. Researchers want to see if this drug is a safe and effective treatment for solid tumors and lymphomas that have not responded to earlier treatment.
Read more
Objectives:
- To see if Indenoisoquinoline LMP400 is a safe and effective treatment for advanced solid tumors or lymphomas.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or lymphomas that have not responded to treatment.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor samples may also be collected. The size and location of the tumors will be determined with imaging studies.
- Indenoisoquinoline LMP400 is given in a 28-day cycle. Participants will receive the drug by intravenous infusion on days 1, 8, and 15 of each cycle, followed by a break of 13 days without the drug.
- Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples will be optional.
- Participants will continue their cycles of treatment as long as the cancer does not grow and there are no severe side effects.
Read the detailed description
Background:
- Indenoisoquinolines are non-camptothecin topoisomerase (Top1) inhibitors that form stable DNA-Top1 cleavage-complexes, have a preference for unique DNA cleavage sites, and are active against camptothecin-resistant cell lines. Unlike camptothecins, indenoisoquinolines are chemically stable and active in cells that over-express ATP-binding cassette (ABC) transporters ABCG2 and multidrug resistance (MDR-1). Top1 inhibitors are potent anticancer agents because stabilizing cleavage complex formation induces replication-and transcription-mediated DNA damage and delays DNA repair, leading to apoptosis. Preclinical and clinical data indicate that baseline tumor levels of Top1 correlate strongly with ability to respond to Top1 inhibitor therapy.
- A first-in-human Phase I study conducted at the NCI of the indenoisoquinoline LMP400 (NSC 743400) on a QD x 5 q28 schedule in patients with refractory solid tumors and lymphomas (10-C-0056) established that this agent is well tolerated. LMP400 shows linear pharmacokinetics with evidence of drug accumulation following 5 days of dosing. We hypothesize that weekly dosing (days 1, 8, 15 q28-day cycle) will increase LMP400 peak levels and exposures, improving clinical activity and safety.
Primary Objectives:
- To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400 in patients with refractory solid tumors and lymphomas.
- To establish the maximum tolerated dose (MTD) of weekly LMP400 in patients with refractory solid tumors and lymphomas.
- To evaluate the pharmacokinetic profile of weekly LMP400.
Secondary Objectives:
- Evaluate the level of Top1 in tumor biopsies pre- and post- administration of LMP400.
- Evaluate the effect of LMP400 on markers of DNA damage and apoptosis, such as >=H2AX and caspase 3, in tumor biopsies pre- and post- LMP400 administration.
Eligibility:
-Patients with histologically confirmed metastatic solid tumors and lymphomas; adequate organ function.
Study Design:
- This is an open-label Phase I trial evaluating weekly administration of LMP400, on days 1, 8, and 15, in 28-day cycles.
- Starting dose is based on the MTD determined from the QD x 5, q28 day schedule currently being evaluated. The study will follow a 3 plus 3 design.
- Once the MTD is established, 10 additional patients will be enrolled at the MTD to further define the pharmacokinetics and evaluate effect of study drug on DNA damage and apoptosis.
- Being tested
- LMP400
- Keywords
- Topoisomerase Inhibitor, Advanced Malignancies, Pharmacodynamics, DNA Damage, Pharmacokinetics
- Medical subject headings
- Neoplasms, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LMP400Drug
Top1 inhibitors such as LMP400 are potent anticancer agents because stabilizing cleavage complex formation induces replication-and transcription-mediated DNA damage and delays DNA repair, leading to apoptosis. Preclinical and clinical data indicate that baseline tumor levels of Top1 correlate strongly with ability to respond to Top1 inhibitor therapy.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Open-label Phase I trial evaluating weekly administration of LMP400, on days 1, 8, and 15, in 28-day cycles. Receives: Drug: LMP400 |
What is being measured
The primary outcome is the main question the study is designed to answer.
To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400 in patients with refractory solid tumors and lymphomas
Measured: Cycle 1
Secondary outcomes (1)
Evaluate the level of Top1 in tumor biopsies pre and post- administration of LMP400
Measured: Cycle 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2013 (estimated)
- Study start15 Feb 2013
- Primary completion19 May 2016
- Study completion27 Oct 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for NeoplasmStudies 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
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Alice P Chen, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01794104
- Sponsor's protocol ID
- 130080
- Other IDs
- 13-C-0080
- Status last verified
- 27 Oct 2017
- First submitted
- 15 Feb 2013
- Last updated
- 27 Sep 2018
- Results posted
- No
Publications
Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70:369-413. doi: 10.1146/annurev.biochem.70.1.369.
PubMed 11395412Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40. doi: 10.1038/nrm831.
PubMed 12042765Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006 Oct;6(10):789-802. doi: 10.1038/nrc1977.
PubMed 16990856Beumer JH, Kennard BC, Holleran JL, Moore N, Zlott J, Miller BM, Kummar S, Chen A, Doroshow J, Park W, Gobburu J, Dunn A. Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions. Cancer Chemother Pharmacol. 2023 Mar;91(3):219-230. doi: 10.1007/s00280-023-04509-8. Epub 2023 Feb 23.
PubMed 36813886
Study at a glance
From the registry record, last updated by the sponsor on 27 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Trial of Weekly Indenoisoquinoline LMP400 in Adults With Relapsed Solid Tumors and Lymphomas
- ClinicalTrials.gov ID
- NCT01794104
- Acronym / sponsor ID
- 130080
- Keywords
- Topoisomerase Inhibitor, Advanced Malignancies, Pharmacodynamics, DNA Damage, Pharmacokinetics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 15 Feb 2013
- Primary completion
- 19 May 2016 (actual)
- Study completion
- 27 Oct 2017 (actual)
- First posted
- 18 Feb 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Indenoisoquinoline LMP400 is an experimental cancer treatment drug. It damages DNA in tumor cells. Tumor cells with damaged DNA may die, resulting in cell death. Researchers want to see if this drug is a safe and effective treatment for solid tumors and lymphomas that have not responded to earlier treatment.
Objectives:
- To see if Indenoisoquinoline LMP400 is a safe and effective treatment for advanced solid tumors or lymphomas.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or lymphomas that have not responded to treatment.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor samples may also be collected. The size and location of the tumors will be determined with imaging studies.
- Indenoisoquinoline LMP400 is given in a 28-day cycle. Participants will receive the drug by intravenous infusion on days 1, 8, and 15 of each cycle, followed by a break of 13 days without the drug.
- Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples will be optional.
- Participants will continue their cycles of treatment as long as the cancer does not grow and there are no severe side effects.
Detailed description
Background:
- Indenoisoquinolines are non-camptothecin topoisomerase (Top1) inhibitors that form stable DNA-Top1 cleavage-complexes, have a preference for unique DNA cleavage sites, and are active against camptothecin-resistant cell lines. Unlike camptothecins, indenoisoquinolines are chemically stable and active in cells that over-express ATP-binding cassette (ABC) transporters ABCG2 and multidrug resistance (MDR-1). Top1 inhibitors are potent anticancer agents because stabilizing cleavage complex formation induces replication-and transcription-mediated DNA damage and delays DNA repair, leading to apoptosis. Preclinical and clinical data indicate that baseline tumor levels of Top1 correlate strongly with ability to respond to Top1 inhibitor therapy.
- A first-in-human Phase I study conducted at the NCI of the indenoisoquinoline LMP400 (NSC 743400) on a QD x 5 q28 schedule in patients with refractory solid tumors and lymphomas (10-C-0056) established that this agent is well tolerated. LMP400 shows linear pharmacokinetics with evidence of drug accumulation following 5 days of dosing. We hypothesize that weekly dosing (days 1, 8, 15 q28-day cycle) will increase LMP400 peak levels and exposures, improving clinical activity and safety.
Primary Objectives:
- To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400 in patients with refractory solid tumors and lymphomas.
- To establish the maximum tolerated dose (MTD) of weekly LMP400 in patients with refractory solid tumors and lymphomas.
- To evaluate the pharmacokinetic profile of weekly LMP400.
Secondary Objectives:
- Evaluate the level of Top1 in tumor biopsies pre- and post- administration of LMP400.
- Evaluate the effect of LMP400 on markers of DNA damage and apoptosis, such as >=H2AX and caspase 3, in tumor biopsies pre- and post- LMP400 administration.
Eligibility:
-Patients with histologically confirmed metastatic solid tumors and lymphomas; adequate organ function.
Study Design:
- This is an open-label Phase I trial evaluating weekly administration of LMP400, on days 1, 8, and 15, in 28-day cycles.
- Starting dose is based on the MTD determined from the QD x 5, q28 day schedule currently being evaluated. The study will follow a 3 plus 3 design.
- Once the MTD is established, 10 additional patients will be enrolled at the MTD to further define the pharmacokinetics and evaluate effect of study drug on DNA damage and apoptosis.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: LMP400Open-label Phase I trial evaluating weekly administration of LMP400, on days 1, 8, and 15, in 28-day cycles. |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Patients must have histologically-documented (confirmed at the Laboratory of Pathology, NCI), solid tumor malignancy, or Hodgkin's disease/non-Hodgkin lymphoma, that is metastatic or unresectable and for which standard curative measures do not exist or are associated with minimal patient survival benefit.
- The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
- Life expectancy >3 months.
- Patients must have normal or adequate organ and marrow function as defined below:
- ---patients with metastatic disease in the liver less than or equal to 5 x ULN
Key exclusion criteria (5 listed)
- Patients must have recovered to at least eligibility levels due to adverse events (AEs) and/or toxicity of prior chemotherapy or biologic therapy. They must not have had major surgery, chemotherapy, radiotherapy, or biologic therapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C, or 2 months for UCN-01). Patients must be greater than or equal to2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a subtherapeutic dose of drug is administered) at the PI s discretion, and should have recovered to eligibility levels from any toxicities. However, patients receiving 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 who are receiving any other investigational agents.
- Patients with known active brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastasis stable for at least 4 weeks following surgery and/or radiation are eligible.
- Uncontrolled incurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LMP400. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
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 |
|---|---|---|
| LMP400Top1 inhibitors such as LMP400 are potent anticancer agents because stabilizing cleavage complex formation induces replication-and transcription-mediated DNA damage and delays DNA repair, leading to apoptosis. Preclinical and clinical data indicate that baseline tumor levels of Top1 correlate strongly with ability to respond to Top1 inhibitor therapy. | Drug | 1 |
Primary outcome
To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400 in patients with refractory solid tumors and lymphomas
Time frame: Cycle 1
1 secondary outcome
Evaluate the level of Top1 in tumor biopsies pre and post- administration of LMP400
Time frame: Cycle 1
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Sep 2018.
- Background: PubMed 11395412Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70:369-413. doi: 10.1146/annurev.biochem.70.1.369.
- Background: PubMed 12042765Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40. doi: 10.1038/nrm831.
- Background: PubMed 16990856Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006 Oct;6(10):789-802. doi: 10.1038/nrc1977.
- Derived from this study: PubMed 36813886Beumer JH, Kennard BC, Holleran JL, Moore N, Zlott J, Miller BM, Kummar S, Chen A, Doroshow J, Park W, Gobburu J, Dunn A. Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions. Cancer Chemother Pharmacol. 2023 Mar;91(3):219-230. doi: 10.1007/s00280-023-04509-8. Epub 2023 Feb 23.
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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)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LMP400 in people with Neoplasm and Lymphoma, run by National Cancer Institute (NCI) at 1 site 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 19 inclusion and 5 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 27 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400 in patients with refractory solid tumors and lymphomas (time frame: Cycle 1). 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 NCT01794104, 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 27 Sep 2018.